Theory of Organic Acid Test Panel OAT Test Resource

Theory of Organic Acid Test Panel OAT test Resource:

Theory of Organic Acid Test Panel (OAT)

Yeast/Fungal Metabolites

Elevated yeast/fungal metabolites suggest a yeast or fungal overgrowth in the gastrointestial tract [GP].

Citramalic (Methylmalic) Acid

• A byproduct of Saccharomyces yeast species, as well as Propionibacterium acnes. • Suggests dysbiosis. • An analog of the Krebs cycle compound malic acid; may interfere with the production of malic acid in the Krebs cycle.

5-hydroxymethyl-2-furoic Acid

• A byproduct of the fungus Aspergillus and probably other species of fungi and yeast as well. • Suggests dysbiosis.

3-oxoglutaric Acid

• Slightly elevated values are found in autism and other disorders. • An analog of the Krebs cycle compound 2-oxoglutaric (alpha-ketoglutaric) acid. • Elevated 3-oxoglutaric acid may correlate with low 2-oxoglutaric acid, possibly indicating an interference with 3-oxoglutaric acid in the Krebs cycle. • Presumably formed from the amino acids lysine and tryptophan.

Furan-2,5-dicarboxylic Acid

• A byproduct of the fungus Aspergillus and probably other species of fungi and yeast as well. • Suggests dysbiosis.

Furancarbonylglycine

• A conjugate of furancarboxylic acid and the amino acid glycine.

Tartaric Acid (3-Hydroxymalic Acid or 2,3-Hydroxy-succinic acid)

• An analog of the Krebs cycle intermediate malic acid that inhibits the Krebs cycle enzyme fumarase that converts fumaric acid to malic acid [Shaw2008]. • A toxic fermentation product of Saccharomyces yeast species. • High levels are associated with autism and fibromyalgia [Shaw2008]. • Damages muscles and kidney [Robertson1968]. • Suggests dysbiosis. • Treatment with antifungal drugs can significantly lower level in urine (also consider naturopathic treatments). • Also found in grapes, cream of tartar, and as a food additive. In low doses is Generally Recognized As Safe (GRAS) by the FDA, but a 12 g dose may be fatal [Shaw2008].

Arabinose

• A metabolite produced in the liver from arabitol (also called arabinitol), which is produced by various yeast species such as Candida albicans, Candida tropicalis, Candida parapsilosis, etc. • Arabinose is a 5-carbon aldose sugar that is not made in significant quantity by human metabolism, but can be found in apples, grapes, and pears and can serve as a marker for yeast overgrowth [Kiehn1979] [Wong1990] [Larsson1994] [Roboz1992]. • Arabinose may be a particular problem for patients with a defect in their pentose metabolism; this defect can be tested for [Shaw2008].

Carboxycitric Acid

• An analog of the Krebs cycle compound citric acid; may interfere with the metabolism of citric acid in the Krebs cycle.

Bacterial Metabolites

4-hydroxybenzoic Acid and 4-hydroxyhippuric Acid

• May be due to bacterial overgrowth, or may be due to fruits such as blueberries [GP2010]. • Metabolite of parabens, which are additives in food, cosmetics and toiletries. Parabens have estrogenic activity and may be associated with breast cancer [GP2010, Routledge1998]. Parabens may uncouple oxidative phosphorylation leading to mitochondrial dysfunction [GP2010].

2-hydroxyphenylacetic Acid

• Produced by overgrowth of several species of bacteria in the GI tract by metabolizing the amino acid tyrosine. • Very elevated values are present in celiac disease and enteritis. • Elevated levels are also seen in PKU [GP2010].

4-hydroxyphenylacetic Acid • Produced by overgrowth of bacteria in the GI tract by metabolizing the amino acid tyrosine. • Treatment with the antibiotic neomycin can significantly lower level in urine (also consider naturopathic treatments). • Very elevated values are present in celiac disease, enteritis, and intestinal resection.

