Organic acid test (OAT) has gained popularity among many functional health experts in recent years. Although OAT markers provide an insight into a wide spectrum of conditions at the cellular level, they come with their own limitations. This article covers the significance and relevance of individual markers. If you are on the fence and wondering if OAT is a right test for you, then this article is for you.

What is the Organic Acid Test?

Organic Acid Test, popularly known as OAT, measures the levels of organic compounds in urine that are produced in our body as a part of many vital biochemical pathways.

A defect in a particular pathway can result in either accumulation or lowered levels of its byproducts. Thus, measuring the levels of these markers can help to identify which metabolic process is blocked or compromised.

Additionally, there is another category of organic acids that are produced as a result of microbial activity (bacteria and yeast) in the gut. This article will not cover those markers.

Abnormal levels of organic acids not only signal insufficient levels of metabolic products, which are required for the proper functioning of our body, but excessive amounts of some organic acids can harm the body, such as in the case where it leads to metabolic acidosis.

Scope of Organic Acid Testing

Conventionally, organic acids testing has been done to assess the inborn genetic defects of metabolism mainly in children. In recent years, however, with the introduction of new markers, OAT has expanded to include the diagnosis of diseases due to non-genetic factors such as nutritional deficiencies, environmental exposure to toxins, or certain drugs.

Abnormal OAT profile has been seen in people with chronic illnesses (such as diabetes, fatigue, kidney disease) and neurological disorders (such as autism, Alzheimer’s disease, ADHD). Prioritizing the treatment by dietary intervention or tailoring the need for specific nutrients has been shown to significantly improve clinical outcomes [1, 2, 3, 4, 5, 6, 7, 8, 9].

In nutshell, OAT markers can provide insight into:

  • Mitochondrial dysfunction/energy metabolism
  • Neurotransmitter levels
  • Glutathione/oxidative stress status
  • Detoxification status
  • Oxalate intolerance/levels
  • Fat/amino acids breakdown
  • Methylation
  • B Vitamin adequacy
  • Toxic exposures
  • Gut health
  • Assessment of neurological disorders

Key Points

  • High levels of organic acids in the blood (organic acidemia), or in the urine (organic aciduria) are typically named after the specific organic acid.
  • Usually, abnormal levels of a single organic acid can point to multiple anomalies. A combination of markers should be used to narrow down the potential root cause.
  • In a majority of disorders, genetic causes of organic acidosis are more severe (often fatal) with extremely high levels of organic acids as compared to corresponding non-genetic variants.

Since, in order to understand the relevance of a marker in a disorder, it is imperative to get the overall picture of the corresponding metabolic pathway, we will provide a brief background of each pathway as we cover individual markers.

Mitochondrial Markers

Mitochondria are the powerhouse of our cells. Byproducts from carbohydrates, fat, and protein enter the mitochondria and are fed into the Krebs cycle and electron transport chain to produce energy in the form of ATP.

Carbohydrate Metabolism

Glycolysis is the first step in glucose metabolism (breakdown of sugar) producing pyruvate and some energy (ATP). This step takes place in the absence of oxygen. Pyruvate, then, enters mitochondria and is converted into acetyl CoA, which is then metabolized in the Krebs cycle to produce more energy in the presence of oxygen.

1) Pyruvic Acid (Pyruvate)

When mitochondrial functions are compromised due to low oxygen supply or other factors, glycolysis becomes the major source of energy producing more pyruvate. Excess pyruvate has an escape route where it is converted to oxaloacetate and lactic acid [10]. Thus, pyruvate levels are usually evaluated with levels of lactic acid and other organic acids.

A defect in energy metabolism can lead to elevated levels. Examples include:

  • Strenuous exercise [11, 12, 13]
  • Migraines [14]
  • Thiamine (vitamin B1) deficiency [15]
  • Magnesium deficiency [15]
  • Circulatory failure (shock) [16]
  • Heart failure [17]
  • Parkinson’s [18]
  • Diabetes [19]
  • Cancer [20, 21]
  • Rare inborn metabolic disorders [22, 23, 24]

2) Lactic Acid (Lactate)

Lactic acid is produced by most tissues in the body as a result of low oxygen levels.

Higher lactic acid levels can be seen in:

