How does an overdose of Tylenol (acetaminophen) cause acidosis?

Mechanisms of Acidosis in Tylenol (Acetaminophen) Overdose

Tylenol overdose causes acidosis through multiple mechanisms, primarily through mitochondrial dysfunction leading to lactic acidosis and through accumulation of 5-oxoproline, both of which can occur early in poisoning before hepatotoxicity develops. 1, 2

Primary Mechanisms of Acidosis

1. Early Lactic Acidosis (Pre-Hepatotoxicity)

• Direct mitochondrial toxicity: The toxic metabolite of acetaminophen, N-acetyl-p-benzoquinone imine (NAPQI), inhibits electron transfer in the mitochondrial respiratory chain, disrupting aerobic respiration 2
• This occurs at very high concentrations of acetaminophen and precedes cellular injury by several hours
• Results in elevated lactate levels proportional to acetaminophen concentration 3
• Can cause high anion gap metabolic acidosis (AGMA) early after massive ingestion, even before liver damage occurs 3

2. 5-Oxoproline (Pyroglutamic Acid) Accumulation

• Acetaminophen depletes glutathione stores, leading to accumulation of 5-oxoproline 4
• Can occur in both:
  • Acute large-quantity ingestions
  • Chronic repeated ingestions, especially in patients with underlying liver disease 4

3. Late Lactic Acidosis (Post-Hepatotoxicity)

• Occurs as a consequence of established liver failure 2
• Primarily due to reduced hepatic clearance of lactate
• In shocked patients, tissue hypoperfusion contributes to peripheral anaerobic respiration, worsening lactic acidosis 2

Clinical Presentation and Significance

Early Acidosis

• Present in approximately 41% of patients on admission with acetaminophen overdose 3
• Usually persists for approximately 1.5 days 3
• Associated with elevated lactate levels (average 4.5 mmol/L) 3
• Often accompanied by altered mental status:
  • Confusion (48% of patients with increased anion gap vs. 3% without) 3
  • Lethargy (39% vs. 6%) 3
  • Coma in severe cases 5, 6

Monitoring and Management

• Arterial ammonia levels should be monitored (critical threshold: 150-200 μmol/L) 1
• Daily monitoring of liver function tests, coagulation studies, and electrolytes is essential 1
• N-acetylcysteine (NAC) is the cornerstone of treatment:
  • Most effective when administered within 8-10 hours of ingestion 1
  • Virtually eliminates mortality risk when given early 1
  • Should be initiated immediately in cases of acetaminophen overdose with levels ≥100 mg/L or when time of ingestion is unknown 1

Prognostic Significance

• Post-resuscitation arterial lactate concentration is a strong predictor of mortality in patients with acetaminophen hepatotoxicity 2
• Included in modified King's College criteria for consideration of liver transplantation 2
• Early high anion gap metabolic acidosis alone is typically self-limited and does not predict clinical outcomes when treated appropriately with NAC 3

Important Clinical Considerations

• Early metabolic acidosis with coma can occur after acetaminophen poisoning, independent of hepatic failure 5
• Consider acetaminophen overdose in patients presenting with unexplained altered mental status and metabolic acidosis 3
• Persistent or late metabolic acidosis without liver failure should prompt investigation for other causes 3
• In cases of severe acidosis with altered mental status, consider:
  • Renal replacement therapy (hemodialysis or continuous renal replacement therapy) 1
  • Intubation and mechanical ventilation 1
  • Fomepizole as adjunctive treatment to inhibit further toxic metabolite formation 1

Early recognition of acetaminophen-induced acidosis and prompt treatment with NAC are critical for preventing progression to severe hepatotoxicity and improving outcomes.