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Serum alanine aminotransferase elevation during 10 days of acetaminophen use in nondrinkers.

ABSTRACT: To describe the changes in serum alanine aminotransferase (ALT) levels in nondrinkers receiving acetaminophen for 10 days.Prospective, open-label study.Outpatient clinical research center.Twenty-four healthy volunteers who reported an average alcohol consumption of less than one drink/day for the 30 days preceding study enrollment.Patients were administered acetaminophen 4 g/day for 10 days (study days 1-10).Serum ALT level, total bilirubin level, and international normalized ratio (INR) were measured on study days 0, 4, 7, 9, 11, and 14. Median ALT level increased from 24 U/L on day 0 to 39 U/L on day 7, and remained elevated through day 11 (39 U/L); these increases were statistically significant (p=0.0002). Median ALT level began to trend down by day 14 (35 U/L). Fourteen subjects (58%) had ALT levels above the upper limit of normal; the largest elevation was 3.8 times the upper limit of normal (day 7). No increases in INR or total bilirubin level were noted during the study, and no subject developed symptoms of liver injury (e.g., abdominal pain, jaundice).Daily use of acetaminophen at the maximum dose of 4 g/day for 10 days caused asymptomatic ALT level elevations in subjects who do not consume alcohol. The clinical implication of these elevations remains unclear. Future studies should evaluate ALT changes and their clinical effects when acetaminophen is given for long periods of time.

SUBMITTER: Heard KJ

PROVIDER: S-EPMC3135016 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Serum alanine aminotransferase elevation during 10 days of acetaminophen use in nondrinkers.

Heard Kennon J KJ Green Jody L JL Dart Richard C RC

Pharmacotherapy 20100801 8

<h4>Study objective</h4>To describe the changes in serum alanine aminotransferase (ALT) levels in nondrinkers receiving acetaminophen for 10 days.<h4>Design</h4>Prospective, open-label study.<h4>Setting</h4>Outpatient clinical research center.<h4>Patients</h4>Twenty-four healthy volunteers who reported an average alcohol consumption of less than one drink/day for the 30 days preceding study enrollment.<h4>Intervention</h4>Patients were administered acetaminophen 4 g/day for 10 days (study days 1 ...[more]

PMID: 20653358

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Project description:BackgroundAcetaminophen (APAP) is the most common cause liver injury following alcohol in US patients. Predicting liver injury and subsequent hepatic regeneration in patients taking therapeutic doses of APAP may be possible using new 'omic methods such as metabolomics and genomics. Multi'omic techniques increase our ability to find new mechanisms of injury and regeneration.MethodsWe used metabolomic and genomic data from a randomized controlled trial of patients administered 4 g of APAP per day for 14 days or longer with blood samples obtained at 0 (baseline), 4, 7, 10, 13 and 16 days. We used the highest ALT as the clinical outcome to be predicted in our integrated analysis. We used penalized regression to model the relationship between genetic variants and day 0 metabolite level, and then performed a metabolite-wide colocalization scan to associate the genetically regulated component of metabolite expression with ALT elevation. Genome-wide association study (GWAS) analyses were conducted for ALT elevation and metabolite level using linear regression, with age, sex, and the first five principal components included as covariates. Colocalization was tested via a weighted sum test.ResultsOut of the 164 metabolites modeled, 120 met the criteria for predictive accuracy and were retained for genetic analyses. After genomic examination, eight metabolites were found to be under genetic control and predictive of ALT elevation due to therapeutic acetaminophen. The metabolites were: 3-oxalomalate, allantoate, diphosphate, L-carnitine, L-proline, maltose, and ornithine. These genes are important in the tricarboxylic acid cycle (TCA), urea breakdown pathway, glutathione production, mitochondrial energy production, and maltose metabolism.ConclusionsThis multi'omic approach can be used to integrate metabolomic and genomic data allowing identification of genes that control downstream metabolites. These findings confirm prior work that have identified mitochondrial energy production as critical to APAP induced liver injury and have confirmed our prior work that demonstrate the importance of the urea cycle in therapeutic APAP liver injury.

Dataset Information

Serum alanine aminotransferase elevation during 10 days of acetaminophen use in nondrinkers.

Publications

Serum alanine aminotransferase elevation during 10 days of acetaminophen use in nondrinkers.

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