Clinical–liver, pancreas, and biliary tractMeasurement of Serum Acetaminophen–Protein Adducts in Patients With Acute Liver Failure
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Study Participants
Serum and data were prospectively collected from January 1998 to the present at 24 sites participating in the U.S. ALF Study Group on more than 880 adult patients who met criteria for ALF, defined as the presence of coagulopathy (prothrombin time ≥15 seconds or international normalized ratio ≥1.5) and hepatic encephalopathy within 26 weeks of first symptoms of illness and without evidence of previous liver disease.14 Informed consent is obtained from the patients’ legal next of kin before
Adducts in Patients With Acetaminophen and Non-Acetaminophen ALF
Acetaminophen protein adducts were present in all 20 serum samples from patients with acetaminophen-related toxicity (median, 1.165 nmol acetaminophen-cysteine/mg protein; range, 0.36–2.83). In contrast, no significant adduct levels were detected in the samples of patients with ALF of other known etiologies (median, 0.005 nmol acetaminophen-cysteine/mg protein; range, 0.0–0.027). Based on these data, the sensitivity and specificity of the adduct assay were 100%. In sera from 15 patients with
Discussion
In this study, we evaluated the role of an assay to measure acetaminophen adducts in patients with known acetaminophen toxicity, other causes of acute liver failure, a large number with indeterminate ALF, and a group of patients who sustained an overdose but demonstrated little evidence of liver damage. The HPLC-EC assay identified all 30 test cases of ALF with known diagnoses as acetaminophen related (or not). The temporal profile of serum adducts paralleled that of aminotransferase levels,
References (26)
- et al.
Immunoblot analysis of protein containing 3-(cystein-S-yl) acetaminophen adducts in serum and subcellular liver fractions from acetaminophen-treated mice
Toxicol Appl Pharmacol
(1990) - et al.
Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcoholanalysis of instances of therapeutic misadventure
Hepatology
(1995) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding
Anal Biochem
(1976)- et al.
Epidemiology of acetaminophen-related overdose
(2002) - et al.
Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States
Ann Intern Med
(2002) Changing patterns of causation and the use of transplantation in the United Kingdom
Semin Liver Dis
(2003)- et al.
Acetaminophen toxicity in an urban county hospital
N Engl J Med
(1997) Drug-induced hepatotoxicity
N Engl J Med
(2003)- et al.
Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo
J Pharmacol Exp Ther
(1973) - et al.
Acetaminophen-induced hepatic injuryprotective role of glutathione in man and rationale for therapy
Clin Pharmacol Ther
(1974)
Paracetamol (acetaminophen)-induced toxicitymolecular and biochemical mechanisms, analogues and protective approaches
Crit Rev Toxicol
Acetaminophen-induced hepatotoxicity
Drug Metab Dispos
A sensitive immunochemical assay for acetaminophen-protein adducts
J Pharmacol Exp Ther
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Supported by NIDDK: DK R-01 58369 and DK067999 (to LJ), the Jean Roberts and the Rollin and Mary Ella King Funds at the Southwestern Medical Foundation, Dallas, and the Stephen B. Tips Fund of Northwestern Medical Foundation. We are grateful to all the coordinators, patients, and families who make this study possible.