3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA)

• Produced by Clostridia species, including but not limited to Clostridium difficile [GP], Clostridium sporogenes, Clostridium botulinum, Clostridium calortolerans, Clostridium mangenoyi, Clostridium ghoni, Clostridium bifermentans, Clostridium sordelli [GP2010]. • Associated with behavioral, gastrointestinal, and neuropsychiatric effects (especially when level exceeds 500 mmol/mol creatinine) [GP2010]. • Elevated values are common in autism, depression, schizophrenia, seizures, and chronic fatigue syndrome colitis tic disorders muscle weakness or paralysis [Shaw2008] [GP]. • Treatment with the antibiotics vancomycin or metronidazole (Flagyl) can significantly lower the HPHPA level in urine [GP]. Addition of probiotics such as Lactobacillus acidophilus GG, Lactobacillus rhamnosus, and Saccharomyces boulardii is also recommended [Shaw2008, GP2010] (also consider naturopathic treatments).

According to [Shaw2008, page 14], Clostridia spp. deaminate the amino acid phenylalanine (which is the precursor of the important neurotransmitters dopamine, norepinephrine, and epinephrine) to form 3-phenyl-propionic acid, which is then hydroxylated in the meta position by Clostridia spp. to form 3-(3-hydroxyphenyl)-propionic acid [Elsden1976] [Bhala1993]. This intermediate is then subjected to human beta-oxidation to form 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), which is detectable in the urine.

An alternative pathway for formation of HPHPA from phenylalanine is via microbial meta- hydroxylation of phenylalanine to form 3-hydroxyphenylalanine (an analog of tyrosine, which is 4-hydroxyphenylalanine), which is then deaminated to form 3-(3-hydroxyphenyl)-propionic acid, which then proceeds to HPHPA as above [Shaw2008].

Vanillylmandelic Acid (VMA) Analog

• Metabolite of the amino acid tyrosine produced by Clostridia species. • Clostridial overgrowth may interfere with the body's production and metabolism of the important neurotransmitters dopamine and norepinephrine, which are made from tyrosine. Elevated values are common in autism, depression, schizophrenia, seizures, and chronic fatigue syndrome. • Treatment with the antibiotics vancomycin or metronidazole (Flagyl) can significantly lower level in urine (also consider naturopathic treatments).

Oxalate Related

Glyceric Acid • Elevated values may be due to microbial sources such as yeast (Aspergillus, Penicillium, probably Candida) [GP2010], or due to dietary sources containing glycerol (glycerin). • Associated with autism, vulvar pain, fibromyalgia [GP2010]. • Elevated values may also indicate an inborn error of metabolism (see oxalic acid).

Glycolic Acid

• Elevated glycolic acid without elevated oxalic acid is most likely a result of GI yeast overgrowth (Aspergillus, Penicillium, probably Candida) [GP2010]. or due to dietary sources containing glycerol (glycerin). • Associated with autism, vulvar pain, fibromyalgia [GP2010]. • Elevated values may also indicate an inborn error of metabolism (see oxalaic acid).

Oxalic Acid (Oxalate)

• Elevated values may be due to many causes, including: o Primary hyperoxaluria (genetic), o Diabetes mellitus, o Cirrhosis, o Vitamin B-6 deficiency, o Sarcoidosis, o Steatorrhea due to pancreatic insufficiency, o Celiac disease, o Bacteria overgrowth, o Aspergillus, penicillium, and possibly Candida overgrowth [GP], o Ileal resection, o Biliary tract disease, o Small bowel disease, o Ethylene glycol poisoning, o Increased intake of foods high in oxalate including rhubarb, spinach, raspberries, beets, chocolate, wheat bran, tea, cashews, pecans, almonds, and peanuts [GP], o Increased vitamin C intake, o Poor fat absorption, perhaps due to excessive fat intake or inadequate bile flow, resulting in increased binding of calcium to fatty acids in the gut and concomitant reduction in binding of calcium to oxalate [GP].

If glycolic acid is also elevated, it may indicate the genetic disease hyperoxaluria type I.

If glyceric acid is also elevated, it may indicate the genetic disease hyperoxaluria type II.

Elevated oxalic acid levels have been associated with:

o Autism [GP], o Vulvar pain [GP], o Fibromyalgia and muscle pain [GP], o Anemia unresponsive to treatment [GP], o Skin ulcers [GP], o Heart abnormalities [GP], o Decreased osteoblast activity and increased bone resorption [GP], o Kidney stone formation [GP], o Painful oxalic acid deposition in various tissues, including: joints, eyes, muscles, blood vessels, brain, and heart [GP].

