Acetaminophen Toxicity

Author: Dylan Martin, PGY-4

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Background

• Tylenol is the most popular over the counter analgesic
• Most common reported toxic exposure to poison control centers
• 2018: 50,000 Tylenol ingestions reported as sole agent with an additional 17k reported in combined exposures
• 100-400 deaths per year in the US alone
• #1 cause of acute liver failure in the U.S
• #2 cause requiring liver transplantation

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Acetaminophen Metabolism

• Mainly hepatically metabolized with small amount excreted unchanged in urine (5-10%) (See Figure 1)
  • Sulfation (20-46%)
  • Glucuronidation (40-67%)
  • Cytochrome P-450 2E1 subunit- oxidizes Acetaminophen to NAPQI (N-Acetyl-P-Benzoquinone Imine)
    • NAPQI is the toxic substance that accumulate in overdose
    • NAPQI is usually detoxified to nontoxic acetaminophen-mercapturate via hepatic glutathione

Mechanism of Tylenol Toxicity:

• During an overdose, sulfation and glucuronidation are fully saturated…leaving all residual Tylenol to be oxidized to NAPQI.
  • When glutathione stores are depleted by NAPQI buildup, the excess NAPQI binds directly to hepatic macromolecules leading to hepatic necrosis

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Question:

Of the three listed patients below, who has the highest risk of developing hepatic necrosis, given our knowledge of the pathophysiology of acetaminophen metabolism?

1. 48 y/o M PMHx sig for EtOH cirrhosis, presenting acutely intoxicated with Tylenol ingestion.
2. 48 y/o M no PMHx, presenting acute intoxicated with Tylenol ingestion.
3. 48 y/o M no PMHx, presenting without EtOH consumption with Tylenol ingestion.

Answer:

Relative risk of developing hepatic necrosis secondary to Tylenol would 1, 3, 2 (from highest to lowest).

• Alcoholics have depleted glutathione stores, so therefore will be relatively less able to detoxify the buildup of NAPQI
  • Alcoholics also have chronically upregulated Cytochrome P-450 2E1 activity, so will more readily metabolize tylenol into NAPQI
• Studies have shown that acute EtOH intoxication actually has an inhibitory effect on CYP-450 and could theoretically decrease the rate of NAPQI build-up and decrease toxicity
  • One study that looked into this subset of patients found that acute alcohol intoxication seemed protective in chronic alcoholics presenting with Tylenol toxicity, but no benefit was found in non-alcoholics

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Clinical Presentation:

Progression of disease follows 4 known stages:

1. Stage 1: First 24 Hours
   • minimal/non-specific symptoms- anorexia, malaise, nausea, vomiting
   • Generally normal labs, potentially mild hypokalemia or metabolic acidosis
2. Stage 2: Days 2-3
   • RUQ pain/ acute hepatitis picture
   • Elevated LFT/Bilirubin, potentially early INR elevations
3. Stage 3: Days 3-4
   • Recurrence of nausea, vomiting, malaise, with addition of AMS, anuria, jaundice
   • Encephalopathy, hepatic failure, metabolic acidosis, coagulopathy, renal failure, pancreatitis
4. Stage 4: Days 5+
   • Either clinical improvement and recovery or deterioration into multi-organ failure and death

Rumack-Matthew Nomogram (See Figure 2):

• Only applies to single acute ingestions from within 4-24 hours
• Cannot be applied to chronic or repeated ingestions
• 4 hour level >200 → 60% chance of hepatic toxicity
• 4 hour level >300 → 90% chance

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Treatment:

• GI Decontamination
  • Early administration of activated charcoal (PO or via NGT)
    • Most effective if given within 1-4 hours of ingestion
    • Can be effective even longer if toxic co-ingestion with a bowel slowing agent (ex: opiates or anticholinergics)
  • No role for gastric lavage or whole bowel irrigation (WBI)

• N-Acetylcysteine- has 2 major benefits
  • Early Stages (First 8 hours):
    • Reduces NAPQI binding to hepatic macromolecules due to its role as a glutathione precursor
    • Can also indirectly increase sulfation to increase the amount of tylenol that can be metabolized in the nontoxic pathways
  • Later Stages (>24 hours):
    • Acts as an antioxidant, decreasing neutrophil infiltration, increasing circulatory flow, increasing oxygen delivery/extraction –> all of which leads to decreased hepatic necrosis
  • NAC is 100% EFFECTIVE at preventing hepatotoxicity if given within 8 hours from time of ingestion
  • Associated with significant benefits even up to 24 hours post ingestion, and is given universally in all cases of Tylenol related hepatotoxicity regardless of time since exposure
  • Safe, well tolerated, okay to give to pregnant patients
    • Only one contraindication: history of NAC-related anaphylaxis
    • Increased risk of anaphylaxis in asthmatics
  • IV and PO regimens exist:
    • IV NAC can cause anaphylactoid reactions
• Dosing NAC in the ED:
  • 20 hour protocol, then continuous infusion
    • Loading: 150mg/kg given over 15min-1hr
      • Give over 1 hr in asthmatics due to increased risk anaphylaxis
    • 1st maintenance dose: 50mg/kg total infused over 4 hours
    • 2nd maintenance dose: 100mg/kg total infused over 16 hours

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Disposition:

• Recheck labs after 20 hour protocol
  • serum tylenol, LFTs, bilirubin, INR
• Continue NAC infusion at 6.25 mg/kg/hr until APAP level zero AND LFT normalized/rapidly improving/patient recovers
• Floor admission is adequate unless:
  • Significant hepatotoxicity
  • Significant co-ingestion requiring closer monitoring (methadone OD leading to overdose, unstable vitals, airway/breathing concerns)

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References:

Chiew AL et al. Massive paracetamol overdose: an obsevational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2). Clin Toxicol 2017;55:1055-1065. PMID: 28644687.

Waring WS, Stephen AF, Malkowska AM, Robinson OD. Acute ethanol coingestion confers a lower risk of hepatotoxicity after deliberate acetaminophen overdose. Acad Emerg Med. 2008 Jan;15(1):54-8. doi: 10.1111/j.1553-2712.2007.00019.x. PMID: 18211314.

Tintinalli JE, Stapczynski JS, Ma OJ, Cline DM, Cydulka RK, Meckler GD: Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7th Edition: http://accessmedicine.com