Genetic variants associated with ALT elevation from therapeutic acetaminophen.

BACKGROUND: Several studies have suggested genetic variants associated with acetaminophen induced liver injury (DILI) following overdose. Genetic variation associated with acetaminophen-induced alanine aminotransferase elevation during therapeutic dosing has not been examined. METHODS: We performed genetic analyses on patients that ingested therapeutic doses of 4 grams of acetaminophen for up to 16 days. We examined 20 genes previously implicated in the metabolism of acetaminophen or the development of immune-mediated DILI using the Illumina Multi-Ethnic Global Array 2. Autosomes were aligned and imputed using TOPMed. A candidate gene region analysis was performed by testing each gene individually using linkage disequilibrium (LD) pruned variants with the adaptive sum of powered scores (aSPU) test from the aSPU R package. The highest measured ALT during therapy, the maximum ALT, was used as the outcome. RESULTS: 192 subjects taking therapeutic APAP were included in the genetic analysis. 136 (70.8%) were female, 133 (69.2%) were Caucasian race, and the median age was 34 years (IQR: 26, 46). Age > 50 years was the only clinical factor associated with maximum ALT increase. Variants in SULT1E1, the gene responsible for Sulfotransferase Family 1E Member 1 enzyme production, were associated with maximum ALT. No single variant drove this association, but rather the association was due to the additive effects of numerous variants within the gene. No other genes were associated with maximum ALT increase in this cohort. CONCLUSION: Acetaminophen induced ALT elevation at therapeutic doses was not associated with variation in most genes associated with acetaminophen metabolism or immune-induced DILI in this cohort. The role of SULT1E1 polymorphism in acetaminophen-induced elevated ALT needs further examination.

Significance of temperature in antimuscarinic toxicity: a case-control study.

INTRODUCTION: Antimuscarinic toxicity can result in temperature dysregulation, but the clinical significance of this is unclear. The objective of this study was to compare peak temperatures between antimuscarinic patients with and without severe clinical outcomes. METHODS: This was a case-control analysis at two large, urban, academic medical centers from January 1, 2016, through December 31, 2021. We compared peak temperature (Tmax) amongst antimuscarinic patients who experienced severe outcomes with those who did not. Severe outcome was defined as seizure, ventricular dysrhythmia, hypotension, or intubation. RESULTS: Fifty-six patients met inclusion criteria of which 23 developed severe outcomes: 16 seizures, 9 cases with hypotension, 5 intubations, and 2 ventricular dysrhythmias. Tmax amongst all patients ranged from 36.4-39.2 °C. There were no fatalities. There was no difference in Tmax in the emergency department or throughout hospitalization between groups, and Tmax was not predictive for the development of severe outcomes. DISCUSSION: Maximum temperatures did not differ between patients with and without severe outcomes in the setting of antimuscarinic toxicity, and temperature was poorly predictive of outcomes. Our findings suggest that mild temperature dysregulation in antimuscarinic toxicity is not a key prognostic indicator for severe outcome. Further study is needed to assess implication of severe hyperthermia.

The Roles of Antidotes in Emergency Situations.

Management of the acutely poisoned patient requires supportive care and timely administration of antidotes to minimize ongoing toxicity and mortality. New applications for old antidotes include utilization of methylene blue and hydroxocobalamin in vasoplegia. Fomepizole is also being evaluated as a potential adjunct in acetaminophen toxicity. Other advancements include individualized acetylcysteine dosing regimens for acetaminophen toxicity and carnitine supplementation in valproic acid toxicity. Additional antidote considerations include administration of lipid emulsion in lipophilic xenobiotic exposure not responsive to standard resuscitative modalities. These expert recommendations provide guidance for providers caring for the acutely poisoned patient.