Glycolysis Intermediates

Lactic Acid (Lactate)

• Elevated values may indicate infection, recent vigorous exercise, B vitamin deficiency, poor perfusion, or intestinal bacterial overgrowth. • Extremely elevated values indicate genetic diseases such as pyruvate dehydrogenase deficiency, glycogen storage diseases, and disorders of fructose metabolism, severe trauma, or life-threatening infections.

Pyruvic Acid (Pyruvate)

2-hydroxybutyric Acid

• Slightly elevated values may indicate infection, recent vigorous exercise, B vitamin deficiency, or poor perfusion. • Significantly elevated values may indicate genetic diseases such as pyruvate dehydrogenase deficiency, glycogen storage disease, or disorders of fructose metabolism, or be the result of severe trauma or life-threatening infections.

Krebs Cycle Intermediates

Succinic Acid (Succinate)

• A Krebs cycle compound that may be elevated due to a deficiency in riboflavin or coenzyme Q10, bacterial conversion of glutamine to succinic acid in the gastrointestinal tract, or inborn error of metabolism.

Fumaric Acid (Fumarate)

• A Krebs cycle compound produced by the dehydrogenation of succinic acid by the enzyme succinic acid dehydrogenase. 2-oxoglutaric Acid (Alpha-ketoglutaric Acid, AKG)

• A Krebs cycle compound. • 2-oxoglutaric acid may be derived from the conversion of glutamic acid to 2-oxoglutaric by deamination or transamination. • Very low values may sometimes be encountered in chronic fatigue syndrome. • Anecdotal reports indicate that autistic symptoms sometimes improve with AKG supplementation in response to low values of this metabolite.

Aconitic Acid

• A Krebs cycle compound. • May be elevated as a result of a deficiency in glutathione since the enzyme aconitase requires reduced glutathione to metabolize aconitic to citric acid.

Citric Acid (Citrate)

• A Krebs cycle compound. • Do not confuse citric acid with ascorbic acid (vitamin C). They are both found in citrus fruit, but are not the same compound. • Elevated citric acid may be due to dietary intake [GP]. • Elevated citric acid may be due to intestinal yeast producing citric acid [GP]. • Elevated citric acid may be due to intestinal yeast metabolites inhibiting the human Krebs Cycle [GP]. • Elevated citric acid may be due to depletion of glutathione, which is a required cofactor for the enzyme aconitase (which metabolizes aconic and citric acids) [GP].

Amino Acid Metabolites

2-hydroxyisovaleric Acid

• Slight elevations may be due to deficiencies of the vitamins thiamine or lipoic acid. • Elevated values are also associated with the genetic diseases maple syrup urine disease or pyruvate dehydrogenase deficiency.

2-oxoisovaleric Acid

3-methyl-2-oxovaleric Acid

2-oxoisocaproic Acid

2-oxo-4-methiobutyric Acid

• Elevated in the genetic disease methioninemia.

Phenyllactic Acid

• Elevated in the genetic diseases PKU and tyrosinemia. • Slight elevations may result from increased dietary intake of phenylalanine.

Phenylpyruvic Acid

• Elevated in the genetic diseases PKU and tyrosinemia. • Slight elevations may result from increased dietary intake of phenylalanine.

Mandelic Acid

• Elevated in the genetic diseases PKU and tyrosinemia. • Slight elevations may result from increased dietary intake of phenylalanine.

Homogentisic Acid

• Elevated in the genetic disease homogentisic aciduria (alkaptonuria).

4-hydroxyphenyllactic Acid

• Significantly elevated in the genetic diseases tyrosinemia and in phenylketonuria. • Slight increase may be due to increased tyrosine intake.

