Is glutathione (Glutathione) effective for treating Non-Alcoholic Fatty Liver Disease (NAFLD)?

Glutathione for NAFLD: Not Recommended Based on Current Evidence

Glutathione is not recommended for the treatment of NAFLD, as it is not mentioned in any major clinical practice guidelines and lacks sufficient evidence to support its use. Lifestyle modifications—including weight loss, Mediterranean diet, and exercise—remain the cornerstone of NAFLD management, with pharmacotherapy reserved for biopsy-proven NASH with significant fibrosis 1, 2, 3.

Why Glutathione Is Not Guideline-Recommended

All major international guidelines for NAFLD management—including the Korean Association for the Study of the Liver (2021), American Association for the Study of Liver Diseases, European Association for the Study of the Liver, and British Society of Gastroenterology—do not include glutathione as a treatment option 1, 2, 4, 3.

The only evidence for glutathione comes from a single small pilot study of 29 patients that showed modest reductions in ALT levels after 4 months of oral glutathione (300 mg/day). 5 This study had critical limitations:

• Open-label design without placebo control
• Small sample size (only 29 completers)
• No histological endpoints (only used transient elastography)
• Patients were younger and had less severe disease among responders
• The authors themselves concluded that "large-scale clinical trials are needed to verify its efficacy" 5

What Guidelines Actually Recommend

First-Line Treatment: Lifestyle Modifications

All NAFLD patients should undergo lifestyle interventions aimed at 7-10% body weight loss through caloric restriction and increased physical activity. 1, 2, 4, 3

• Weight loss targets: 5-7% weight loss improves steatosis; 7-10% improves inflammation and fibrosis; >10% can achieve NASH resolution and fibrosis regression 1, 4, 3
• Dietary approach: Mediterranean diet is the most recommended pattern, characterized by reduced refined carbohydrates, avoidance of fructose-containing beverages, increased monounsaturated and omega-3 fatty acids, and high fiber intake 1, 4, 3
• Physical activity: 150-300 minutes of moderate-intensity aerobic exercise weekly or 75-150 minutes of vigorous-intensity exercise, plus resistance training 1, 2, 4
• Alcohol restriction: All alcohol consumption should be restricted in NAFLD patients to reduce liver-related events 2

Pharmacotherapy: Only for Biopsy-Proven NASH with Significant Fibrosis

Pharmacologic treatment should be reserved for patients with biopsy-proven NASH and significant fibrosis (stage ≥2), not for simple steatosis. 1, 2, 3

The guideline-supported options include:

• Vitamin E (800 IU/day): For non-diabetic patients with biopsy-proven NASH without cirrhosis 1, 2, 3
• Pioglitazone (30 mg/day): For patients with biopsy-proven NASH with or without diabetes 1, 2, 3
• GLP-1 receptor agonists (liraglutide, semaglutide): Preferred for patients with type 2 diabetes and NASH/fibrosis 1, 2, 3
• Resmetirom: For non-cirrhotic MASH with significant fibrosis if locally approved 3

Clinical Algorithm for NAFLD Management

1. All NAFLD patients: Implement lifestyle modifications (diet, exercise, weight loss) and treat metabolic comorbidities (diabetes, hypertension, dyslipidemia) 1, 2, 4

2. Low-risk patients (FIB-4 <1.3): Continue lifestyle modifications only; annual follow-up with non-invasive fibrosis assessment 1, 2

3. High-risk patients (FIB-4 >2.67 or evidence of significant fibrosis):

   • Consider liver biopsy for definitive diagnosis 1, 3
   • If biopsy confirms NASH with stage ≥2 fibrosis, add pharmacotherapy (vitamin E, pioglitazone, or GLP-1 agonists) 2, 3
   • Follow-up every 6 months with liver function tests and non-invasive fibrosis markers 2

4. Cirrhotic patients: HCC surveillance every 6 months with ultrasound ± AFP; variceal screening 2, 4

Important Caveats

• Rapid weight loss (>1 kg/week) should be avoided as it may worsen portal inflammation and fibrosis in some patients 1, 4
• Statins are safe and should be used to treat dyslipidemia despite liver disease 1, 2
• Metformin is not recommended as a specific treatment for NAFLD as it has no significant effect on liver histology 4
• Bariatric surgery should be considered for appropriate candidates with obesity and NAFLD, as it can achieve NASH resolution in up to 85% of patients 1

Given the lack of guideline support, absence of robust clinical trial data, and availability of evidence-based alternatives, glutathione cannot be recommended for NAFLD treatment at this time. Patients should focus on proven lifestyle interventions, and those with biopsy-confirmed NASH with significant fibrosis should consider guideline-supported pharmacotherapy 1, 2, 3.