Volume 130, Issue 3, Pages 687-694 (March 2006) Measurement of Serum Acetaminophen–Protein Adducts in Patients With Acute Liver Failure  Timothy J. Davern, Laura P. James, Jack A. Hinson, Julie Polson, Anne M. Larson, Robert J. Fontana, Ezmina Lalani, Santiago Munoz, A. Obaid Shakil, William M. Lee  Gastroenterology  Volume 130, Issue 3, Pages 687-694 (March 2006) DOI: 10.1053/j.gastro.2006.01.033 Copyright © 2006 American Gastroenterological Association Institute Terms and Conditions

Figure 1 Schematic diagram of acetaminophen metabolic pathways. Metabolism of the parent compound is principally via glucuronidation and sulfation, with only a small fraction normally being metabolized via cytochrome 450 (in particular, CYP2E1) to NAPQI, the reactive intermediate form. In the presence of adequate glutathione stores, NAPQI is converted into a harmless, water-soluble conjugate; however, if the capacity to detoxify is exceeded, then NAPQI can covalently bind to cell proteins via cysteine residues. The acetaminophen–protein adducts so formed may enter the serum with cell death and release of intracellular proteins. Gastroenterology 2006 130, 687-694DOI: (10.1053/j.gastro.2006.01.033) Copyright © 2006 American Gastroenterological Association Institute Terms and Conditions

Figure 2 Acetaminophen–CYS adduct levels and ALT levels measured serially from day 1 to 7 in 4 patients with either known acetaminophen toxicity (A–C) or indeterminate ALF (D). In each case, the decline in serum adduct concentration approximates that of ALT. On presentation, patients A and B had histories of excessive acetaminophen dosing and detectable serum acetaminophen levels, whereas patient C had a history of excessive dosing but an undetectable acetaminophen level, and patient D had neither history nor an elevated serum acetaminophen level. Gastroenterology 2006 130, 687-694DOI: (10.1053/j.gastro.2006.01.033) Copyright © 2006 American Gastroenterological Association Institute Terms and Conditions

Figure 3 Serum levels of acetaminophen–CYS adducts in patient groups. (a) Patients with ALF secondary to known acetaminophen overdose. (b) Patients with ALF owing to nonacetaminophen causes. (c) Patients with acetaminophen overdose but no ALF. (d) Patients with ALF of indeterminate etiology and detectable serum adducts. (e) Patients ALF of indeterminate etiology and negative adducts. The boxes represent the 25th–75th IQR and the horizontal line represents the median. The extremes of the population are represented by the endmarks. Gastroenterology 2006 130, 687-694DOI: (10.1053/j.gastro.2006.01.033) Copyright © 2006 American Gastroenterological Association Institute Terms and Conditions