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Hepatology International

, Volume 13, Issue 5, pp 641–648 | Cite as

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

  • Natasha Kamal
  • Christopher KohEmail author
  • Niharika Samala
  • Robert J. Fontana
  • Andrew Stolz
  • Francisco Durazo
  • Paul H. Hayashi
  • Elizabeth Phillips
  • Tongrong Wang
  • Jay H. Hoofnagle
  • for the Drug-Induced Liver Injury Network
Original Article
  • 145 Downloads

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.

Keywords

Hepatotoxicity Leukemia Antineoplastic agents Jaundice Cholestasis Fatty liver 

Abbreviations

ALT

Alanine aminotransferase

Alk P

Alkaline phosphatase

ALL

Acute lymphoblastic leukemia

AST

Aspartate aminotransferase

BMI

Body mass index

DILIN

Drug-Induced Liver Injury Network

DILI

Drug-induced liver injury

E. coli

Escherichia coli

RUCAM

Roussel Uclaf Causality Assessment Method

Notes

Acknowledgements

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.

Author contributions

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.

Funding

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.

Supplementary material

12072_2019_9971_MOESM1_ESM.docx (22 kb)
Supplementary material 1 (DOC 23 kb)

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Copyright information

© Asian Pacific Association for the Study of the Liver 2019

Authors and Affiliations

  • Natasha Kamal
    • 1
  • Christopher Koh
    • 1
    Email author
  • Niharika Samala
    • 2
  • Robert J. Fontana
    • 3
  • Andrew Stolz
    • 4
  • Francisco Durazo
    • 5
  • Paul H. Hayashi
    • 6
  • Elizabeth Phillips
    • 7
  • Tongrong Wang
    • 8
  • Jay H. Hoofnagle
    • 9
  • for the Drug-Induced Liver Injury Network
  1. 1.Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesBethesdaUSA
  2. 2.Division of Gastroenterology and HepatologyIU Health University HospitalIndianapolisUSA
  3. 3.Division of Gastroenterology and HepatologyUniversity of Michigan HospitalAnn ArborUSA
  4. 4.Division of Gastrointestinal and Liver DiseasesKeck School of Medicine of USCLos AngelesUSA
  5. 5.Division of Digestive Diseases, Pfleger Liver Institute and General Surger SuiteUniversity of California, Los AngelesLos AngelesUSA
  6. 6.Division of Gastroenterology and HepatologyUNC School of MedicineChapel HillUSA
  7. 7.Department of Medicine, Infectious DiseasesVanderbilt University Medical CenterNashvilleUSA
  8. 8.DCRI, Duke UniversityDurhamUSA
  9. 9.Liver Disease Research Branch, Division of Digestive Diseases and NutritionNIDDK, NIHBethesdaUSA

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