  • Strenuous exercise, when there is an imbalance between oxygen delivery and energy requirements in the muscles [25, 26, 27, 28, 29, 29]
  • Asthma [30, 31]
  • Thiamine (vitamin B1) deficiency, often encountered in malnutrition [32, 33, 34, 35]
  • Magnesium deficiency [36]
  • Gut bacterial dysbiosis, found in short bowel syndrome and after gastric bypass surgery [37, 38, 39, 40, 41, 42]
  • Probiotics – in people who are susceptible [43, 44]
  • Diabetes [45, 46, 47, 48]
  • Inflammatory bowel disease (IBD) [45]
  • Seizures [49, 50]
  • Thyrotoxic crisis, caused by excessive release of thyroid hormones [51, 52, 53]
  • Conditions that decrease blood flow or oxygen supply to the tissues, such as bleeding (hemorrhage) and anemia [54, 55, 56, 57, 58]
  • Physical injury (trauma) and burns [31, 59, 60]
  • Exposure to toxins such as cyanide (found in bitter almonds), carbon monoxide, toluene, or the pesticide fenaminosulf [61, 62, 63, 64, 65]
  • Alcohol intoxication, including ingestion of ethanol, propylene glycol, ethylene glycol, and alcohol-containing products such as hand sanitizer [66, 67, 40, 68, 69]
  • Malaria [70]
  • Liver failure [31, 71]
  • Heart failure [31]
  • Cancer and cancer therapy [72, 73, 74, 75]
  • Sarcoidosis [76]
  • Inherited metabolic disorders due to genetic mutations [77, 78, 79, 80]

A wide range of drugs can increase lactic acid levels, including:

  • Metformin, used in the treatment of diabetes [81, 82, 83]
  • Beta-2 agonists such as albuterol (salbutamol), used to treat asthma [84, 85, 86, 87, 88, 89, 90, 91]
  • Venlafaxine (Effexor), an antidepressant [92]
  • Antiviral drugs such as Viekira Pak (ombitasvir/paritaprevir/ritonavir), tenofovir, entecavir (Baraclude), and telbivudine (Sebivo, Tyzeka) [93, 94, 95, 96]
  • Antiretroviral medication used to treat HIV, such as zidovudine (AZT, Retrovir) or stavudine (Zerit) [97, 98, 99]
  • Antibiotics linezolid (Zyvox) and chloramphenicol [100, 101, 102, 103]
  • Epinephrine (adrenalin) [104]
  • Paracetamol (acetaminophen, Panadol) [105]
  • Valproic acid, used to treat seizures [106]
  • Chemotherapeutics such as carboplatin (Paraplatin) [107]
  • Drugs of abuse, such as cocaine and synthetic marijuana [108, 109]

Severity and symptoms of lactic acidosis can vary widely depending on which metabolic pathway is not functional and can range from severe neurological degeneration in newborns (Leigh syndrome) and early death to relatively normal life with episodes of vomiting, nausea, and generalized weakness [110].

Analysis of various biochemical metabolites as well as multiple organic acids should be taken into consideration while making a diagnosis.

  • Lactic acidosis, when accompanied with low fasting blood sugar (hypoglycemia) indicates a block in glucose synthesis (gluconeogenesis). Biotin deficiency may be suspected, as it is a cofactor for pyruvate carboxylase (one of the enzymes involved in gluconeogenesis) [10].
  • Low levels of Krebs cycle metabolites along with lactic acidosis suggest mitochondrial damage or impairment of the Krebs cycle or deficiency of PDHC [10].
  • Lactic acidosis can be used as a marker for upper urinary tract infection in children [111].

After careful investigation, therapy should be targeted towards the underlying cause, e.g. fasting and a low carbohydrate diet are not recommended in case of defects of gluconeogenesis. While in the case of PDHC deficiency, high carbohydrate diet should be avoided.

Vitamin supplementation with biotin (vitamin B7), riboflavin (vitamin B2), thiamine (vitamin B1), and magnesium can be helpful [112, 7, 15, 36, 113].

Energy Production – Krebs Cycle

Krebs cycle (also called tricarboxylic acid or TCA cycle) is center for the energy production from carbohydrates, fats, and proteins. The cycle consists of a series of reactions, with metabolites entering at various steps from other metabolic pathways [114].

One of the primary functions of the cycle is to generate NADH & FADH, which are utilized to produce energy in the form of ATP in the electron transport chain (ETC). Any impairment in any step due to genetic or environmental factors can lead to high or low organic acids.

The Krebs cycle inputs include pyruvate, byproducts of fatty acids or from the several amino-acids (glutamate, alanine) [114]. Additionally, thyroid hormones and cortisol influence the Kreb cycle [115, 114].

1) Succinic acid (Succinate)

Succinic acid, besides being Krebs cycle intermediate, can also enter the cycle through branched-chain amino acid metabolism. Succinic acid metabolism is also linked with heme synthesis, ketone bodies utilization, and the GABA shunt [116].

Elevated levels may be due to:

  • Vitamin B2 deficiency [117, 118, 119]
  • CoQ10 deficiency [120]
  • Bacterial infections [121, 122]
  • Exposure to toxins and heavy metals [123, 124, 125, 126]
  • Diabetes [127, 128]
  • Bleeding (hemorrhage)/injury [129]
  • High altitude, due to low oxygen [130]
  • Fibromyalgia (urine) [131]
  • Cancer [132, 133]
  • Down syndrome [134]
  • Rare genetic disorders, such as succinate dehydrogenase deficiency [135, 136, 137]

Low levels can be due to:

  • Deficiency or inadequacy of branched-chain amino acids (BCAAs such as valine, isoleucine) or impairment of the pathway involving the breakdown of BCAAs for energy production, which can be due to vitamin B12 or B6 deficiency.

