Unrecognized acetaminophen toxicity as a cause of indeterminate acute liver failure

Despite extensive investigations, the cause of liver injury in 14% of patients with acute liver failure remains unknown (indeterminate). In a pilot study using a novel assay, highly specific acetaminophen‐cysteine adducts were detected in 7 of 36 indeterminate patients (19%). To extend these observa...

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Published in	Hepatology (Baltimore, Md.) Vol. 53; no. 2; pp. 567 - 576
Main Authors	Khandelwal, Niraj, James, Laura P., Sanders, Corron, Larson, Anne M., Lee, William M.
Format	Journal Article
Language	English
Published	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.02.2011 Wiley Wolters Kluwer Health, Inc
Subjects	Acetaminophen - adverse effects Acetylcysteine - therapeutic use Adult Analgesics Analgesics, Non-Narcotic - adverse effects Bilirubin - blood Biological and medical sciences Chemical and Drug Induced Liver Injury - blood Chemical and Drug Induced Liver Injury - diagnosis Chemical and Drug Induced Liver Injury - drug therapy Drug Overdose Female Free Radical Scavengers - therapeutic use Gastroenterology. Liver. Pancreas. Abdomen Hepatology Humans Liver Liver Failure, Acute - blood Liver Failure, Acute - chemically induced Liver Failure, Acute - diagnosis Liver. Biliary tract. Portal circulation. Exocrine pancreas Male Medical sciences Middle Aged Other diseases. Semiology Prognosis Retrospective Studies Severity of Illness Index Survival Rate Toxicity Transaminases - blood Liver failure Paracetamol Analgesic Toxicity Acute Antimigrainous agent Gastroenterology Antipyretic Digestive diseases Hepatic disease
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ISSN	0270-9139 1527-3350 1527-3350
DOI	10.1002/hep.24060

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Summary:	Despite extensive investigations, the cause of liver injury in 14% of patients with acute liver failure remains unknown (indeterminate). In a pilot study using a novel assay, highly specific acetaminophen‐cysteine adducts were detected in 7 of 36 indeterminate patients (19%). To extend these observations, sera from 110 subjects enrolled in the Acute Liver Failure Study Group registry with indeterminate acute liver failure were analyzed with a similar but more efficient and sensitive adduct assay. As positive controls, another 199 patients with known or presumed acetaminophen‐induced liver failure were assessed for the presence and quantity of adducts. Clinical, laboratory, and outcome data were compared for the two groups. On the basis of previous data for known therapeutic exposures and acetaminophen overdoses, an adduct concentration ≥1.0 nmol/mL of serum indicated a definite acetaminophen overdose. Among the 110 indeterminate cases, 18% had assay values ≥1.0 with a median level of 9.2 nmol/mL; 94.5% of the positive controls (known acetaminophen cases) had values ≥1.0 nmol/mL. Regardless of the initial diagnosis, subjects with elevated adduct levels demonstrated the clinical profile and hyperacute biochemical injury pattern associated with acetaminophen overdose: a predominance of female gender, very high aminotransferase levels, and low bilirubin levels. Conclusion: These data confirm and extend previous observations regarding the high (18%) prevalence of unrecognized or uncertain acetaminophen toxicity among subjects with indeterminate acute liver failure. N‐Acetylcysteine use was limited in this group, presumably because of the lack of a specific diagnosis of acetaminophen toxicity. (HEPATOLOGY 2011;53:567‐576.)
Bibliography:	Potential conflict of interest: Dr. Lee consults for Eli Lilly, Novartis, and Gilead. He receives grants from Bristol‐Myers Squibb, Vertex, SPRI, Siemens, and GlobeImmune. Dr. Larson is on the speakers' bureau of HCV Nova and SNPA Meeting Solutions. Dr. James is part owner of the Acetaminophen Toxicity Diagnostics. fax: 214‐645‐6111 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 The Acute Liver Failure Study Group from 1998-2006 was comprised of the following investigators and coordinators who worked tirelessly in support of this study: William M. Lee (PI), Anne M. Larson, Carla Pezzia, Kruti Joshi, Nahid Attar, Corron Sanders, University of Texas Southwestern Medical Center, Dallas, TX; Oren K. Fix, University of Washington, Seattle, WA; Timothy J. Davern, Kristine Partovi, University of California at San Francisco, San Francisco, CA; Lawrence U. Liu, Manuela Tiangco-Zuniga, Mt Sinai Medical Center, New York, NY; Timothy M. McCashland, Tamara Bernard, University of Nebraska, Omaha, NE; J. Eileen Hay, Cindy Groettum, Mayo Clinic, Rochester, MN; Natalie G. Murray, Sonnya Coultrup, Baylor University Medical Center, Dallas, TX; A. Obaid S. Shaikh, Linda Gooch, Diane Morton, University of Pittsburgh Medical Center, Pittsburgh, PA; Andres T. Blei, Daniel R. Ganger, Jeanne Gottstein, Northwestern University Medical School, Chicago, IL; Atif Zaman, Jonathan M. Schwartz, Kenneth Ingram, Willscott E. Naugler, Harlene Finn, Suni Wilson, Oregon Health & Science University, Portland, OR; Steven Han, Val Peacock, University of California at Los Angeles, Los Angeles, CA; Robert J. Fontana, Suzanne Welch, University of Michigan Medical Center, Ann Arbor, MI; Michael Schilsky, Noelle Sowers, Yale University School of Medicine, New Haven, CT; Brendan M. McGuire, Stacy Eddleman, Dorothy Faulk, University of Alabama, Birmingham, AL; Raymond T. Chung, Anna Rutherford, Michael Chen, Massachusetts General Hospital, Boston, MA; Robert S. Brown Jr., Jonathan Kim, Rudi Odeh-Ramadan, Columbia-Presbyterian Medical Center/Cornell-New York Hospital, New York, NY; Adrian Reuben, Stacey Minshall, Medical University of South Carolina, Charleston, SC; Santiago Munoz, Andres Riera, Stacey Carmody, Victoria Rudzik, Albert Einstein Medical Center, Philadelphia, PA; K. Rajender Reddy, Mical Campbell, Mary Hammond, Wojciech Blonksi, Kimberley Kime, University of Pennsylvania, Philadelphia, PA; Todd Stravitz, Melanie White, Virginia Commonwealth University, Richmond, VA; Lorenzo Rossaro, Laura Lester, Monica Ruiz, Yulia Suprun, University of California Davis, Sacramento, CA; Raj Satyanarayana, David Kramer, Dana Kontras, Mayo Clinic, Jacksonville, Jacksonville, FL; Tarek Hassenein, Fatma Barakat, Lita Petcharaporn, University of California at San Diego, San Diego, CA.
ISSN:	0270-9139 1527-3350 1527-3350
DOI:	10.1002/hep.24060