Module 3: Clinical Manifestations

Acetaminophen toxicity can range from asymptomatic to fulminant hepatic failure depending on the dose ingested and timing of antidotal therapy. Understanding the typical progression of clinical effects helps clinicians recognize toxicity early and intervene appropriately. This module reviews the common signs, symptoms, and laboratory abnormalities seen with acetaminophen poisoning through each phase from initial ingestion to resolution. Special populations such as pregnant women, neonates, and patients with preexisting liver disease are also discussed.

Key Sections:

• Phase I: Initial 12-24 Hours
• Phase II: Onset of Hepatotoxicity (24-36 Hours)
• Phase III: Maximal Hepatotoxicity (72-96 Hours)
• Phase IV: Recovery
• Special Populations
  • Pediatrics
  • Pregnancy
  • Preexisting Liver Disease

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3.1 Phase I: Initial 12-24 Hours

• Largely asymptomatic until liver injury begins
• Nonspecific symptoms may include:
  • Nausea, vomiting, malaise, diaphoresis
  • Right upper quadrant abdominal pain
• Rarely, massive overdoses may cause:
  • CNS depression, decreased mental status
  • Severe high anion gap metabolic acidosis
  • Elevated lactate
  • Hypoglycemia
  • Death in extreme cases
• No laboratory evidence of hepatotoxicity yet

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3.2 Phase II: Onset of Hepatotoxicity (24-36 Hours)

• Elevation of serum aminotransferases indicates liver injury
  • AST elevates first, followed by ALT
• Acetaminophen toxicity defined as:
  • AST or ALT >1000 IU/L
• May have nausea/vomiting, malaise
• PT elevation in some cases
• Renal dysfunction rare

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3.3Phase III: Maximal Hepatotoxicity (72-96 Hours)

• Peak liver injury manifests as:
  • Marked AST/ALT elevation (>10,000 IU/L common)
  • Prolonged PT/INR
  • Hypoglycemia
  • Metabolic acidosis
  • Hyperammonemia
  • Acute kidney injury
  • Encephalopathy or coma
• Multiorgan dysfunction
  • Cerebral edema
  • Acute respiratory distress syndrome
  • Cardiovascular collapse
  • Disseminated intravascular coagulation
• Death most common during this phase

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3.4 Phase IV: Recovery

• Most laboratory abnormalities normalize within 4-7 days in survivors
• Transaminases downtrend, AST earlier than ALT
• Complete hepatic regeneration expected
• Renal function improves but may have mild residual impairment
• No cases of chronic liver dysfunction reported

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3.5 Special Populations

Pediatrics

• Children appear relatively protected from acetaminophen hepatotoxicity
• Theories include:
  • Increased sulfation capacity
  • Smaller ingested doses
  • Formulation differences (pediatric elixirs)
• Risk factors:
  • Doses >200 mg/kg
  • Repeated supratherapeutic dosing
  • Concurrent illnesses like febrile infections

Pregnancy

• Fetal risk highest with maternal toxicity in late 2nd/3rd trimester
• Fetal effects:
  • 1st trimester: increased risk of spontaneous abortion
  • 2nd trimester: potential fetal demise
  • 3rd trimester: possible fetal hepatotoxicity
• Maternal toxicity linked to poor fetal outcomes
• NAC considered safe and should be initiated per standard criteria

Preexisting Liver Disease

• Underlying hepatic impairment increases susceptibility to toxicity
• Lower doses may produce injury
• Consider treatment at lower serum acetaminophen thresholds
• Close monitoring essential even with NAC therapy
• May require liver transplant earlier

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High Yield Learning Points:

• Phase I of acetaminophen toxicity is largely asymptomatic with nonspecific symptoms only. Hepatic injury has not begun yet.
• Elevation of serum AST and ALT indicates the onset of hepatotoxicity in Phase II, typically within 24-36 hours post-ingestion.
• Phase III represents peak hepatotoxicity, with marked transaminase elevation, coagulopathy, hypoglycemia, and multiorgan failure. Most fatalities occur during this stage.
• Phase IV reflects recovery in survivors, with normalization of laboratory abnormalities and complete hepatic regeneration expected within 4-7 days.
• Special populations such as pregnant women, neonates, and those with liver disease have unique considerations for toxicity risk and require close monitoring.