2) α-Ketoglutaric acid (KGA)

It is an intermediate in the Krebs cycle and also produced by the breakdown of glutamate.

Elevated levels are suggestive of:

  • Alpha-ketoglutarate supplements
  • Thiamine (vitamin B1) deficiency [138, 139]
  • Riboflavin (vitamin B2) deficiency [140, 139]
  • Niacin (vitamin B3) deficiency [139]
  • Pantothenate (vitamin B5) deficiency [139]
  • Lithium [141]
  • Obesity [142, 143]
  • Fatty liver disease [142, 143]
  • Diabetes [144, 145]
  • Cancer [146, 147]
  • Rare genetic disorders [148, 149, 150, 151, 78, 152, 153, 154]

3) Citric Acid (Citrate)

Citric acid is the first product of the Krebs cycle, when Acetyl CoA reacts with oxaloacetate. The amount of citrate produced in mitochondria, however, is minuscule compared to that found in bones. Bones are the main source of citrate and release it into the blood as needed.

Elevated levels may be caused by:

  • Eating foods high in citric acid, or taking citric acid-containing supplements, such as potassium or magnesium citrate [155]
  • Malic acid supplements [156]
  • High sodium levels [157]
  • Higher blood glucose levels [158]
  • Diabetes and diabetic nephropathy [159, 157]

Low citrate levels can result from:

  • Dietary citrate deficiency [160]
  • Starving or ketosis [161, 162, 160]
  • Magnesium deficiency [163]
  • Low potassium (hypokalemia) [161]
  • Too much acid in the body (metabolic and cellular acidosis) [160, 164, 161]
  • Exercise [165, 166]
  • Excess sodium [160]
  • Cola-flavored carbonated beverages [167]
  • High parathyroid hormone levels (hyperparathyroidism) [160]
  • E. coli infection [168]
  • Rare genetic disorders [169]
  • Loop and thiazide-like diuretic [158]
  • Topiramate (Topamax), an anticonvulsant [170]

These increase your risk of having low citrate levels:

  • A diet low in vegetable fibers [171]
  • Low urine volume (dehydration) [171]
  • Higher intake of non-dairy animal protein [157]
  • Higher body mass index (BMI) [157]
  • Gout/high uric acid levels [157]

Lower uric acid levels in the urine are linked to kidney stones and osteoporosis [172, 173, 173, 174, 175].

4) Aconitic acid (Aconitate)

High values indicate:

  • Inadequate Glutathione [19]
  • Mitochondrial disorder

5) Fumaric acid (Fumarate)

Fumarate levels can be elevated in:

  • Strenuous exercise [165, 166]
  • Calorie restriction [176]
  • Diabetes [177]
  • Kidney disease [178]
  • Cancer [146]
  • Down syndrome [134]
  • Rare genetic diseases such as fumarase deficiency or mitochondrial disease [179, 180, 181, 182, 183]

Krebs Cycle Disorders

Most of the cases of Krebs cycle disorders show high lactic acid levels along with abnormal levels of metabolites specific to the source of defect [114].

Symptoms include:

  • Low energy/fatigue
  • Brain issues (encephalopathy)
  • Low muscle tone
  • Seizures
  • Metabolic acidosis

If levels of α-Ketoglutaric acid are elevated without an increase in other metabolites, high glutamate is suspected.

High levels of several Krebs cycle metabolites along with high lactic acid suggest a defect in electron transport chain (ETC), which can be due to deficiency of Vitamin B2 or Coenzyme Q10, mitochondrial damage due to drug/antibiotics use, or infection. Defects in ETC also affects fatty acids metabolism. Supplementation with Carnitine, Coenzyme Q10, Niacin, or Vitamin B2 can be helpful [2, 4, 184, 1].

High levels of citric acid and aconitic acid, accompanied by low pyroglutamic acid (discussed later) indicates depletion of glutathione. Supplementing with glutathione or N-acetyl cysteine may be useful.

Fatty acid metabolism

Fatty acid breakdown may serve as an important source of energy in periods of stress such as fasting, strenuous exercise, illness, especially in heart, skeletal muscles and liver [185, 186].

Beta-oxidation, which occurs in the mitochondria, is the main pathway through which fatty acids generate acetyl-CoA, which is the fuel that allows the mitochondria to create usable energy (ATP).

Medium- and short-chain fatty acids are transported directly into the mitochondria, but long-chain fatty acids need carnitine to get transported across the mitochondrial membrane [185, 186].

1) Suberic Acid/Sebacic acid/Adipic acid

Adipic and Suberic acids are breakdown products of fatty acids [1] and are generally accumulated when the breakdown (oxidation) of fats is impaired. Their presence clearly indicates defective mitochondrial function.

