DECREASED urinary pyroglutamate levels if:

→ Arsenic exposure

→ Medical conditions

• Autism spectrum disorder

• Hyperglycemia

→ Protein-calorie malnutrition or protein malabsorption

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LOW LEVELS of pyroglutamate may occur if there are nutritional enzyme inhibitions or inherited low-activity enzyme variants present in the synthesis pathway, or if there are low levels of its precursor glutathione available. Pyroglutamate is a breakdown product of glutathione; it can be used on a different biochemical pathway to synthesize glutamate, one of the building blocks for glutathione. The recycling of glutathione increases with increased oxidative stress. Glutathione levels may also be affected by low dietary protein, liver disorders, inflammation, infections, stress hormones and high blood sugar. Arsenic exposure may decrease pyroglutamate and increase hippurate levels. Pyroglutamate and lactate levels may be lower in some individuals with Autism Spectrum Disorder (ASD).

→ If indicated, consider supporting glutathione synthesis with vitamins B6, glycine and N-acetylcysteine. If there is no response to these nutrients, consider the use of oral liposomal glutathione instead.

• GGT, a biomarker on liver function tests, may be high if glutathione levels are low.

→ High levels of methylmalonate and quinolinate, with low levels of cis-aconitate and isocitrate, may also indicate oxidative stress. Consider antioxidant supports.

• Antioxidant supports may include CoQ10, alpha-lipoic acid, vitamins C and E, curcumin, resveratrol, etc. Fresh fruits and vegetables are rich in antioxidant compounds.

→ Arsenic may be found in well water, in factory-farmed poultry, alcoholic beverages and as a pesticide contaminant in conventionally-farmed fruits and vegetables. Arsenic exposure can increase alpha-ketoglutarate and pyruvate, while citrate, succinate, and pyroglutamate levels decrease.

Elevated urinary pyroglutamate (= 5-Oxoproline) levels when:

→ Diet

• Increased casein consumption

→ Inborn errors of metabolism

• These disorders are usually diagnosed in infancy

→ Medications

• Chronic acetaminophen use
  • Beta-hydroxybutyrate and 2-hydroxyphenylacetate may also increase

→ Medical conditions

• Sulfur amino acid, glycine or glutathione insufficiency

• Sickle cell anemia

• High-risk HPV infection may increase

→ Oxidative stress

→ Pyroglutamic acid supplements

→ Toxic metals (except arsenic)

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HIGH LEVELS of pyroglutamate may occur if there are inherited low-activity enzyme variations on its breakdown pathway or if there are higher levels of its downstream products glutamate/glutamine. High levels of downstream products can inhibit the further breakdown
of pyroglutamate. Pyroglutamate is an intermediary in the glutathione recycling pathway that increases as the rate of glutathione recycling and oxidative stress increases. Pyroglutamate levels can increase, and hippurate levels decrease, with exposure to toxic metals (other than arsenic). Pyroglutamate may be used as a supplement to enhance cognitive performance and reduce anxiety. High levels of Firmicutes bacteria (Clostridia, Lactobacillus, etc.) in the gut microbiome may contribute to pyroglutamate levels.

→ Support glutathione synthesis, recycling, and antioxidant functions

• If indicated, consider supporting glutathione synthesis with vitamin B6, glycine, and N-acetylcysteine. Selenium can support the antioxidant enzyme glutathione peroxidase. If there is no response to these nutrients, consider the use of oral liposomal glutathione instead.

→ If indicated, consider an evaluation of the gastrointestinal microbiome.