title: External validation of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity from paracetamol overdose.
abstract: BACKGROUND
  Risk prediction in paracetamol (acetaminophen, or APAP) poisoning treated with acetylcysteine helps guide initial patient management and disposition. The paracetamol-aminotransferase multiplication product may be a useful and less time-sensitive risk predictor.
  
  
  OBJECTIVE
  The aim of this study was to validate this multiplication product in an independent cohort of patients with paracetamol overdose.
  
  
  METHODS
  Using an existing toxicology dataset of poisoned patients from two large inner-city United Kingdom teaching hospitals, we retrospectively identified by electronic search all paracetamol overdoses from February 2005 to March 2013. We assessed the diagnostic accuracy of the multiplication product (serum APAP concentration × alanine transaminase [ALT] activity), especially at the pre-specified cut-off points of 1 500 mg/L × IU/L (10 000 micromol/L × IU/L) and 10 000 mg/L × IU/L (66 000 micromol/L × IU/L). The primary outcome was hepatotoxicity defined by a peak ALT > 1000 IU/L.
  
  
  RESULTS
  Of 3823 total paracetamol overdose presentations, there were 2743 acute single, 452 delayed single (> 24 h post overdose), 426 staggered (ingestion over > 1 h), and 202 supratherapeutic ingestions. Altogether, 34 patients developed hepatotoxicity. Among the acute single-ingestion patients, a multiplication product > 10 000 mg/L × IU/L had a sensitivity of 80% (95% confidence interval [CI]: 44%, 96%) and specificity of 99.6% [99.3%, 99.8%], while a product > 1 500 mg/L × IU/L had a sensitivity of 100% [66%, 100%] and specificity of 92% [91%, 93%]. Overall, 16 patients with a multiplication product > 10 000 mg/L × IU/L developed hepatotoxicity (likelihood ratio: 250, 95% CI: 130, 480), and 4 patients with a multiplication product between 1 500 and 10 000 (likelihood ratio: 2.5, 95% CI: 1.0, 6.0). No patient with a product < 1 500 mg/L × IU/L who received acetylcysteine developed hepatotoxicity.
  
  
  CONCLUSIONS
  Regardless of ingestion type, a product > 10 000 mg/L × IU/L was associated with a very high likelihood, and < 1 500 mg/L × IU/L with a very low likelihood, of developing hepatotoxicity in patients treated with acetylcysteine.
authors.affiliation: Emergency Physician and Clinical Toxicologist, Victorian Poisons Information Centre and Austin Toxicology Service, Austin Hospital , Victoria , Australia.
authors.forename: Anselm
authors.initials: A
authors.lastname: Wong
authors.forename: Marco L A
authors.initials: ML
authors.lastname: Sivilotti
authors.forename: Paul I
authors.initials: PI
authors.lastname: Dargan
authors.forename: David M
authors.initials: DM
authors.lastname: Wood
authors.forename: Shaun L
authors.initials: SL
authors.lastname: Greene
mesh_terms: D000082:Acetaminophen / Q000097:blood / Q000506:poisoning*; D000111:Acetylcysteine / Q000627:therapeutic use; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood*; D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000506:poisoning*; D000931:Antidotes / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy / Q000209:etiology; D004796:Clinical Enzyme Tests; D016208:Databases, Factual; D003661:Decision Support Techniques; D062787:Drug Overdose; D005260:Female; D006784:Hospitals, Teaching; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D015415:Biomarkers; D000082:Acetaminophen; D000410:Alanine Transaminase; D000111:Acetylcysteine
keywords: Acetaminophen; Liver; Poisoning; Risk; Score