Elevated levels can be seen in the following situations [187, 186]:

  • Carnitine palmitoyltransferase (CPT I & II) deficiency
  • Carnitine-acylcarnitine translocase (CACT) deficiency
  • HMG-COA lyase deficiency
  • Vitamin B2 deficiency (FAD, an active form of B2), an enzyme important for mitochondrial function [1]
  • Carnitine deficiency or inadequacy: Low carnitine levels primarily affect long-chain fatty acids oxidation through impairment of their transportation through mitochondria
  • Diabetes [188]
  • Glutaric acidemia type 2 [1]
  • Jello consumption

2) Ethylmalonic Acid (EMA)

Ethylmalonic acid is elevated when the mitochondria are not using fats as fuel as much.

Beta oxidation is lower, possibly as a result of a deficiency of short-chain acyl dehydrogenases (SCAD) or other acyl-CoA dehydrogenases [189, 190].

Alongside ethylmalonic acid, urinary levels of other organic acids such as adipic acid, glutarate, suberic, sebacic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids are also elevated [1].

3) Methylsuccinic Acid

Methylsuccinic acid is a byproduct of ethylmalonic acid and is associated with brain impairment seen in ethylmalonic aciduria.

Defects in Fatty Acid Oxidation

Defects in fatty acid oxidation pathways can have a variety of symptoms depending upon where the pathway is blocked [187].

Symptoms in infants are:

  • Excess ammonia (hyperammonemia)
  • Low blood sugar (hypoglycemia)
  • Metabolic acidosis
  • Heart disease (cardiomyopathy)
  • Sudden death

Late onset can be manifested as:

  • Neuropathy
  • Muscle weakness (myopathy)
  • Retina damage (retinopathy)

Accumulation of urinary organic acids from both fatty acids and amino acid metabolism (isovaleric acid, glutaric acid) indicate the defects in dehydrogenation at multiple levels, a cofactor deficiency (B2, CoQ10) can be considered.

This observation along with the accumulation of intermediates of Krebs cycle, particularly signals deficiency of CoQ10, if adequate fumaric acids levels rule out B2 deficiency.

A secondary glycine deficiency (just like carnitine) can be present, as glycine conjugation is the major pathway for the disposal of many fatty acyl moieties [191].

Suggestions:

  • Severe episodes are managed with intravenous fluids and therapy with carnitine. Patients are advised to avoid periods of catabolic stress [186].
  • In chronic cases, a diet restricted in fat and protein is advisable.
  • Supplementation with riboflavin, Coenzyme Q10 (COQ10), and l-carnitine has been shown to be effective in some patients [1, 2, 3, 4, 184].
  • Glycine supplementation may be helpful to replenish lost glycine in the form of acylglycine.

Ketone bodies (Acetoacetic acid and 3-hydroxybutyric acid)

Ketone bodies (acetoacetate and 3-hydroxybutyrate) are produced in the liver from fatty acids to be used as an energy source by other tissues in case of glucose/carbohydrate shortage. Elevated levels can be categorized as ketosis (mild to moderate increase, 0.6 – 3 mmol/L, often transient) and ketoacidosis (extremely high levels >5mmol/L, often pathological).

Elevated levels can be caused by:

  • Fasting and prolonged exercise
  • Conditions that cause hormonal imbalances [192]
  • Diabetes – In diabetic ketoacidosis, high levels of ketones are produced in response to low insulin levels and high levels of glucagon. Diabetic ketoacidosis is the most common disease-based cause of ketosis and occurs most often in Type 1 diabetes (but also Type 2) [192].
  • Cortisol deficiency
  • Growth hormone deficiency
  • Toxic ingestions of alcohol or salicylates
  • Certain rare inborn errors of metabolism
  • Vitamin B12 deficiency [193]
  • Ketogenic diet

B vitamins and Other Nutritional markers

1) Glutaric Acid / 3-Hydroxyglutaric Acid (Vitamin B2 Marker)

Glutaric acid levels can be high in:

  • Vitamin B2 deficiency
  • Celiac disease [194]
  • Genetic disorders called glutaric acidemias (very high glutaric acid levels) [195, 196, 197]

Glutaric acid is also increased in a subset of children with autism [198]. Conversely, subjects with glutaric acidemia can have autistic features, e.g. lack of language and social skills, poor eye contact and stereotypical behavior [199].

If your glutaric acid levels are elevated:

  • Supplementation with B2, CoQ10 may be helpful [200]
  • Carnitine can improve symptoms [195, 201]
  • Restrict dietary amino acids that can be converted into glutaric acids, such as lysine [202, 203]

2) Methylmalonic acid (Vitamin B12 Marker)

Methylmalonic acid (MMA) is a good indicator of Vitamin B12 deficiency since Vitamin B12 is required for MMA to be converted to succinyl-CoA. When B12 is low, MMA levels in the blood and urine increase [204].

