Gastroenterology

Gastroenterology

Volume 130, Issue 3, March 2006, Pages 687-694
Gastroenterology

Clinical–liver, pancreas, and biliary tract
Measurement of Serum Acetaminophen–Protein Adducts in Patients With Acute Liver Failure

https://doi.org/10.1053/j.gastro.2006.01.033Get rights and content

Background & Aims: Acetaminophen toxicity is the most common cause of acute liver failure (ALF) in the United States and Great Britain, but may be underrecognized in certain settings. Acetaminophen–protein adducts are specific biomarkers of drug-related toxicity in animal models and can be measured in tissue or blood samples. Measurement of serum adducts might improve diagnostic accuracy in acute liver failure (ALF) patients. Methods: We measured serum acetaminophen–protein adducts using high-pressure liquid chromatography with electrochemical detection in coded sera of 66 patients with ALF collected prospectively at 24 US tertiary referral centers. Samples were included from 20 patients with well-characterized acetaminophen-related acute liver failure, 10 patients with ALF owing to other well-defined causes, 36 patients with ALF of indeterminate etiology, and 15 additional patients without ALF but with known acetaminophen overdose and minimal or no biochemical liver injury. Results: Acetaminophen–protein adducts were detected in serum in 100% of known acetaminophen ALF patients and in none of the ALF patients with other defined causes, yielding a sensitivity and specificity of 100%. In daily serial samples, serum adducts decreased in parallel with aminotransferase levels. Seven of 36 (19%) indeterminate cases demonstrated adducts in serum suggesting that acetaminophen toxicity caused or contributed to ALF in these patients. Low adduct levels were present in 2 of 15 patients with acetaminophen overdose without significant liver injury. Conclusions: Measurement of serum acetaminophen–protein adducts reliably identified acetaminophen toxicity, and may be a useful diagnostic test for cases lacking historical data or other clinical information.

Section snippets

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,

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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.

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