3-indoleacetic Acid

• A metabolite of the amino acid tryptophan. • Elevated values may be found in Hartnup disease, a genetic neurological disease due to defective renal and intestinal transport of certain neutral amino acids. • Elevations of lesser magnitude appear to be of bacterial origin. Neurotransmitter Metabolites

Homovanillic Acid (HVA, Homovanillate)

• Metabolite of the catecholamine neurotransmitter dopamine, and can serve as a surrogate marker of dopamine levels in circulation [GP]. • May be elevated due to: o Stress or sympathetic nervous stimulation (elevated adrenal output)[PA-OAT] o Deficiency of Cu or Vitamin C [PA-OAT] o Administration of catecholamine precursors such as L-DOPA, tyrosine or phenylalanine [PA-OAT] o Neuroblastoma, ganglioblastoma, or pheochromacytoma tumors (consider 24- hour VMA and HVA test if OAT results exceed twice normal limit) [GP] o MAO inhibitors [PA-OAT] o Dopaminergic medications (L-Dopa, Levodopa, Sinemet, Methyldopa) [PA- OAT] o Dopamine containing foods/supplements (macuna, bananas) [PA-OAT] o SNRI (Welbutrin) [PA-OAT] o Tricyclic antidepressants [PA-OAT] o Amphetamines [PA-OAT] o Appetite suppressants [PA-OAT] o Caffeine [PA-OAT] o Quercetin [PA-OAT] • Low levels of HVA can be due to: o Low levels of dopamine secondary to deficiencies of BH4, Fe, or tyrosine [PA- OAT] o Low adrenal function [PA-OAT] o Poor conversion of dopamine to HVA secondary to deficiencies of SAM, Mg, FADH2, or NADH [PA-OAT] • If HVA levels are significantly higher than VMA levels, the patient may be having trouble converting dopamine to norepinephrine due to a copper or vitamin C deficiency, or trouble converting norepinephrine to VMA due to low COMT (Catecholamine O- Methyl Transferease) or MAO (Mono-Amine Oxidase) enzyme activity [PA-OAT] • Signs of low dopamine levels include: o Sleepiness [PA-OAT] o Fatigue [PA-OAT] o Low motivation [PA-OAT] o Low mood [PA-OAT] o Depression [PA-OAT] o Addiction issues [PA-OAT] o Cravings [PA-OAT] o Pleasure-seeking (to boost level) [PA-OAT] • Signs of elevated dopamine levels include: o Loss of memory [PA-OAT] o Insomnia [PA-OAT] o Agitation [PA-OAT] o Hyperactivity [PA-OAT] o Mania [PA-OAT] o Hyper-focus [PA-OAT] o High stress [PA-OAT] o Anxiety [PA-OAT] o Addictions [PA-OAT] o Cravings [PA-OAT] o Pleasure-seeking (to maintain high)[PA-OAT]

Vanillylmandelic Acid (VMA, Vanilmandelate)

• Metabolite of catecholamine neurotransmitters norepinephrine & epinephrine, and can serve as a surrogate marker of norepinephrine/epinephrine levels in circulation [GP]. • May be elevated due to: o Physical or psychological stress or sympathetic nervous stimulation (elevated adrenal output) [PA-OAT]) o Administration of catecholamine precursors such as L-DOPA, tyrosine or phenylalanine. o Drugs (see HVA) o Neuroblastoma, ganglioblastoma, and pheochromacytoma tumors (consider 24- hour VMA and HVA test if OAT results exceed twice normal limit) [GP]. • Low levels of VMA can be due to: o Low levels of dopamine precursor. o Trouble converting norepinephrine to VMA secondary to low COMT (Catecholamine O-Methyl Transferease) enzyme activity [PA-OAT]. o Trouble converting norepinephrine to VMA secondary to low MAO (Mono- Amine Oxidase) enzyme activity, including MAO-Inhibitor drugs [PA-OAT] • Signs of low norepinephrine/epinephrine levels include: o Addictions [PA-OAT] o Cravings [PA-OAT] o Fatigue [PA-OAT] o Low blood pressure [PA-OAT] o Low muscle tone [PA-OAT] o Intolerance to exercise [PA-OAT] o Depression [PA-OAT] o Loss of alertness [PA-OAT] • Signs of elevated norepinephrine/epinephrine levels include: o Feeling stressed [PA-OAT] o Aggression [PA-OAT] o Violence [PA-OAT] o Impatience [PA-OAT] o Anxiety [PA-OAT] o Panic [PA-OAT] o Worry [PA-OAT] o Insomnia [PA-OAT] o Paranoia [PA-OAT] o Increased tingling/burning [PA-OAT] o Loss of memory [PA-OAT] o Pain sensitivity [PA-OAT] o High blood pressure [PA-OAT] o Heart palpitations [PA-OAT]