MMA levels increase early in the course of vitamin B12 deficiency, when total B12 levels in the blood are still normal, thus making MMA a better marker for functional B12 deficiency [205].

Elevated levels can also be caused by:

  • Pregnancy [206]
  • Common harmless genetic mutations [207]
  • Genetic disorders (methylmalonic acidemia) [208]

If you have high MMA levels, increase the intake of B12-rich food and consider taking B12 supplements.

Levels can be low in kidney disease, even when vitamin B12 deficiency is present [209].

3) Pyridoxic acid (Vitamin B6 Marker)

Pyridoxic acid is the product of vitamin B6 breakdown. Vitamin B6 is needed for more than 160 different metabolic reactions within the body. It works with B6-dependent enzymes, which are important for amino acid production and breakdown and the production of neurotransmitters, such as serotonin, noradrenalin, and GABA [210, 211, 212].

While blood vitamin B6 levels reflect tissue saturation, urinary pyridoxic acid responds almost immediately to change in dietary intake [213]. Approximately 40 – 60% of dietary vitamin B6 is excreted as pyridoxic acid [213, 214, 215].

Levels are elevated in:

  • Increased intake of B6 or supplementation with this vitamin [216]
  • Fasting [217]
  • Ginkgo seed poisoning increases pyridoxic acid but decreases vitamin B6 [218]

Low levels are suggestive of:

  • Low vitamin B6 [216]
  • Riboflavin (vitamin B2) deficiency [213, 219]
  • High oxalates [220]
  • Low neurotransmitters [210]
  • Impaired kidney function [213, 221, 216]

If your pyridoxic levels are low, consider vitamin B6 supplements [213].

Because of potential confounders, such as dietary fluctuation or kidney dysfunction, it is important to evaluate other biomarkers in combination with pyridoxic acid when needed.

4) Pantothenic Acid (Vitamin B5)

High levels may be due to recent supplementation and are generally of no concern [222, 223].

Low levels can indicate nutritional deficiency [222, 223].

If you have low pantothenic acid levels, consider B5 supplements.

5) Ascorbic acid (Vitamin C)

Ascorbic acid (Vitamin C) is a water-soluble vitamin and powerful antioxidant. Levels in urine reflect recent dietary intake rather than overall status in tissues [224].

Since a part of ascorbic acid is converted to oxalic acid, individuals with kidney disorders may have increased risk of oxalate kidney stones from excess vitamin C intake [225].

Additionally, excessive doses can lead to fatal heart disease (cardiomyopathy) and iron overload (hemochromatosis), potentially due to enhanced iron absorption and iron-induced tissue damage [226].

If your levels are low, increase your dietary intake of vitamin C-rich fruits and vegetables. You can also use supplements.

6) 3-Hydroxy-3-Methylglutaric Acid / 3-Methylglutaric Acid / 3-Methylglutaconic Acid (Coenzyme Q10)

These organic acids are needed for the production of coenzyme Q10 and cholesterol.

Elevated levels can indicate [227]:

  • Decreased Coenzyme Q10 [228]
  • Ongoing therapy with cholesterol-lowering drugs (statins) [229, 228]
  • Mitochondrial dysfunction [227]
  • Genetic disorders (very high levels) [227, 230]

If your levels are high:

  • Riboflavin or coenzyme Q10 supplementation can help [227]
  • Restriction of dietary protein and fat also may help [231]
  • Fasting can make things worse, by favoring the production of ketones from fatty acids, leading to the accumulation of 3-hydroxy-3-methylglutaric acid [231]
  • Carnitine is often low in inborn metabolic deficiencies, where carnitine supplementation can help with alleviating symptoms [201]

7) Methylcitric Acid (Biotin/Vitamin B7)

High levels can be due to:

  • Biotin deficiency, sometimes caused by eating raw eggs [232, 233]
  • Vitamin B12 deficiency [234, 235, 236]
  • Genetic disorders [237, 238]

In a study of 281 subjects aged 65 and older, those with elevated methylcitric acid had worse cognitive function [239].

Methylation Markers

Uracil (Folate) /Thymine

High values of uracil suggest folic acid deficiency because folate is required for converting (methylating) uracil to thymine [240].

Both uracil and thymine are high in a rare genetic disease, dihydropyrimidine dehydrogenase deficiency. This disease has been linked to seizures and autism [241+, 242].

Detoxification Markers

Low is good for detoxification markers. Higher levels mean there’s toxic exposure and/or increased oxidative stress.

1) 2-Methylhippuric Acid

Methylhippuric acid is a marker of toluene and xylene exposure [243, 244, 245]. Common sources for xylene exposure are paint thinners, building products, fuel, exhaust fumes, and industrial solvents. Toluene is found in paint thinner, contact cement, and model airplane glue.

2) Orotic Acid

Orotic acid is produced from excess ammonia (hyperammonemia).

Elevated levels indicate:

Arginine supplementation can be beneficial in some cases [245].

