What is the evidence for using glutathione (GSH) in treating liver injury?

Glutathione in Liver Injury: Evidence and Clinical Application

Direct Answer

Glutathione (GSH) supplementation, specifically as N-acetylcysteine (NAC), shows benefit in severe alcoholic hepatitis when combined with corticosteroids, improving 1-month survival and reducing hepatorenal syndrome and infections, though it is not effective as monotherapy. 1

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Evidence for Glutathione in Specific Liver Injury Contexts

Alcoholic Hepatitis (Strongest Clinical Evidence)

Combination Therapy (NAC + Corticosteroids):

• NAC combined with prednisolone 40 mg daily improved 1-month survival (8% mortality vs 24% with prednisolone alone) in severe alcoholic hepatitis 1
• The combination reduced infection rates (19% vs 42% at 6 months) and hepatorenal syndrome incidence (12% vs 25%) 1
• Critical limitation: No significant survival difference at 6 months (the primary endpoint), suggesting short-term benefit only 1

Monotherapy (NAC Alone):

• NAC monotherapy showed no significant effect compared to placebo 1, 2
• NAC alone was inferior to corticosteroids for short-term survival 1, 2
• Should not be used as standalone treatment 2

Mechanism in Alcoholic Liver Disease:

• Ethanol metabolism depletes mitochondrial glutathione and increases oxidative stress 1
• Acetaldehyde impairs glutathione function, causing oxidative stress and apoptosis through mitochondrial damage 1
• NAC replenishes hepatocyte glutathione stores, functioning as an antioxidant 1

Ischemia-Reperfusion Injury (Experimental Evidence)

Intravenous GSH Administration:

• Continuous IV GSH (200 μmol/h/kg) during reperfusion reduced serum ALT/AST by 50-60% after 60-120 minutes of warm ischemia in rats 3
• Improved survival after 2 hours of ischemia (6 of 9 vs 3 of 9 rats) and restored sinusoidal blood flow 3
• GSH infusion increased plasma GSH levels 10-40 fold but did not affect intracellular GSH content, suggesting extracellular antioxidant action 3

Endotoxin-Enhanced Injury:

• GSH infusion (22 μmol/kg/hr) attenuated reperfusion injury by 55% in GSH-depleted animals with endotoxin challenge 4
• GSH rapidly reacts with reactive oxygen species (H₂O₂ and HOCl) generated by Kupffer cells 4

Clinical translation caveat: These are animal studies; human liver surgery applications remain investigational 3

Cholestatic Liver Injury

Limited Efficacy:

• In 7-day bile duct obstruction models, antioxidants (vitamin E, trolox) prevented lipid peroxidation and GSH oxidation but did not improve liver enzyme activities, bilirubin, or histology 5
• Suggests bile salt detergent action, not oxidative stress, is the primary mechanism of injury in cholestasis 5

Pediatric Considerations

Cysteine Supplementation (GSH Precursor):

• High-dose cysteine (81 mg/kg/day) in preterm infants was safe but did not increase plasma cystine or GSH concentrations compared to 45 mg/kg/day 1
• NAC (20-50 mg/kg/day) added to parenteral nutrition decreased liver enzyme elevations and tended to increase blood GSH in children requiring home parenteral nutrition 1
• No firm recommendations exist for pediatric GSH/NAC supplementation due to limited clinical efficacy data 1

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Clinical Algorithm for GSH/NAC Use in Liver Injury

Severe Alcoholic Hepatitis (Discriminant Function ≥32 or MELD ≥21)

1. First-line: Prednisolone 40 mg daily for 28 days 2
2. Consider adding: NAC infusion during first 5 days of corticosteroid therapy 1
   • Assess response at day 7 using Lille model 2
   • Monitor for infections and hepatorenal syndrome 1
3. If corticosteroids contraindicated: Use pentoxifylline (not NAC monotherapy) 2
4. Essential concurrent measure: Alcohol abstinence (most important intervention) 2

Liver Resection/Transplantation Surgery

• Investigational only: IV GSH during reperfusion shows promise in animal models but lacks human trial validation 3
• Consider in research protocols for prolonged warm ischemia scenarios 3

Other Liver Injuries

• Not recommended: Insufficient evidence for GSH/NAC in cholestatic injury 5, drug-induced liver injury (except acetaminophen overdose), or chronic liver disease 1

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Important Caveats and Pitfalls

Avoid These Common Errors:

• Do not use NAC as monotherapy for alcoholic hepatitis - it is ineffective alone 1, 2
• Do not expect long-term survival benefit - NAC+corticosteroids improve only 1-month, not 6-month survival 1
• Do not assume intracellular GSH replenishment - IV GSH acts primarily as extracellular antioxidant 3
• Do not use in cholestatic injury expecting benefit - oxidative stress is not the primary mechanism 5

Optimal Duration Unclear:

• Most evidence supports 5-day NAC infusion with corticosteroids 1
• Longer duration benefits require additional study 1, 2

S-Adenosyl-L-Methionine (SAMe) Alternative:

• SAMe is a GSH precursor showing no significant effects on mortality, liver-related mortality, or complications in meta-analyses 1
• Not recommended for alcoholic liver disease 1

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Strength of Evidence Summary

High-quality evidence (Guidelines):

• NAC+corticosteroids for severe alcoholic hepatitis: moderate quality, short-term benefit only 1, 2

Experimental evidence only:

• IV GSH for ischemia-reperfusion injury: promising animal data, no human trials 3, 4

Insufficient evidence:

• GSH/NAC for cholestatic injury 5, chronic alcoholic liver disease 1, pediatric applications 1