What is the treatment for acetaminophen (N-acetyl para-aminophenol) induced hepatitis using N-acetyl cysteine (NAC)?

Treatment of Acetaminophen-Induced Hepatitis with N-Acetylcysteine

N-acetylcysteine (NAC) should be administered immediately to all patients with acetaminophen-induced hepatitis, regardless of time since ingestion, as it reduces mortality from 80% to 52% and provides benefit even in established liver failure. 1

Immediate Administration Protocol

Start NAC without delay when acetaminophen-induced hepatotoxicity is suspected or confirmed, even if presentation is beyond 24 hours post-ingestion. 1, 2 The Rumack-Matthew nomogram does NOT apply to patients with established hepatitis or those presenting >24 hours after ingestion—treatment decisions must be based on clinical presentation, acetaminophen levels, and liver function tests rather than nomogram placement. 1

Dosing Regimens

Intravenous NAC (preferred for established hepatitis): 1, 2, 3

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes
• Second dose: 50 mg/kg over 4 hours
• Third dose: 100 mg/kg over 16 hours (total 21-hour protocol)

Oral NAC (alternative): 1, 3

• Loading dose: 140 mg/kg by mouth or nasogastric tube diluted to 5% solution
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours)

The 72-hour oral regimen may be superior when treatment is delayed, though IV NAC is generally preferred for established hepatitis. 1

Clinical Benefits in Established Hepatotoxicity

NAC provides substantial mortality reduction even in fulminant hepatic failure: 1

• Reduces mortality from 80% to 52%
• Reduces cerebral edema from 68% to 40%
• Reduces need for inotropic support from 80% to 48%

Early NAC treatment (<10 hours) in fulminant hepatic failure results in 100% survival without progression or dialysis, while late treatment (>10 hours) results in 37% mortality and 51% requiring dialysis. 1

Duration of Treatment in Hepatitis

Continue NAC beyond the standard protocol until specific criteria are met: 1

• Acetaminophen level is undetectable AND
• Transaminases (AST/ALT) are declining AND
• INR normalizes AND
• No clinical signs of hepatotoxicity remain

Do NOT stop NAC if any of these red flags are present: 1

• Any elevation in AST or ALT above normal
• Rising transaminases
• Any coagulopathy
• Detectable acetaminophen level
• Clinical signs of ongoing hepatotoxicity

For patients with severe hepatotoxicity (AST >1000 IU/L), NAC should be continued until transaminases are declining and INR normalizes. 1

Special Considerations for High-Risk Populations

Chronic alcohol users should receive NAC even with acetaminophen levels in the "non-toxic" range, as severe hepatotoxicity can occur with doses as low as 4-5 g/day in this population. 1, 4 These patients have documented severe hepatotoxicity at therapeutic doses due to altered metabolism. 1

Cirrhotic patients, particularly those who are malnourished or actively drinking, are at higher risk of acetaminophen hepatotoxicity even at therapeutic doses and require immediate NAC administration. 4

Adjunctive Management

Activated charcoal (1 g/kg) should be given just prior to starting NAC if the patient presents within 4 hours of ingestion, though NAC should never be delayed for charcoal administration. 1, 3

ICU-level care is required for patients with severe hepatotoxicity (AST >1000 IU/L) or coagulopathy, with early consultation to transplant hepatology. 1 Monitor for complications including encephalopathy, coagulopathy, renal failure, and metabolic derangements. 1

Mechanism of Action

NAC protects the liver by maintaining or restoring glutathione levels, or by acting as an alternate substrate for conjugation with the reactive toxic metabolite of acetaminophen. 3 Following large overdoses (≥150 mg/kg), glucuronide and sulfate conjugation pathways become saturated, resulting in increased formation of reactive metabolite that depletes hepatic glutathione stores and causes cellular necrosis. 3

Adverse Effects

Adverse reactions are generally mild and should not prevent NAC administration: 4, 3

• Nausea/vomiting: <5%
• Skin rash: <5%
• Bronchospasm: 1-2%
• Anaphylactic reactions: rare

Transient patchy skin erythema or mild urticaria during the loading dose occurs in approximately 14% of patients but rarely requires discontinuation of therapy. 5

Critical Pitfall

Do not withhold NAC based on timing alone. Even when initiated >24 hours post-ingestion, NAC still provides benefit and reduces mortality in acetaminophen-induced hepatitis. 1, 6, 7 Low or absent acetaminophen levels do NOT rule out acetaminophen poisoning if ingestion was remote or occurred over several days. 1