3) Glucaric Acid

Urinary glucaric acid levels indicate overall liver detoxification status.

Elevated levels suggest exposure to pesticides, herbicides, petrochemicals, alcohol, or medication [257, 258, 259, 260, 261, 262, 263, 264, 265, 266].

4) 2-Hydroxyhippuric Acid

Salicyluric acid (also called 2-Hydroxyhippuric acid) is formed in the body as it eliminates excess salicylates, such as aspirin [267].

People who take aspirin have elevated salicyluric acid [267].

Slightly more salicyluric acid is excreted in the urine of vegetarians than in non-vegetarians, consistent with the observation that fruits and vegetables are important sources of dietary salicylates. However, these levels are nowhere near as high as the levels seen in people taking aspirin [267].

5) Pyroglutamic Acid

Pyroglutamic acid, also called 5-oxoproline, is a metabolite of glutathione. High levels can signal glycine deficiency or glutathione depletion [268, 269, 270].

Elevated levels can be seen in case of:

These can help decrease pyroglutamic acid:

  • Supplementing with glutathione or N-acetylcysteine (NAC) [280]
  • Selenium [281, 282]

6) 2-Hydroxybutyric Acid

This acid, also known as α-hydroxybutyrate (AHB), is produced as a byproduct of the breakdown of sulfur-containing amino acids. Its production increases when there’s an increase in oxidative stress or in glutathione production due to higher detoxification demands [283].

Elevated levels are encountered in:

2-hydroxybutyric acid may be useful as an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population [289, 290].

Neurotransmitter Metabolism Markers

1) Phenylalanine and Tyrosine Metabolites

The catecholamines- norepinephrine (noradrenalin), epinephrine (adrenalin), and dopamine are released when the body is under physical or emotional stress. Their metabolites, vanillylmandelic acid and homovanillic acid, also increase as a result.

Certain drugs (L-dopa, dopamine, epinephrine, and norepinephrine), that can be metabolized to HVA and VMA, will falsely elevate the levels in urine.

1a) Vanillylmandelic Acid

VMA is the end product of the breakdown of ‘fight-or-flight’ hormones norepinephrine and epinephrine, also known as noradrenalin and adrenalin.

VMA levels are elevated by stress and anxiety [291, 292].

Significant elevations in VMA levels are found in tumors, such as pheochromocytoma, a tumor of the adrenal gland and neuroblastoma, a nerve tissue cancer that occurs mainly in children [293, 294].

1b) Homovanillic Acid

Homovanillic acid (HVA) is the breakdown product of the ‘feel-good’ brain chemical dopamine.

These increase HVA:

  • Eating dopamine-rich foods such as bananas [295]
  • Anorexia and bulimia [296, 297]
  • Autism [298]
  • Exposure to air pollution [299]
  • Drugs such as L-dopa [300]
  • Huntington’s disease [301]
  • A rare genetic disorder resulting in beta-hydroxylase deficiency – that’s the enzyme needed to convert dopamine into adrenalin [302]
  • Tumors such as neuroblastoma or pheochromocytoma [303]

Low HVA values have been associated with:

  • ADHD and learning problems [304, 305]
  • Childhood trauma [306]
  • Monoamine oxidase-A (MAO) deficiency, a rare genetic disorder that occurs mostly in men [307]

HVA levels increase after consuming:

  • Cocoa extract [308]
  • Bananas [309]
  • Dietary flavonols commonly found in foodstuffs such as tomatoes, onions, and tea [310]
  • Quercetin [311]

1c) HVA/VMA Ratio

An elevated ratio indicates decreased conversion of dopamine to norepinephrine by the enzyme dopamine beta-hydroxylase (DBH). It can happen in:

  • Clostridia infection [312]
  • ADHD [313]
  • Genetic disorder (Dopamine beta-hydroxylase deficiency) [314]
  • Menkes disease, a lethal disorder associated with copper metabolism [315]
  • Neuroblastoma [316, 317]

2) Tryptophan Metabolism

Tryptophan is an essential amino acid that can be metabolized through different pathways.

A major route is the kynurenine pathway, resulting in the production of the NAD (nicotinamide adenosine dinucleotide). About 95% of tryptophan is metabolized this way [318, 319, 320].

The kynurenine pathway is stimulated by inflammatory molecules, particularly interferon gamma and has been associated with many diseases because of the neuroexcitatory nature of kynurenine metabolites [318].

Another important pathway is the one through which tryptophan (<5%) is converted into serotonin, which is further metabolized to melatonin and 5-hydroxyindoleacetic acid (5-HIAA) [321, 322].

2a) Quinolinic Acid

Quinolinic acid is considered the most active intermediate in the kynurenine pathway.

Quinolinic acid has a neurotoxic effect. Evidence suggests that quinolinic acid is involved in [323, 324]:

  • Neurodegenerative diseases, such as Huntington’s and Alzheimer’s
  • Depression, mood disorders, and suicidality

In animals, quinolinic acid impairs learning and memory [325, 326, 327].

