What is the major adverse reaction to acetaminophen (paracetamol) overdose?

Major Adverse Reaction to Acetaminophen Overdose

The major adverse reaction to acetaminophen overdose is liver failure (B). Acetaminophen overdose is the most common cause of acute liver failure in Western countries, with hepatotoxicity occurring when toxic metabolites overwhelm the liver's protective glutathione stores 1, 2.

Mechanism of Hepatotoxicity

Acetaminophen is primarily metabolized in the liver through two main pathways:

• The major pathway produces harmless end products
• A minor pathway creates a toxic intermediate compound (N-acetyl-p-benzoquinone imine or NAPQI) that is normally neutralized by glutathione 3

In overdose situations:

• Glutathione stores become depleted
• The toxic NAPQI accumulates and damages liver tissue
• Hepatotoxicity typically occurs when plasma concentrations exceed 150 μg/mL, far above therapeutic levels (5-20 μg/mL) 3

Risk Factors for Hepatotoxicity

Several factors increase the risk of liver damage from acetaminophen:

• Unintentional overdoses (5.18 times higher risk)
• Alcohol abuse (2.21 times higher risk)
• Underlying liver disease (3.50 times higher risk) 2
• Doses exceeding 10 g/day, though toxicity can occur with lower doses in susceptible patients 1
• Medications that induce CYP450 enzymes 1

Clinical Progression of Acetaminophen Toxicity

Untreated acetaminophen poisoning typically follows a predictable course:

1. Initial phase (0-24 hours): Nonspecific symptoms including nausea, vomiting
2. Latent period (24-72 hours): Rising liver transaminases
3. Hepatic phase (72-96 hours): Signs of liver dysfunction including jaundice, coagulopathy, and encephalopathy 3

Management of Acetaminophen Overdose

The American Association for the Study of Liver Diseases recommends:

1. Activated charcoal administration for patients presenting within 4 hours of ingestion 4
2. Immediate N-acetylcysteine (NAC) administration when acetaminophen levels or rising aminotransferases indicate impending liver injury 4
3. NAC may be used even when acetaminophen ingestion is only suspected 4

NAC administration significantly improves outcomes:

• 28% absolute reduction in mortality in patients with hepatic failure
• Decreased rates of cerebral edema and need for inotropic support 4
• Most effective when given within 8 hours but beneficial up to 24 hours post-ingestion 1

Monitoring and Prognosis

• Very high aminotransferases (>3,500 IU/L) strongly correlate with acetaminophen poisoning 4, 1
• Early contact with a liver transplant center is crucial if liver failure develops 4, 1
• Without appropriate treatment, acetaminophen overdose can progress to fulminant hepatic failure and death 5

While kidney failure and CNS effects (drowsiness) can occur with acetaminophen overdose, and gastrointestinal symptoms like diarrhea may be present initially, liver failure represents the predominant life-threatening adverse reaction that defines acetaminophen toxicity.