Published online September 1, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. e676-e681 (doi:10.1542/peds.2006-0069)
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ARTICLE

Detection of Acetaminophen Protein Adducts in Children With Acute Liver Failure of Indeterminate Cause

Laura P. James, MDa,b, Estella M. Alonso, MDc, Linda S. Hynan, PhDd, Jack A. Hinson, PhDb, Timothy J. Davern, MDe, William M. Lee, MDd, Robert H. Squires, MDf and the Pediatric Acute Liver Failure Study Group

a Pediatrics
b Pharmacology and Toxicology, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute, Little Rock, Arkansas
c Department of Pediatrics, Siragusa Transplant Center, Children's Memorial Hospital and Northwestern University Feinberg School of Medicine, Chicago, Illinois
d University of Texas Southwestern Medical Center at Dallas, Dallas, Texas
e University of California at San Francisco, San Francisco, California
f Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania

OBJECTIVE. Acetaminophen cysteine protein adducts are a widely recognized correlate of acetaminophen-mediated hepatic injury in laboratory animals. The objective of this study was to use a new assay for the detection of acetaminophen cysteine protein adducts in children with acute liver failure to determine the role of acetaminophen toxicity in acute liver failure of unknown cause.

METHODS. Serum samples from children with acute liver failure were measured for acetaminophen cysteine protein adducts using high-performance liquid chromatography with electrochemical detection. For comparison, samples from children with well-characterized acetaminophen toxicity and children with known other causes of acute liver failure also were measured for acetaminophen cysteine protein adducts. The analytical laboratory was blinded to patient diagnoses.

RESULTS. Acetaminophen cysteine protein adduct was detected in 90% of samples from children with acute liver failure that was attributed to acetaminophen toxicity, 12.5% of samples from children with acute liver failure of indeterminate cause, and 9.6% of samples from children with acute liver failure that was attributed to other causes. Adduct-positive patients from the indeterminate cause subgroup had higher levels of serum aspartate aminotransferase and alanine aminotransferase and lower levels of bilirubin. Adduct-positive patients also had lower rates of transplantation and higher rates of spontaneous remission.

CONCLUSIONS. A small but significant percentage of children with acute liver failure of indeterminate cause tested positive for acetaminophen cysteine protein adducts, strongly suggesting acetaminophen toxicity as the cause of acute liver failure. An assay for the detection of acetaminophen cysteine protein adducts can aid the diagnosis of acetaminophen-related liver injury in children.

Key Words: acetaminophen • liver failure • alanine aminotransferase

Abbreviations: APAP—acetaminophen • ALF—acute liver failure • NAPQI—N-acetylbenzoquinoneimine • APAP-CYS—acetaminophen cysteine adducts • PALF—Pediatric Acute Liver Failure • PR—prothrombin time • INR—International Normalized Ratio • HPLC-EC—high-performance liquid chromatography with electrochemical detection • ALT—alanine aminotransferase • NAC—N-acetylcysteine

Accepted Mar 8, 2006.




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