5-hydroxyindoleacetic Acid (5-hydroxyindoleacetate, 5-HIAA )

• A metabolite of tryptophan [?] that can serve as a surrogate marker of serotonin levels in circulation [GP]. • May be elevated due to: o Ingestion of tryptophan or 5-HTP supplements. o 5-HIAA may be elevated due to increased turnover of serotonin secondary to SSRI use. o Carcinoid syndrome [GP] o Bronchial adenoma of carcinoid type [GP] o Carcinoid tumor (very high) [PA-OAT] o Celiac sprue [GP] o Tropical sprue [GP] o Whipple's disease [GP] o Oat cell carcinoma of the bronchus [GP] o Intake of foods high in hydroxyindoles such as walnuts, avocados, eggplants, pineapples, plums, tomatoes [GP], butternuts, black walnuts, plantain, pecans, [PA-OAT], pineapple, bananas [PA-OAT] [GP] • Low levels of serotonin can be due to: o Decreased intake of tryptophan o Depressive illnesses [GP] o Small intestine resection [GP] o Mastocytosis [GP] o PKU [GP] o Hartnup disease [GP] o Decreased availability of tryptophan (caused by elevated estrogen [?], cortisol, or inflammation. These push tryptophan down the kynuerenine pathway rather than the serotonin pathway) [PA-OAT] o Low levels of estrogen [?], because the estrogen receptor beta (ERb) induces tryptophan hydroxylase, which is the rate-limiting step for making 5-HTP (a precursor of serotonin). • Only 1% of the serotonin in circulation is made in the brain; 80% is made in the gut [PA- OAT]. • Serotonin promotes gut motility and activates smooth muscle [PA-OAT]. • Serotonin is found in a number of areas of the brain, including: o Dorsal raphe nucleus (DRN) in the brain stem, which is also rich in estrogen receptors [PA-OAT] o Forebrain (cerebrum, thalamus, hypothalamus, pituitary, limbic) [PA-OAT]

6-Hydroxymelatonin Sulfate (6-OHMS) • A metabolite of melatonin that can serve as a surrogate marker of melatonin levels in circulation [PA-OAT].

Pyrimidines

Uracil

• A pyrimidine (DNA building block) that is elevated in the genetic disease dihydropyrimidine dehydrogenase deficiency. In this genetic disease, the pyrimidine thymine is also elevated. • Elevations of uracil and orotic acid are found in the genetic diseases OTC deficiency and citrullinemia.

Thymine

• A pyrimidine (DNA building block) that is elevated in the genetic disease dihydropyrimidine dehydrogenase deficiency. In this genetic disease, the pyrimidine uracil is also elevated.

Fatty Acid Metabolites

3-hydroxybutyric Acid

• Ketone derived from excessive fatty acid oxidation. • May be elevated due to fasting or starvation, diabetes mellitus, use of high fat (ketogenic) diets, and in several genetic diseases.

Acetoacetic Acid

• Ketone derived from excessive fatty acid oxidation. • May be elevated due to fasting or starvation, diabetes mellitus, use of high fat (ketogenic) diets, nausea, influenza, or to any of several genetic diseases [GP].

Ethylmalonic Acid

• Fatty acid metabolites. • Value may be elevated in ketosis, fasting, deficiency of the fat-transporting molecule carnitine, genetic deficiencies of fatty acid metabolism and the genetic disease multiple acyl dehydrogenase deficiency, excessive intake of adipic acid-containing foods such as Jell-O, and by increased intake of foods containing medium chain triglycerides such as coconut oil.

