Acetaminophen poisoning

Epidemiology

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Leading cause of acute liver failure

Etiology

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Pathophysiology

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• Exhaustion of hepatic metabolic pathways causes accumulation of a toxic metabolite of acetaminophen, N-acetyl-p-benzoquinoneimine (NAPQI).
  • Glutathione initially inactivates NAPQI, but its reserves are eventually depleted, leading to NAPQI accumulation.
  • NAPQI → irreversible oxidative hepatocyte injury → liver cell necrosis
• APAP-induced hepatotoxicity
  • Defined as peak AST or ALT > 1000 IU/L
  • Most commonly caused by APAP overdose
  • Occurs rarely at therapeutic doses in patients with:
    • Alcohol consumption
    • Prolonged fasting
    • Chronic liver disease

Clinical features

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• Nausea, vomiting
• Pallor
• RUQ pain
• Signs of acute liver failure

Diagnostics

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Differential diagnostics

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t

Feature	Salicylate (ASA)	Acetaminophen (APAP)	Reye Syndrome
Path	Uncouple oxidative phosphorylation (leads to hyperthermia); Direct stimulation of resp center.	Glutathione depletion $\to$ NAPQI $\to$ centrilobular hepatic necrosis.	Mito dysfunction ($\downarrow$ $\beta$-oxidation) $\to$ Microvesicular fatty change in liver
Hx/Trigger	OD; Wintergreen oil	OD (esp. w/ CYP inducers/EtOH)	Child + Virus + ASA
Key Sx	Tinnitus, Hyperthermia, Tachypnea	RUQ pain, Fulminant liver failure	Encephalopathy, Vomiting
Labs/Path	Mixed Resp Alk + Met Acidosis	Zone 3 Necrosis, $\uparrow \uparrow$ AST/ALT	Microvesicular fatty liver, $\downarrow$ Glucose, $\uparrow$ Ammonia
Tx	NaHCO3 (Alkalinize urine), Dialysis	N-acetylcysteine (restore glutathione)	Supportive

Treatment

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• Antidote: PO or IV N-acetylcysteine (NAC) is used to treat and prevent APAP-induced hepatoxicity.
  • NAC regenerates glutathione