However, urinary levels of quinolinic acid are not a reflection of the levels in the brain [328].

Elevated levels are caused by:

  • Tryptophan supplementation or higher protein intake [329]
  • Inflammation [330]
  • Exposure to phthalates [331]
  • Exposure to lead [325]
  • High cortisol, by stimulating TDO (tryptophan 2,3-dioxygenase) – the first enzyme in the kynurenine pathway that converts tryptophan to kynurenine [332]

These may help attenuate some of the negative effects of quinolinic acid on the brain, based on studies in animals and cells:

2b) Kynurenic Acid

Kynurenic acid (KYNA) acts as a neuroprotectant and anticonvulsant. It acts in the opposite direction to quinolinic acid [357].

Furthermore, kynurenic acid may have a systemic anti-inflammatory effect by:

However, high levels in the brain can impair cognitive function and are associated with schizophrenia [318, 362, 363].

It’s important to know that blood and urine levels of kynurenic acid often don’t correlate with tissue levels (e.g. brain, gut).

Elevated blood and urine levels can be caused by:

  • Tryptophan supplementation
  • Dietary kynurenic acid intake
  • Chronic inflammation [330, 364]
  • IBD [365]
  • Genetic disorders (kynureninase deficiency)

Lower levels in blood and probably urine are found in people with:

Kynurenic acid can be found in:

Endurance exercise increases kynurenic acid production [378].

Kynurenic acid levels may decrease during pregnancy [379].

2c) 5-Hydroxyindoleacetic Acid

5-hydroxyindoleacetic acid (5-HIAA) is a metabolite of serotonin. Levels in urine are used as a marker to determine the levels of serotonin in the body.

Low 5-HIAA in the cerebrospinal fluid has been associated with aggressive behavior and suicide by violent means, correlating with reduced serotonin levels [380, 381].

However, urinary levels of 5-HIAA, do not reflect the brain (cerebrospinal fluid) content. The majority of the 5-HIAA in blood and urine come from the gut [382, 383, 384, 385].

These increase urine 5-HIAA:

  • Tryptophan and 5-hydroxytryptophan (5-HTP) supplements [386, 387]
  • Tryptophan-rich foods: banana, plantain, pineapple, kiwi fruit plums, tomatoes, and walnuts [388, 389]
  • Salt restriction [390]
  • Celiac disease and bacterial gut overgrowth [391+, 392]
  • Metabolic syndrome and diabetes [393, 394]
  • Carcinoid tumors [395, 396, 397]
  • Gastric cancer [398]

These decrease urine 5-HIAA:

  • Kidney disease [399]
  • Drugs such as antidepressants (monoamine oxidase inhibitors) and acetaminophen (Panadol) [389]
  • Diets low in tryptophan [382]

Urine 5-HIAA levels were found to be lower in people with migraines and higher in those with anxiety [400, 292].

Elevated serotonin (hyperserotonemia) is one of the most consistent findings in autism [401, 402].

Higher 5-HIAA levels were linked with lower sperm concentration, motility, and sperm vitality in 20 volunteers [403].

2d) Quinolinic Acid/ 5-HIAA

A high ratio indicates:

  • Low serotonin [332]
  • Excess protein intake [329]
  • Exposure to phthalates [331]
  • Inflammation [330]
  • High cortisol [332]

3) Gamma-Hydroxybutyric Acid

Gamma-hydroxybutyric acid (GHB) occurs naturally in the nervous system and can be found in trace amounts in the brain. It is produced from glutamate and can be converted to GABA, a major inhibitory neurotransmitter [404, 405].

GHB is also present in trace amounts in many alcoholic and non-alcoholic drinks, including tonic water and wine [406 407].

In addition, it is used as a psychoactive drug for the treatment of sleep disorders, fibromyalgia and alcoholism [408, 409, 410].

This compound is also notorious for being abused as a recreational and dance club drug [411, 412].

Slightly elevated levels may occur in:

  • Pregnancy [413]
  • Smoking [414]
  • Drug use/abuse [412]

Very high levels of gamma-hydroxybutyric acid indicate a genetic disorder [415].

Oxalate Metabolism Markers

Oxalate metabolites include glyceric acid, glycolic acid, and oxalic acid. It’s good to have all of these low.

Glyceric and glycolic acids are elevated in genetic disorders (hyperoxaluria type I and II) [416].

Oxalic acid (oxalate) is elevated in:

  • Excessive dietary intake of oxalate-rich foods [417]
  • Low calcium intake, as calcium decreases oxalate absorption in the gut [418, 417]
  • High vitamin C supplementation [419+, 420]
  • Prolonged antibiotics use [421]
  • Ethylene glycol poisoning [422]

Elevated urinary oxalate concentrations (hyperoxaluria) are associated with kidney stones.

