What is the recommended dose and indication for glutathione supplementation in patients, particularly those with a history of liver or kidney disease, or those undergoing chemotherapy?

Glutathione Dose and Indication

Glutathione supplementation has extremely limited clinical indications, with parenteral glutamine (not glutathione) being the only form with established evidence at 0.35-0.6 g/kg/day for specific oncology patients, while oral glutathione has negligible systemic bioavailability and no proven clinical benefit. 1, 2

Critical Distinction: Glutamine vs. Glutathione

The evidence base primarily addresses glutamine (a precursor amino acid), not glutathione itself. These are distinct compounds with different clinical applications. 1

Established Clinical Indications

Parenteral Glutamine (NOT Glutathione)

Hematopoietic Stem Cell Transplantation (HSCT):

• Recommended dose: 0.6 g/kg/day of parenteral glutamine for patients undergoing HSCT 3, 1
• May minimize intestinal mucosal atrophy, reduce chemotherapy/radiotherapy-induced liver damage, and potentially improve nitrogen balance and immune function 3
• Grade B recommendation from ESPEN guidelines 3

Surgical Patients on Exclusive Parenteral Nutrition:

• Consider parenteral glutamine at 0.35-0.5 g/kg/day for surgical patients who cannot be fed enterally and require exclusive PN 3, 1
• Evidence is controversial, with recent large trials showing no significant benefit 3
• Recommendation downgraded due to conflicting evidence 3

Oral Glutathione: No Established Indications

Oral glutathione has negligible systemic bioavailability due to hydrolysis by intestinal and hepatic gamma-glutamyltransferase, making it ineffective for increasing circulating glutathione levels. 2 A study in healthy volunteers showed that even a 3-gram oral dose failed to increase plasma glutathione concentrations. 2

Contraindications and Critical Safety Warnings

Absolute Contraindications for High-Dose Parenteral Glutamine:

• Critically ill patients with multi-organ failure - associated with increased mortality 1
• Acute kidney injury or chronic kidney disease with kidney failure 1

Specific Patient Populations

Patients with Liver Disease

• One small case series suggested potential benefit of IV glutamine (as dipeptide) with vitamin E for hepatic veno-occlusive disease following high-dose chemotherapy, but this is anecdotal evidence only 4
• No established dosing recommendations exist 4

Patients with Kidney Disease

• High-dose parenteral glutamine is contraindicated in patients with acute kidney injury or chronic kidney disease with kidney failure 1
• One older study suggested parenteral reduced glutathione (1,200 mg) improved anemia parameters in hemodialysis patients, but this lacks contemporary validation 5

Patients Undergoing Chemotherapy

• ESPEN states there are insufficient consistent clinical data to recommend glutamine supplementation during conventional cytotoxic or targeted therapy 3, 1, 6
• MASCC/ISOO recommends against intravenous glutamine for preventing oral mucositis in patients receiving high-dose chemotherapy 6
• Concerns exist that glutamine may stabilize cancer cells and potentially promote tumor growth 6

Common Pitfalls and Caveats

Confusion Between Glutamine and Glutathione:

• Most clinical evidence pertains to glutamine supplementation, not glutathione 1
• These are pharmacologically distinct compounds with different mechanisms and bioavailability 2

Route of Administration Matters:

• Oral glutathione is essentially ineffective due to poor absorption 2
• Only parenteral glutamine has demonstrated clinical benefits in select populations 1

Avoid in Critical Illness:

• Do not use high-dose parenteral glutamine in critically ill patients with organ dysfunction - this increases mortality risk 1

Lack of Evidence for Common Uses:

• No data support glutathione for cystic fibrosis 1
• Insufficient evidence for skin lightening despite popular use in Asia 7
• No proven benefit for routine chemotherapy support 3, 6

Algorithm for Clinical Decision-Making

1. Is the patient undergoing HSCT?

   • Yes → Consider parenteral glutamine 0.6 g/kg/day 3, 1
   • No → Proceed to step 2

2. Is the patient a surgical patient requiring exclusive PN who cannot be fed enterally?

   • Yes → May consider parenteral glutamine 0.35-0.5 g/kg/day (evidence mixed) 3, 1
   • No → Proceed to step 3

3. Does the patient have critical illness with multi-organ failure OR acute/chronic kidney failure?

   • Yes → Do not use glutamine 1
   • No → Proceed to step 4

4. Is the patient undergoing conventional chemotherapy?

   • Yes → Do not use glutamine - insufficient evidence and potential tumor promotion concerns 3, 6
   • No → No established indication for glutamine or glutathione supplementation

For oral glutathione specifically: There is no established clinical indication due to negligible bioavailability. 2