Methylsuccinic Acid

Adipic Acid (Adipate)

• Included in OAT by Metametrix. • Fatty acid metabolite (6-carbon dicarboxylic acid). • Product of peroxisomal fatty acid oxidation [Metametrix]. • Value may be elevated in: o Fasting [GP], ketosis [GP] or metabolic acidosis [Metametrix]. o Excessive intake of adipic acid-containing foods such as Jell-O, espeically if suberic acid is not elevated [GP; Metametrix]. o Increased intake of foods containing medium chain triglycerides such as coconut oil [GP]. o Functional deficiency of the fat-transporting molecule carnitine which may prevent entry of long chain fatty acids into mitochondria, leading to incomplete fatty acid oxidation [GP; Metametrix]. Consider supplementation with 500 to 1000mg L-Carnitine TID (CI with certain thyroid medications); or L-Lysine 1000mg QD to TID (precursor to carnitine); also consider SAMe, Vitamin B6, Mg, Vitamin C, Fe, niacin, and adequate protein intake [Metametrix]. o Mitochondrial dysfunction. Consider Vitamin B2 100mg BID [Metametrix]. o Genetic deficiencies of fatty acid metabolism [GP]. o Genetic disease multiple acyl dehydrogenase deficiency [GP]. o Environmental toxins [Metametrix]. o Periodic mild weakness [Metametrix]. o Nausea [Metametrix]. o Fatigue [Metametrix]. o Hypoglycemia [Metametrix]. o Recurrent infections [Metametrix]. o Sweaty-feet odor [Metametrix]. o Reye syndrome (inhibition of FA oxidation associated with aspirin, viral infections, and genetic mutations) [Metametrix]. o Isolated high values of adipic acid only (i.e. not suberic) may be found in patients with ADD, lethargy and seizures [GP].

Suberic Acid (Suberate)

• Included in OAT by Metametrix. • Fatty acid metabolite (8-carbon dicarboxylic acid). • Product of peroxisomal fatty acid oxidation [Metametrix]. • Value may be elevated in: o Fasting [GP], ketosis [GP] or metabolic acidosis [Metametrix]. o Functional deficiency of the fat-transporting molecule carnitine [GP; Metametrix]. See adiptic acid (above) for treatment [Metametrix]. o Mitochondrial dysfunction. Consider Vitamin B2 100mg BID [Metametrix]. o Genetic deficiencies of fatty acid metabolism [GP]. o Genetic disease multiple acyl dehydrogenase deficiency [GP]. o Increased intake of foods containing medium chain triglycerides such as coconut oil [GP]. o Environmental toxins [Metametrix]. o Periodic mild weakness [Metametrix]. o Nausea [Metametrix]. o Fatigue [Metametrix]. o Hypoglycemia [Metametrix]. o Recurrent infections [Metametrix]. o Sweaty-feet odor [Metametrix]. o Reye syndrome (inhibition of FA oxidation associated with asprin, viral infections, and genetic mutations) [Metametrix].

Ethylmalonic Acid (Ethylmalonate)

• Included in OAT by Metametrix. • Five-carbon branched chain dicarboxylic acid formed in isoleucine metaolism [Metametrix]. • Value may be elevated in: o Functional deficiency of the fat-transporting molecule carnitine. See adiptic acid (above) for treatment [Metametrix]. o May indicate compromise of short-chain fatty acid oxidation, leading to elevation of butyrate which may be converted to ethylmalonic acid [Metametrix]. o Riboflavin deficiency [Metametrix]. o Inability to form or oxidize butyrylcarnitine [Metametrix].

Sebacic Acid

Toxic Indicators

Pyroglutamic Acid (Oxoproline)

• A metabolite of the antioxidant glutathione and is extremely elevated in the genetic disease pyroglutamic acidurea and following the use of the antibiotics flucloxacillin and netelmicin. • Low values may be found due to glutathione depletion following oxidative stress or after exposure to toxic solvents or pesticides such as chloroform, DDT, or polybrominated biphenyls (PBBs) and polychlorinated biphenyls (PCBs).

Orotic Acid

• Elevated level suggests urea cycle defect. • Elevated levels are most commonly associated with ammonia toxicity. When ammonia is elevated, it is biochemically converted to carbamyl phosphate and then orotic acid. Elevated ammonia may occur due to liver toxicity, viral liver infection, GI bleeding, portal systemic shunting of blood, drug toxicity, Reye's syndrome, as well as inborn errors of ammonia metabolism. • Elevated orotic acid may also be found in leukemias and lymphomas, possibly due to the increased production of pyrimidines.

