Asparaginase-induced hepatotoxicity: rapid development of cholestasis and hepatic steatosis
- 145 Downloads
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.
Eight cases from 5 DILIN centers were reviewed for clinical course, laboratory values, imaging, and histopathology.
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.
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.
KeywordsHepatotoxicity Leukemia Antineoplastic agents Jaundice Cholestasis Fatty liver
- Alk P
Acute lymphoblastic leukemia
Body mass index
Drug-Induced Liver Injury Network
Drug-induced liver injury
- E. coli
Roussel Uclaf Causality Assessment Method
The authors would like to thank Dr. Huiman Barnhart of the Duke Clinical Research Institute for her help in retrieving and analyzing data from the DILIN database and Drs. Connie Cheng and Allen Brinker of The Division of Pharmacovigilance, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Review, FDA for their help in retrieving and analyzing data from the FDA FAERS database.
NK: study concept and design, interpretation of data, drafting of manuscript, critical revision of manuscript for important intellectual content, statistical analysis. CK: study concept and design, critical revision of the manuscript for important intellectual content, study supervision. NS, RF, AS, FD, PHH: study concept and design, critical revision of the manuscript for important intellectual content. EP: conduct and analysis of HLA testing, critical revision of the manuscript for important intellectual content. TW: statistical analysis, development of graphics, and critical revision of the manuscript for important intellectual content. JHH: study concept and design, critical revision of the manuscript for important intellectual content, study supervision.
The DILIN Network is structured as a U01 cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under grants: 2U01-DK065176-06 (Duke), 2U01-DK065201-06 (UNC), 2U01-DK065184-06 (Michigan), 2U01-DK065211-06 (Indiana), 5U01DK065193-04 (UConn), 5U01-DK065238-08 (UCSF/CPMC), 1U01-DK083023-01 (UTSW), 1U01-DK083027-01 (TJH/UPenn), 1U01-DK082992-01 (Mayo), 1U01-DK083020-01 (USC). Additional funding is provided by CTSA grants: UL1 RR025761 (Indiana), UL1TR000083 (UNC), UL1 RR024134 (UPenn), UL1 RR024986 (Michigan), UL1 RR024982 (UTSW), UL1 RR024150 (Mayo) and in part by the Intramural Research Program of the NIDDK and the National Cancer Institute. EP reports grants from NHMRC of Australia and from the NIH: P50GM115305, P30AI110527, R21AI139021, R34AI136815.
Compliance with ethical standards
Conflict of interest
Natasha Kamal has nothing to disclose. Christopher Koh has nothing to disclose. Niharika Samala has nothing to disclose. Andrew Stolz has nothing to disclose. Paul H. Hayashi has nothing to disclose. Tongrong Wang has nothing to disclose. Jay H. Hoofnagle has nothing to disclose. Francisco Durazo receives consulting fees from Intercept Pharmaceuticals. Robert J. Fontana receives grant support from Abbvie, Gilead Sciences and Bristol-Myers-Squibb and consulting fees from Sanofi-Aventis. Elizabeth Phillips receives personal fees from UpToDate and Biocryst and holds patent for HLA-B*57:01 testing for abacavir hypersensitivity without financial remuneration.
Informed consent in studies with human subjects
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study. The DILIN Prospective Study was approved by the Institutional Review Boards of the enrolling clinical centers, and all participants provided written informed consent.
- 4.Broome JD. Studies on the mechanism of tumor inhibition by l-asparaginase. Effects of the enzyme on asparagine levels in the blood, normal tissues, and 6C3HED lymphomas of mice: differences in asparagine formation and utilization in asparaginase-sensitive and -resistant lymphoma cells. J Exp Med 1968;127:1055–1072CrossRefGoogle Scholar
- 5.Earl M. Incidence and management of asparaginase-associated adverse events in patients with acute lymphoblastic leukemia. Clin Adv Hematol Oncol 2009;7:600–606Google Scholar
- 7.Zubrod CG. The clinical toxicities of l-asparaginase: in treatment of leukemia and lymphoma. Pediatrics 1970;45:555–559Google Scholar
- 8.Cairo MS. Adverse reactions of l-asparaginase. Am J Pediatr Hematol Oncol 1982;4:335–339Google Scholar
- 16.Urayama KY, Thompson PD, Taylor M, et al. Genetic variation in the extended major histocompatibility complex and susceptibility to childhood acute lymphoblastic leukemia: a review of the evidence. Font Oncol 2013;3:300Google Scholar
- 21.Webber BL, Freiman I. The liver in kwashiorkor. A clinical and electron microscopic study. Arch Pathol 1974;98:400–408Google Scholar
- 26.Jenkins R, Perlin E. Severe hepatotoxicity from Escherichia coli l-asparaginase. J Natl Med Assoc 1987;79(775):779Google Scholar