Last week we discussed how to evaluate oxidative stress that results from exposure to environmental toxins. Antioxidants protect against the damage from toxins but they don’t remove them. This week we will take a look at markers relating to toxin accumulation and how well the body is equipped to get rid of toxins.
The first marker, 2-methyhippurate, is a marker of exposure to xylene. Xylene is a volatile solvent that is basically hard to avoid. It is found in fuel and exhaust fumes, cigarette smoke, dry cleaning fluid, industrial degreasers, and new cars. New buildings are major sources since xylene outgasses from paint, new carpet, and many building materials.
Xylene can cause neurotoxic symptoms such as brain fog, fatigue, headache, depression, or mood changes. Studies have found that it can adversely affect learning, behavior, and memory in offspring exposed in utero; with chronic exposure it can cause changes to liver, heart, kidneys, lungs, and nervous system.
The compound 2-methylhippurate is formed by the Phase II conjugation of the amino acid glycine to xylene. This is the process by which xylene is detoxified and can be removed from the body via the kidneys. High levels of 2-methylhippurate in the urine indicate current exposure to xylene. When levels are high, glycine supplementation is warranted to help support the detoxification process. It is also important to examine the source and minimize exposure to xylene.
Ammonia is a major endogenous (formed in the body) toxic by-product of our metabolic processes. It is also formed in high amounts by gut bacteria. High levels of ammonia can cause symptoms as simple as headaches, fatigue, and brain fog, to more severe symptoms such as difficulty in walking, rapid breathing, behavioral changes, intellectual impairment, and even seizures. The human body has several mechanisms to remove this toxin. The major form of excretion of ammonia is by the formation of urea from arginine. If there is not enough arginine or the ammonia burden is too high for the urea cycle to keep up, orotate is formed and is a secondary way to remove the toxin. Therefore high levels of orotate in the urine can indicate arginine deficiency and/or a heavy ammonia burden, often from an overgrowth of gut bacteria (dysbiosis). Whenever I see an elevated orotate I look down the page at the dysbiosis section to see if there is evidence of bacterial overgrowth in the small bowel that could contribute to hyperammonemia. If so, work towards balancing the dysbiosis with probiotics and, in some cases, antimicrobials.
Detoxification of toxic substances occurs in either one or two phases. The first phase oxidizes the toxin using cytochrome P450 enzymes. Glucarate is the by-product of the oxidation of glucose in this phase. Glucarate is then used as a substrate for the second phase conjugation reactions that make the lipid-soluble toxins water soluble for efficient excretion by the kidneys. Therefore, glucarate in the urine is a good indicator of overall liver detoxification demand. When glucarate is high it means that Phase I and Phase II liver detoxification pathways are actively working to get rid of toxic compounds. Elevations specifically suggest exposure to pesticides, herbicides, fungicides, petrochemicals, alcohol, and drugs. When high, it is best to work towards avoidance of these exposures, but to also help support liver detoxification with nutrients such as N-acetylcysteine (NAC), glycine, lipoic acid, and milk thistle.
The last three markers under this section give you a good look at your patient’s glutathione status. Glutathione is a potent antioxidant and is crucial for maintaining good health. When α-hydroxybutyrate (AHB) is high it means that the body is actively working to make glutathione (see figure below from the book, Laboratory Evaluations for Integrative and Functional Medicine).
Pyroglutamate is seen as a glutathione-wasting marker. Pyroglutamate is a product of the gamma-glutamyl cycle (GGC) in the renal tubules. This cycle functions to recover amino acids and glutathione. When this pathyway is disrupted, either by toxicant effects, lack of ATP, or genetic polymorphisms of the cycle enzymes, pyroglutamte is released.
Sulfate excretion is a way to check your total body status of sulfur-containing amino acids. Sulfate is used in Phase II liver conjugation reactions to remove toxins. Also, high rates of glutathione synthesis under conditions of acute high oxidatitve stress can cause high urinary sulfate levels. Low urinary sulfate is an indication that total body glutathione is low due to chronic demand. In this case, sulfur-containing amino acids such as NAC and methionine are needed.
When assessing glutathione status in your patient, it is useful to look at all three of these markers to determine the severity of the deficiency. The best intervention to correct any of these abnormalities is to supplement with sulfur-containing compounds such as NAC, methionine, or MSM. Additional nutrients to help support glutathione status are glycine and alpha-lipoic acid.
These six markers on the Organix Profile can provide valuable information on your patient’s toxic burden and detoxification ability.
Stay tuned for the last installment in this series—Intestinal Dysbiosis markers.