What are the Symptoms of Glutathione Deficiency? 

Virtually all cells in the body contain an abundance of glutathione, known as the body’s “master antioxidant." Glutathione is involved in essential cellular functions, including protecting the cell from oxidative stress, and is vital to overall health and wellness.  

When glutathione levels are suboptimal or deficient, it affects health throughout the body, resulting in symptoms and increased risk for chronic diseases. Most often, deficiency results from inadequate intake of glutathione and nutrients needed for glutathione production. Low levels of glutathione can also result from increased demand for glutathione. In rare cases, a genetic condition may limit the body’s ability to produce glutathione. 

Today’s article will explore the symptoms and causes of glutathione deficiency and how to increase glutathione levels with supplementation. 

Keep reading to learn more about: 

• What exactly is glutathione, and what does it do? 
• Glutathione deficiency and associated disease risk
• Glutathione synthase deficiency, a rare disease
• Liposomal glutathione supplementation to increase glutathione levels

Let’s dive in!  

What is Glutathione?

Glutathione is a tripeptide composed of three amino acids: cysteine, glycine, and glutamic acid (glutamate). A peptide is a small protein. (Source 1) 

Most cells produce glutathione. Production requires a considerable metabolic input from ATP, methyl groups, and specific nutrients, including B vitamins, selenium, and amino acids. A well-functioning methylation cycle generates the amino acid cysteine, which you can read more about here. (Source 1, 2)

Glutathione serves many purposes, including: 

• Powerful antioxidant that helps maintain redox balance and neutralize free radicals
• Reduces oxidative stress
• Supports liver detoxification of mercury and other toxins
• Cofactor for antioxidant enzymes
• Regenerates vitamin C and vitamin E
• Immune system regulation (Source 1, 2, 3)

Because glutathione is an antioxidant, it exists in two forms, the reduced form, abbreviated GSH, and the oxidized form, abbreviated GSSG. Healthy cells have a higher amount of GSH, the active form that neutralizes free radicals turning it into GSSG. Then, GSSG regenerates into GSH. (Source 2)

Glutathione Deficiency and Disease Risk

Glutathione is easily measured in red blood cells (erythrocytes). However, there is a wide variation in glutathione levels among individuals, and there aren’t established reference ranges. (Source 1)

Another marker of glutathione levels is gamma-glutamyl transferase (GGT), the rate-limiting enzyme in glutathione synthesis. When cells need more glutathione, they up-regulate GGT. GGT levels correlate with disease risk. (Source 2)

It’s common to have single nucleotide polymorphisms (SNPs) in the genes that code for GGT and the enzyme glutathione-s-transferase (GST). These genetic changes can affect levels of glutathione, along with dietary glutathione and nutrients required for glutathione metabolism. (Source 1)

Suboptimal and deficient glutathione levels are associated with aging and an increased risk for chronic diseases, including: 

• Mitochondrial dysfunction 
• Neurodegenerative disease, including Alzheimer’s and Parkinson’s disease
• Cancer
• Chronic liver disease
• Metabolic disease, including diabetes and hypertension
• Cardiovascular disease
• Pulmonary 
• Infertility
• Autoimmune diseases, including lupus and multiple sclerosis
• Mental health disorders
• Cystic fibrosis (Source 1, 2) 

A viral illness, including SARS-CoV-2, the virus that causes Covid-19, can also cause glutathione deficiency. (Source 4, 5)

Initial symptoms of low glutathione may be non-specific and include fatigue, brain fog, sleep disturbance, and low immunity. Over time, oxidative stress, inflammation, and disease risk increase. 

Rare Diseases - Glutathione Synthase Deficiency

Glutathione synthase deficiency, or proglutamicaciduria, is the most severe form of glutathione deficiency. Glutathione synthase (GSS) deficiency is an inherited autosomal recessive disease caused by genetic mutations in the GSS gene that codes for the GSS enzyme.  It is different and more severe than the SNPs in other glutathione-related genes discussed above. (Source 6)

Glutathione synthase deficiency is a rare disorder, affecting less than one in 100,000 people. Symptoms appear in infants within four weeks of birth, and diagnosis is based on 5-oxoprolinuria, increased levels of 5-oxoproline in the urine. (Source 7, 8)

The disease can be mild, moderate, or severe, and symptoms include:

• Hemolytic anemia (a rare anemia caused by the breakdown of red blood cells)
• Metabolic acidosis (acid buildup)
• Recurrent bacterial infections
• Seizures
• Intellectual disability 
• Ataxia (loss of coordination) (Source 6)

Supplementation to Raise Glutathione Concentrations

Dietary strategies support the prevention of glutathione depletion. Certain foods and nutrients such as protein, whey protein, B vitamins, vitamin C, selenium, and brassica vegetables support healthy glutathione levels. (Source 1)

In cases where glutathione demands are high, or there are genetics inhibit glutathione production, glutathione supplementation is often very effective. 