Hydroxyhippuric Acid (hydroxy-benzoylglycine)

• A conjugate of the amino acid glycine and hydroxybenzoic acid (salicylic acid). • Elevated values may be due to the use of aspirin (salicylates) or due to the growth of GI bacteria producing salicylates [GP]. • Also increased after the ingestion of the artificial sweetener aspartame (Nutrasweet) [GP].

According to [Shaw2008, page 14], HPHPA, which is a metabolite derived from Clostridium spp. metabolism, can undergo further human beta-oxidation to form 3-hydroxy-benzoic acid, which is then conjugated with glycine in the liver's phase-2 detoxification step to produce 3- hydroxy-benzoylglycine, also known as 3-hydroxyhippuric acid.

Vitamin Indicators and Metabolites

Methylmalonic Acid (Ethylmalonate)

• Moderate increases may be due to vitamin B-12 deficiency.html. • Elevated values may also be due to the genetic disease methylmalonic aciduria [GP].

Xanthurenic Acid (Xanthanurenate)

• Xanthurenic Acid is a tryptophan metabolite that may be elevated with vitamin B-6 deficiency (conversion of tryptophan to NAD requires B-6; in the absence of B-6, Xanthurenic Acid is produced instead [PA-OAT]. • Elevated levels are a functional marker of intracellular vitamin B-6 deficiency.html, inflammation, or excess estrogen or cortisol [PA-OAT]. • Complexes with insulin and decreases insulin sensitivity [PA-OAT]. • Complexes with iron and causes oxidative damage to DNA (increases 8-OH dG marker for oxidative damage) [PA-OAT]. Pyroglutamic Acid (Pyroglutamate)

• Elevated levels are a marker of Glutathione Deficiency [PA-OAT]. • [PA-OAT] also suggests that low levels may also indicate a glutathione deficiency, but that this suggestion lacks scientific support.

Note that glutathione is an important antioxidant, and is necessary for detoxifying estrogen metabolites 4-OH-E1 and 4-OH-E2 [PA-OAT].

Ascorbic Acid (Vitamin C)

• An important antioxidant. • Low values may indicate dietary deficiency (scurvy). • Frequently low in chronic fatigue syndrome. • High values are usually due to dietary intake and are of no concern except that in individuals with bacteria overgrowth of the GI tract, ascorbic acid may be converted to oxalic acid, which can lead to kidney stones. There is a low probability that elevated vitamin C will cause kidney stones if oxalic acid is in the normal range.

Kynurenic Acid

• The reaction by which kynurenine is converted to hydroxyanthranilate is catalyzed by an enzyme requiring vitamin B-6. Thus, elevations of kynurenic acid may indicate a vitamin B-6 deficiency. • High values in individuals with the yeast overgrowth syndrome may be due to yeast interference.

Methylcitric Acid

• High levels indicate biotin deficiency and/or an inborn error of metabolism affecting biotin pathways. • Low values of methylcitric acid have no known significance.

Pyridoxic Acid

• The main urinary metabolite of pyridoxine (Vitamin B6) and is a measure of recent dietary intake. • Low values of pyridoxic acid in the urine indicate low recent intake while high values indicate high recent dietary intake.

Pantothenic Acid (Vitamin B5)

• Urinary excretion reflects dietary intake. • High values are not necessarily undesirable. • Individuals may have a much higher than usual requirement for this cofactor. Miscellaneous Organic Acids

Glutaric Acid

• Elevated in the genetic diseases glutaric academia types I and II. • Moderate increases may be due to deficiencies in riboflavin and coenzyme Q10, or celiac disease. • Moderate increases are common in autism possibly due to defective vitamin absorption or microbial production in the GI tract.

N-acetyl Aspartic Acid

• High values are due to the genetic disease Carnavan's disease, a potentially fatal disease causing spongy degeneration of the brain.

