What is the treatment for severe acute liver injury with N-acetylcysteine (NAC)?

N-Acetylcysteine for Severe Acute Liver Injury

Administer N-acetylcysteine (NAC) immediately to all patients with severe acute liver injury regardless of etiology, as it significantly improves transplant-free survival and reduces mortality. 1

Immediate Administration Protocol

Begin NAC without delay in the following scenarios:

• Any suspected or confirmed acetaminophen overdose - even if acetaminophen levels are pending, undetectable, or the ingestion history is unclear 2
• All cases of acute liver failure regardless of cause - including non-acetaminophen etiologies such as ischemic hepatitis, viral hepatitis, or drug-induced liver injury 3, 1
• When aminotransferases exceed 3,500 IU/L - this strongly suggests acetaminophen toxicity even without confirmatory history 2

Dosing Regimens

Intravenous Route (Preferred for Severe Cases)

The IV route is strongly preferred in acute liver failure because oral administration is often precluded by gastrointestinal bleeding, altered mental status, or encephalopathy 2, 4:

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes 2, 1
• Second dose: 50 mg/kg over 4 hours 2, 1
• Third dose: 100 mg/kg over 16 hours 2, 1
• Total treatment duration: 21 hours for the standard IV protocol 4

Oral Route (Alternative)

Use oral NAC only if IV access is unavailable and the patient can safely tolerate oral intake 2:

• Loading dose: 140 mg/kg orally or via nasogastric tube, diluted to 5% solution 2, 1
• Maintenance: 70 mg/kg every 4 hours for 17 doses 2, 1
• Total treatment duration: 72 hours 5

Evidence for Efficacy

Acetaminophen-Induced Liver Injury

NAC dramatically reduces mortality when initiated early:

• Within 8-10 hours: Hepatotoxicity incidence of only 2.9-6.1% with no acetaminophen-related deaths 2
• 10-16 hours: Hepatotoxicity rises to 26.4-29% 2
• 16-24 hours: Hepatotoxicity reaches 62%, but NAC still provides significant benefit 2
• Beyond 24 hours: NAC retains value even 48+ hours post-ingestion 2

Non-Acetaminophen Acute Liver Failure

NAC provides substantial benefit across all etiologies of acute liver failure:

• Transplant-free survival: Increases from 26% to 64% (OR = 4.81,95% CI 3.22-7.18) 3
• Overall survival: Improves from 59% to 76% (OR = 2.30,95% CI 1.54-3.45) 3, 1
• Post-transplant survival: Enhanced with OR = 2.44 1

Mechanisms of Action in Severe Liver Injury

NAC provides multiple protective effects beyond glutathione repletion:

• Improves tissue oxygen delivery and reduces hepatic hypoxia 3
• Provides antioxidant effects and scavenges reactive oxygen species 3, 6
• Reduces inflammatory response and cytokine synthesis 3
• Decreases cell death through anti-apoptotic mechanisms 3

Critical Management Considerations

Monitoring Requirements

All patients with severe acute liver injury receiving NAC require intensive monitoring 2, 1:

• ICU admission with frequent assessment 2, 1
• Serial laboratory tests: AST, ALT, bilirubin, INR, creatinine, BUN, glucose, electrolytes 4
• Track encephalopathy grade regularly 3

Early Transplant Center Contact

Contact a liver transplant center immediately upon diagnosis of acute liver failure - do not wait to see if NAC will be effective 2, 1. This is critical because:

• Prognosis depends heavily on etiology 2
• Transplant evaluation takes time to complete 2
• Window for successful transplantation may be narrow 3

Activated Charcoal Consideration

If acetaminophen ingestion occurred within 4 hours of presentation:

• Administer activated charcoal (1 g/kg orally) immediately before starting NAC 2
• Charcoal remains beneficial up to 3-4 hours post-ingestion 2
• Charcoal does not reduce NAC effectiveness 2

Safety Profile and Adverse Effects

NAC is remarkably safe with minimal contraindications:

• Common side effects: Nausea, vomiting (oral route), diarrhea, constipation 1
• Anaphylactoid reactions: Occur during IV loading dose in <5% of patients 2, 7
• Bronchospasm: Rare (1-2%), primarily in patients with reactive airway disease 3, 1
• Skin rash: Less than 5% of patients 1

Managing Anaphylactoid Reactions

If allergic reactions occur during IV infusion:

• Discontinue the infusion temporarily 2
• Administer antihistamines 2
• Give epinephrine for bronchospasm 2
• Restart NAC at a slower infusion rate 7

Common Pitfalls to Avoid

Do not delay NAC while waiting for:

• Acetaminophen levels to return 2, 1, 4
• Confirmation of ingestion history 2, 1
• Determination of exact etiology 1

Do not rely solely on the Rumack-Matthew nomogram in:

• Chronic alcoholics - they have increased susceptibility 4
• Malnourished patients - altered metabolism increases risk 4
• Patients on CYP2E1 inducers (e.g., isoniazid) - enhanced toxic metabolite formation 4
• Extended-release acetaminophen ingestions - requires second level at 8-10 hours 4
• Repeated supratherapeutic ingestions - nomogram does not apply 2, 4

Do not assume low or undetectable acetaminophen levels exclude toxicity:

• Ingestion may have occurred days earlier 2
• Patients can present in liver failure with undetectable levels 7
• Multiple doses over time are not captured by single measurements 2

Duration of Treatment Controversy

The optimal duration remains debated:

• Standard 21-hour IV protocol may be too short for large ingestions 7, 8
• Full 72-hour oral course may be unnecessary in many cases 8
• Monitor ALT levels - peak ALT correlates with clearance of toxic metabolites and can guide discontinuation 8
• Continue NAC beyond standard protocols if liver injury is progressing or severe 7, 5