Chronic Acetaminophen Toxicity

Acetaminophen (Tylenol) is the most commonly consumed medication in the United States.  Most people just assume that it is benign and can be taken with impunity.  The truth, however, is that acetaminophen is toxic when taken in excess both acutely and chronically.  The following blog discusses a recent study out of Britain that proves just how toxic acetaminophen is when consumed regularly.  The dangers of this medication are clear and immediate.

Study Synopsis and Perspective

Repeated doses of slightly too much acetaminophen can be fatal, according to the results of a large study published online November 22, 2011 in the British Journal of Clinical Pharmacology.

Br J Clin Pharmacol. Published online November 22, 2011.

Study Highlights

During a 16-year period, 938 patients were admitted to the Scottish Liver Transplantation Unit for severe acute liver injury.

  • 663 patients (70.7%) had acetaminophen-induced severe acute liver injury.
  • Severe acute liver injury was defined as a sudden deterioration in liver function with coagulopathy in the absence of chronic liver disease.
  • Acetaminophen overdose was defined as more than 4 g/day of acetaminophen ingestion within 7 days of presentation, a serum acetaminophen level of more than 10 mg/L, a serum ALT level of more than 1000 IU/L within 7 days of a history of acetaminophen ingestion, and exclusion of other causes of acute severe liver injury.
  • All patients were treated with continuous NAC at 6.25 mg/kg/hour until the international normalized ratio was less than 2.
  • King's College Hospital poor prognostic criteria were used to identify patients most likely to die without liver transplantation.
  • Mean age of the patients was 34 years, and 52.5% were women.
  • 450 patients (73.6%) took a single-time overdose of more than 4 g of acetaminophen.
  • 161 (24.3%) took a staggered overdose of acetaminophen, defined as 2 or more supratherapeutic doses at more than an 8-hour interval resulting in a cumulative dose of more than 4 g/day.
  • Patients taking a staggered overdose vs those with a single-time overdose were more likely to be older, more likely to abuse alcohol, more likely to have taken alcohol concomitantly with the overdose, less likely to receive NAC in the referring hospital, had lower serum acetaminophen levels at admission (37.8 vs 75.6 mg/L), and had lower total acetaminophen ingestion (24 vs 27 g).
  • Compared with patients taking a single-time overdose, those taking a staggered overdose had the following findings:
    • Lower admission ALT (4622 vs 8415 IU/L)
    • Lower sodium level (134 vs 136 mmol/L)
    • Higher creatinine level (172 vs 114 µmol/L)
    • Lower albumin (33 vs 37 g/L)
    • Lower platelet count (113 vs 130 x 109/L)
    • Increased likelihood of encephalopathy on admission (43.5% vs 34.5%) or at any stage (55.9% vs 46.9%)
    • Increased need for renal replacement therapy
    • Increased need for mechanical ventilation (47.8% vs 38.2%)
    • Decreased spontaneous survival duration (62.7% vs 72.4%)
    • Similar prothrombin time, King's College Hospital poor prognostic criteria, transplantation, and development of encephalopathy during admission
  • In patients with staggered acetaminophen overdose, independent predictors of death were hepatic encephalopathy on admission, increased prothrombin time, leukocytosis, renal impairment, and hypoalbuminemia.
  • 396 (88.0%) of 450 patients with single-time overdose had data on the accurate timing of dose: 19.7% presented to emergency services within 12 hours of the last acetaminophen dose, 35.4% presented after 12 to 24 hours, and 44.9% presented after 24 hours (delayed presentation).
  • Patients who presented to the hospital after 24 hours, at 12 to 24 hours, and within 12 hours had the following respective findings:
    • Lower serum acetaminophen levels (37 vs 89 vs 139 mg/L)
    • Higher creatinine levels (162 vs 94 vs 94 µmol/L)
    • Increased likelihood for development of hepatic encephalopathy during illness (57.3% vs 41.4% vs 28.2%)
    • Increased need for mechanical ventilation (47.2% vs 32.9% vs 20.5%)
    • Increased need for renal replacement therapy (39.9% vs 22.9% vs 12.8%)
    • Increased King's College Hospital poor prognostic criteria (33.7% vs 19.3% vs 10.3%)
    • Decreased spontaneous survival duration (64.0% vs 76.4% vs 88.5%)
    • Similar ALT, bilirubin, albumin, sodium, prothrombin time, and platelet count
  • In patients with single-time overdose, independent predictors of death were delayed presentation (> 24 hours; OR, 2.25; P = .009), older age, hepatic encephalopathy on admission, leukocytosis, and prothrombin time.
  • King's College Hospital poor prognostic criteria had a decreased sensitivity for staggered overdose vs single-time overdose (77.6% vs 89.9%), but the specificity was similar.
  • Study limitations were reliance on patient recall for the time and dose of acetaminophen use and lack of data on other medications or recent fasting.

 

Clinical Implications

 

  • Patients with staggered overdose vs those with a single-time overdose of acetaminophen are more likely to have encephalopathy on admission, need renal replacement therapy or mechanical ventilation, and have higher mortality rates.
  • In patients with a single-time overdose of acetaminophen, delayed presentation (> 24 hours) to the hospital vs presentation at 12 to 24 hours or within 12 hours is linked with a higher risk for death or the need for liver transplantation.
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