What is the recommended N‑acetylcysteine (NAC) dosing for acute liver injury from acetaminophen overdose and for non‑acetaminophen acute liver failure, and is NAC indicated for chronic liver disease?

N-Acetylcysteine for Liver Injury: Dosing and Indications

Acetaminophen-Induced Acute Liver Failure

Start NAC immediately in all cases of known or suspected acetaminophen overdose without waiting for confirmatory serum levels, as early treatment within 8 hours reduces severe hepatotoxicity to only 2.9% compared to 26.4% when delayed beyond 10 hours. 1, 2, 3

Standard IV Dosing Protocol (Preferred Route)

• Loading dose: 150 mg/kg in 5% dextrose over 15 minutes 2, 3
• Second dose: 50 mg/kg over 4 hours 2, 3
• Third dose: 100 mg/kg over 16 hours (total 21-hour protocol) 2, 3

Alternative Oral Dosing

• Loading dose: 140 mg/kg orally or via nasogastric tube 2, 3
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses (total 72 hours) 2, 3

Critical Timing Considerations

• Within 8 hours: Maximum efficacy with only 2.9% developing severe hepatotoxicity 3, 4
• 8-10 hours: Hepatotoxicity increases to 6.1% 3, 4
• Beyond 10 hours: Severe hepatotoxicity occurs in 26.4% of cases 3, 4
• Beyond 24 hours: NAC still reduces mortality from 80% to 52% in established liver failure—never withhold treatment regardless of delay 1, 3, 4

Special Clinical Scenarios Requiring Immediate NAC

• Established hepatic failure: Administer NAC regardless of time since ingestion, as it reduces mortality from 80% to 52%, cerebral edema from 68% to 40%, and vasopressor requirements from 80% to 48% 1, 3, 4
• Unknown ingestion time with detectable levels: Start NAC immediately 2, 3, 4
• Very high transaminases (>3,500 IU/L): Highly correlated with acetaminophen poisoning even without confirmatory history 3, 4
• Chronic alcohol users: Treat even with levels in "non-toxic" range, as hepatotoxicity occurs with doses as low as 4 g/day 3, 4
• Extended-release formulations: Require prolonged monitoring and potentially extended NAC treatment 3, 4

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Non-Acetaminophen Acute Liver Failure

Initiate NAC in all cases of acute liver failure regardless of etiology, as it significantly improves transplant-free survival (odds ratio 4.81) and overall survival (odds ratio 2.30) in adult patients. 1, 2

Dosing for Non-Acetaminophen ALF

The same IV protocol used for acetaminophen overdose applies, though some centers use extended infusions: 1, 5

• Standard 21-hour protocol as above, OR 1, 2
• Extended protocol: After initial 21-hour course, continue 150 mg/kg in 500 mL dextrose 5% over 24 hours until two consecutive normal INRs are obtained 5

Evidence for Efficacy

• Transplant-free survival: Improves from 27% to 40% overall, and from 30% to 52% in early coma grades (I-II) 1, 6
• Overall survival: Increases from 59% to 76% in adult patients 1
• Post-transplant survival: Improves from 71.4% to 85.7% 1
• Benefit confined to early coma grades: Patients with coma grades I-II benefit significantly, while those with grades III-IV typically require emergency transplantation 1, 6

Mechanism of Benefit

NAC improves hepatic recovery as measured by decreased ALT and bilirubin levels, reflecting reduced hepatocyte necrosis and improved bile excretion, though INR and creatinine show less consistent improvement 7, 6

Important Caveats

• This represents a GRADE 2+ recommendation (lower quality evidence than acetaminophen cases) but with strong clinical agreement 1
• The benefit is most pronounced when started early in the disease course (coma grades I-II) 1, 6
• Patients with advanced encephalopathy (grades III-IV) show minimal benefit and typically require transplantation 6

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Chronic Liver Disease

NAC is NOT indicated for chronic liver disease. The evidence and guidelines focus exclusively on acute liver failure and acute liver injury from acetaminophen overdose. 1, 2

NAC has no established role in chronic hepatitis, cirrhosis, or other chronic liver conditions based on current guideline recommendations. 1, 2

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Safety Profile and Adverse Effects

• Nausea and vomiting: Most common, occurring in 10-14% of patients 1, 8, 6
• Skin rash: Less than 5% of cases 1
• Transient bronchospasm: 1-2% of patients 1
• Generally well tolerated: Serious adverse effects are rare and should not delay treatment 1, 6

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Critical Management Pitfalls to Avoid

• Never delay NAC while awaiting acetaminophen levels if overdose is suspected—start immediately 2, 3, 4
• Low or absent acetaminophen levels do NOT rule out poisoning if ingestion was remote or occurred over several days 3, 4
• The Rumack-Matthew nomogram does NOT apply to presentations >24 hours post-ingestion, repeated supratherapeutic ingestions, or extended-release formulations 3, 4
• Contact liver transplant center early for all acute liver failure cases regardless of etiology 1, 2
• Do not stop NAC prematurely if any transaminase elevation persists, INR remains elevated, or acetaminophen is still detectable 3, 4