If your oxalate metabolites are elevated, you should:

  • Avoid oxalate-rich foods, such as spinach, beets, rhubarb, sweet potatoes, chocolate, and nuts [417]
  • Replace tea and coffee with water. These beverages are also high in oxalates [423]
  • Optimize your calcium [417]
  • Hydrate; dehydration promotes kidney stone formation [424]
  • Make sure you’re not over-supplementing with vitamin C [419+, 420]

Amino Acid Metabolites

Low levels of amino acid metabolites are good. Higher levels mean there is impaired enzyme activity, most often due to genetic causes.

1) Keto and Hydroxy Derivatives of Amino Acids

Various markers can be included in this category, such as 2-hydroxyisovaleric acid, 2-oxovaleric acid, 3-methyl-2-oxovaleric acid, 2-hydroxyisocaproic acid, and 2-oxoisocaproic acid.

These are metabolites of branched-chain amino acids (BCAA) leucine, isoleucine, and valine [425].

Elevated levels can occur in:

  • Lactic acidosis – a buildup of lactic acid in the body that lowers blood pH [426]
  • Ketoacidosis [426, 427]
  • Thiamine and lipoic acid deficiency [428]
  • Alcohol dependence (2-hydroxyisovaleric acid) [429]
  • Gut bacterial overgrowth [425]
  • Genetic disorders such as maple syrup disease (buildup of 2-ketoisovaleric acid, 2-ketoisocaproic acid) and isovaleric acidemia (buildup of 2-ketoisocaproic acid, 3-hydroxyisovaleric acid) [425]

These may help:

  • Thiamine supplementation [430]
  • Glycine and/or carnitine supplementation to remove toxins by conjugation [425]
  • Dietary protein restriction, or restriction of precursor amino acids [425]
  • Reduction of propionic acid producing gut bacteria using antibiotics [425]

2) 2-Oxo-4-Methiolbutyric Acid

This organic acid is involved in several metabolic disorders involving methionine metabolism.

3) Phenyllactic acid / Phenylpyruvic Acid

These are metabolites of the amino acid phenylalanine.

Elevated levels occur in:

  • Increased dietary intake of phenylalanine (slight elevation)
  • A genetic disease called phenylketonuria (very high levels) [431, 432]. People who are carriers of the disease also have elevated levels [431].

4) Mandelic Acid

High levels can be observed in:

  • Increased dietary phenylalanine or phenylethylamine, or supplementation [433]
  • Occupational styrene exposure [434, 435]
  • Phenylketonuria [436+]

In a study of over 5,000 men, higher urinary mandelic acid levels were associated with lower testosterone [437].

5) Homogentisic Acid

Homogentisic acid increases in a genetic disorder called alkaptonuria. Urine that has significant levels of homogentisic acid darkens after air exposure [438, 439].

6) 4-Hydroxyphenyllactic Acid

4-hydroxyphenyllactate is a tyrosine metabolite.

Levels can be elevated in:

  • People who have a high tyrosine intake (slight elevation)
  • Tyrosinemia (elevated blood tyrosine levels) [440, 441]
  • Bacterial overgrowth (Short bowel syndrome) [442]
  • Bifidobacteria and lactobacilli produce considerable amounts of hydroxyphenyllactic acid [443]
  • Genetic disorders [440]

7) N-Acetylaspartic Acid

Levels are elevated in a genetic disorder called Canavan disease, that causes brain degeneration due to an accumulation of N-acetylaspartic acid [444, 445].

In a rat genetic model of Canavan disease, lithium citrate significantly decreased levels of N-acetylaspartic acid [445].

8) Malonic Acid

Slightly elevated levels are probably not significant.

High levels are linked with rare metabolic disorders malonic aciduria and malonyl/CoA decarboxylase deficiency [446, 447].

Bottom Line

There is no doubt OAT testing can provide you with a wealth of information about your health. However, there are certain things to keep in mind when choosing to do an OAT test.

Pros:

  • OAT is a urine test. There is no need to draw blood which makes the testing more convenient, especially in the case of children.
  • The test covers a lot of markers, providing a sneak peek of multiple metabolic pathways simultaneously. Basically, it makes it possible to look at the bigger picture when it comes to the way your body is working.

Cons:

  • Many organic acids require the collection of 24 hr urine in order to provide accurate information.
  • Most organic acids are indirect or non-specific markers and can be falsely elevated due to benign conditions. That is why they should never be relied upon in isolation. A combination of markers should be used to get a good picture of the underlying cause.
  • Often, urinary levels do not reflect the levels in tissues. This is especially the case for neurotransmitter markers. If there is an issue with neurotransmitters, more invasive CSF (cerebrospinal fluid) testing is way more reliable.
  • OAT testing does not provide a complete picture of micronutrient imbalances – it doesn’t include fat-soluble vitamins and minerals. So if you suspect a chronic health or neurological condition associated with these, you may want to invest in another type of test.
  • Parasitic infections are not covered by an OAT test.

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