Taking glutathione itself is problematic because it is a peptide, and peptides break down in the digestive system. One way around this is to take N-acetyl cysteine (NAC) as a glutathione precursor. However, relying on NAC doesn’t take away the need for energy, methylation, and other nutrients required for glutathione production. 

(By the way, you can read more about NAC and other options for glutathione supplementation, along with safety guidelines and best practices in What to Avoid When Taking Glutathione).

The most effective way to increase glutathione levels is with a liposomal product. A phospholipid membrane encompasses glutathione to mimic your own cell membranes. Liposomal glutathione bypasses digestive breakdown and allows for increased absorption and bioavailability. (Source 1, 9)

In a 2017 clinical trial, participants were given oral liposomal glutathione daily (500 mg or 1000 mg) for one month. Several glutathione blood markers were routinely measured. After only one week, glutathione levels increased by up to 40%! Researchers also observed decreased markers of oxidative stress. (Source 9)

Liposomal glutathione in doses up to 1000 mg per day is generally safe, and side effects are rare, although we don’t recommend taking glutathione during pregnancy or breastfeeding. Always discuss supplements with your healthcare provider, especially if you take any medication or have a medical condition. 

Core Med Science Liposomal Glutathione Capsules provide 500 mg per dose in a popular sunflower and palm phospholipid. Our physician-formulated product is free of allergens, including soy, dairy, gluten, eggs, alcohol, nuts, and GMOs. We manufacture our products in the United States with China-free ingredients in an FDA-registered, cGMP third-party certified facility. In other words, we make the highest quality product using best practices. 

Suboptimal or deficient glutathione levels contribute to symptoms and disease risk. Liposomal glutathione supplements offer a convenient way to increase glutathione levels safely and effectively. With more of this “master antioxidant” on board, you will support health and wellness now and into the future. 

References:

1. Minich, D. M., & Brown, B. I. (2019). A Review of Dietary (Phyto)Nutrients for Glutathione Support. Nutrients, 11(9), 2073. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770193/ 
2. Pizzorno J. (2014). Glutathione!. Integrative medicine (Encinitas, Calif.), 13(1), 8–12. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684116/ 
3. Wu, G., Fang, Y. Z., Yang, S., Lupton, J. R., & Turner, N. D. (2004). Glutathione metabolism and its implications for health. The Journal of nutrition, 134(3), 489–492. Full text: https://www.sciencedirect.com/science/article/pii/S0022316623026639?via=ihub 
4. Labarrere, C. A., & Kassab, G. S. (2022). Glutathione deficiency in the pathogenesis of SARS-CoV-2 infection and its effects upon the host immune response in severe COVID-19 disease. Frontiers in microbiology, 13, 979719. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9582773/ 
5. Kumar, P., Osahon, O., Vides, D. B., Hanania, N., Minard, C. G., & Sekhar, R. V. (2021). Severe Glutathione Deficiency, Oxidative Stress and Oxidant Damage in Adults Hospitalized with COVID-19: Implications for GlyNAC (Glycine and N-Acetylcysteine) Supplementation. Antioxidants (Basel, Switzerland), 11(1), 50. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773164/ 
6. NIH Genetic and Rare Diseases Information Center. Glutathione synthase deficiency. Accessed August 10. 2023 at: https://rarediseases.info.nih.gov/diseases/10047/glutathione-synthetase-deficiency 
7. Kaur, P., Chaudhry, C., Panigrahi, I., Srivastava, P., & Kaur, A. (2022). Gas Chromatography Mass Spectrometry Aided Diagnosis of Glutathione Synthetase Deficiency. Laboratory medicine, 53(3), e59–e61. Abstract: https://pubmed.ncbi.nlm.nih.gov/34791353/ 
8. Njålsson R. (2005). Glutathione synthetase deficiency. Cellular and molecular life sciences : CMLS, 62(17), 1938–1945. Abstract: https://pubmed.ncbi.nlm.nih.gov/15990954/ 
9. Sinha, R., Sinha, I., Calcagnotto, A., Trushin, N., Haley, J. S., Schell, T. D., & Richie, J. P., Jr (2018). Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. European journal of clinical nutrition, 72(1), 105–111. Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389332/