3-hydroxy-3-methylglutaric (HMG) Acid

• A precursor in the production of cholesterol in both humans and yeast. • Moderate increases are probably due to yeast overgrowth of the GI tract and might also implicate yeast overgrowth with elevated serum cholesterol. • Both yeast and humans produce these same compounds as a precursor of steroid hormones. • Elevated values are found in the genetic disease 3-hydroxy-3-metylglutaric aciduria.

Malonic Acid

• Elevated values may be associated with the genetic disease malonyl CoA decarboxylase deficiency.

Methylglutaric Acid

• Elevated values may be associated with the genetic diseases 3-hydroxy-3-methylglutaric aciduria and in 3-methylglutaconic aciduria.

Hippuric Acid

• A conjugate of benzoic acid and glycine formed in the liver as part of the normal phase-II detoxification pathway. • May be elevated due to bacteria overgrowth of the GI tract producing benzoic acid, which is absorbed into the portal circulation. Treatment includes Lactobacillus rhamnosus [GP2010]. • Other sources that increase benzoic acid are the environmental toxin toluene and the food preservative sodium benzoate, as well as foods such as apples, pears, tea, coffee, sunflower seeds, carrots, blueberries, cherries, potatoes, tomatoes, eggplant, sweet potatoes, peaches [GP2010]. • Low values of hippuric acid may be due to depletion of glycine due to competing detoxification reactions or due to low amounts of bacteria after antibiotic use.

4-hydroxybutyric Acid

• Elevated values may indicate the rare genetic disease 3-methylglutaconic aciduria. • Elevated values may also indicate excessive intake of the muscle builder 4- hydroxybutyric acid (also called gamma-hydroxybutyric acid), which can cause severe myalgia or death.

Phenylcarboxylic Acid

• Elevated values indicate overgrowth of GI bacteria.

Indole-like Compound Acids

• Most likely derived from tryptophan. • Elevated values indicate overgrowth of GI bacteria and are commonly elevated along with 3-indoleacetic acid.

References regarding Organic Acid Test Panel (OAT)

[Shaw2008] Shaw W. Biological Treatments for Autism & PDD, Third Edition. (2008).

• [GP] Great Plains Laboratory. Physician Training Lecture Notes and Documentation. Full text

[GP2010] Great Plains Lab Report, 2010.

[Metametrix] Metametrix Handbook: Clinical Reference Manual, 2nd Edition. (2010).

[Shaw2005] Shaw W, Kassen E, Chaves E. Increased urinary excretion of analogs of Krebs cycle metabolites and arabinose in two brothers with autistic features. Clin Chem. 2005 Mar;51(3):672-3.

[Elsden1976] Elsden SR, Hilton MG, Waller JM. The end products of the metabolism of aromatic amino acids by Clostridia. Arch Microbiol. 1976 Apr 1;107(3):283-8.

[Bhala1993] Bhala A, Bennett MJ, McGowan KL, Hale DE. Limitations of 3- phenylpropionylglycine in early screening for medium-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr. 1993 Jan;122(1):100-3.

[Robertson1968] Robertson B, Lonnell L. Human tartrate nephropathy. Report of a fatal case. Acta Pathol Microbiol Scand. 1968;74(3):305-10. [Kiehn1979] Kiehn TE, Bernard EM, Gold JW, Armstrong D. Candidiasis: detection by gas- liquid chromatography of D-arabinitol, a fungal metabolite, in human serum. Science. 1979 Nov 2;206(4418):577-80.

[Wong1990] Wong B, Brauer KL, Clemens JR, Beggs S. Effects of gastrointestinal candidiasis, antibiotics, dietary arabinitol, and cortisone acetate on levels of the Candida metabolite D- arabinitol in rat serum and urine. Infect Immun. 1990 Feb;58(2):283-8.

[Larsson1994] Larsson L. Determination of microbial chemical markers by gas chromatography-mass spectrometry--potential for diagnosis and studies on metabolism in situ. Review article. APMIS. 1994 Mar;102(3):161-9. Review.

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Unless specifically noted above, references used in the construction of this web page include the following:

[FDM] Lecture notes from Functional Medicine University.

[SCNM] Lecture notes from Southwest College of Naturopathic Medicine.

[UT] Lecture notes from the University of Tennessee graduate programs in Chemistry, Microbiology, and Biochemistry.