Natasha Kamal1, Christopher Koh2, Niharika Samala3, Robert J Fontana4, Andrew Stolz5, Francisco Durazo6, Paul H Hayashi7, Elizabeth Phillips8, Tongrong Wang9, Jay H Hoofnagle10. 1. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 10 Center Drive, 5-2740NW, Bldg 10, Bethesda, MD, 20892-1804, USA. 2. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 10 Center Drive, 5-2740NW, Bldg 10, Bethesda, MD, 20892-1804, USA. Christopher.Koh@nih.gov. 3. Division of Gastroenterology and Hepatology, IU Health University Hospital, 550 N University Blvd. Suite 1710, Indianapolis, IN, 46202, USA. 4. Division of Gastroenterology and Hepatology, University of Michigan Hospital, Floor 2, 1500 E Medical Center Dr. SPC5051, Ann Arbor, MI, 48109, USA. 5. Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of USC, 1983 Marengo St., Los Angeles, CA, 90033, USA. 6. Division of Digestive Diseases, Pfleger Liver Institute and General Surger Suite, University of California, Los Angeles, 200 UCLA Medical Plaza, Suite 214, Los Angeles, CA, 90095, USA. 7. Division of Gastroenterology and Hepatology, UNC School of Medicine, 101 Manning Drive, First Floor, Chapel Hill, NC, 27514, USA. 8. Department of Medicine, Infectious Diseases, Vanderbilt University Medical Center, 1161 21st Ave South, Nashville, TN, 37232, USA. 9. DCRI, Duke University, 300 W. Morgan Street, Durham, NC, 27701, USA. 10. Liver Disease Research Branch, Division of Digestive Diseases and Nutrition, NIDDK, NIH, 6707 Democracy Blvd, Room 6005, Bethesda, MD, 20852, USA.
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.
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.
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