Organic Acids, Comprehensive, Quantitative, Urine [Quest Diagnostics]

2-Hydroxyglutaric acid is identifiable in urine by routine organic acid analysis.

What is 2-hydroxyglutaric aciduria?

2-hydroxyglutaric aciduria is a rare neurometabolic disorder characterized by the significantly elevated levels of hydroxyglutaric acid in one's urine. It is either autosomal recessive or autosomal dominant.

2-hydroxyglutaric aciduria is a condition that causes progressive damage to the brain. The major types of this disorder are called D-2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA).

2-Hydroxyisocaproic acid (aka Leucic acid / α-hydroxyisocaproic acid / HICA) is a metabolite of the branched-chain amino acid leucine.

2-Hydroxyisovaleric acid (aka 2-Hydroxy-3-methylbutyric acid) is a branched-chain amino acid metabolite.

2-Methyl-3-hydroxybutyric acid, which is also known as 3-Hydroxy-2-methyl-butanoic acid (HMBA) is a normal urinary metabolite involved in the isoleucine catabolism, as well as presumably beta-oxidation of fatty acids and ketogenesis, excreted in abnormally high amounts in beta-ketothiolase deficiency.

Beta-ketothiolase deficiency is an inherited disorder in which the body cannot effectively process a protein building block (amino acid) called isoleucine. This disorder also impairs the body's ability to process ketones, which are molecules produced during the breakdown of fats.

2-Methylacetoacetic acid is a metabolite that has an increased excretion in patients with acetoacetyl-CoA thiolase deficiency. Thiolases are ubiquitous and important enzymes. Several isoenzymes are known, which can occur in the cytosol, the mitochondria, or the peroxisomes. Thiolases are CoA-dependent enzymes which catalyze the formation of a carbon-carbon bond in a Claisen condensation step and its reverse reaction via a thiolytic degradation mechanism. Mitochondrial acetoacetyl-coenzyme A (CoA) thiolase (T2) is important in the pathways for the synthesis and degradation of ketone bodies as well as for the degradation of 2-methylacetoacetyl-CoA. Moreover, 2-methylacetoacetic acid is found to be associated with beta-ketothiolase deficiency, which is also an inborn error of metabolism. 2-Methylacetoacetic acid is found in urine and can be used as a biomarker for the diagnosis of beta-ketothiolase deficiency.

2-OH-3ME-Valeric (aka 3-Methyl-2-oxovaleric acid) is an abnormal metabolite that arises from the incomplete breakdown of branched-chain amino acids. 

Moderate increase may result from lactic acidosis, episodic ketosis, or thiamine/lipoic acid deficiency. Significant elevations are associated with genetic issues, MSUD, and pyruvate dehydrogenase deficiency.

- 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.

3-Methyl-2-oxovaleric acid is an abnormal metabolite that arises from the incomplete breakdown of branched-chain amino acids. 

Moderate increase may result from lactic acidosis, episodic ketosis, or thiamine/lipoic acid deficiency. Significant elevations are associated with genetic issues, MSUD, and pyruvate dehydrogenase deficiency.

- 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-OXO-Butyric Acid is also known as Alpha-ketobutyric acid.

- Alpha-ketobutyric acid results from the breakdown of threonine or methionine during glutathione production.

- Specifically, cystathionine is metabolized to alpha-ketobutyric acid and cysteine.

- a- ketobutyric acid enters the mitochondrial matrix and get converted to propionyl-CoA by the branched chain keto-acid dehydrogenase complex (BCKDHC) and enters the Krebs cycle at succinyl-CoA.

- Evaluate lactate and the branched chain keto acids

- Evaluate alpha-hydroxybutyric acid

- Associated Nutrients: Vitamin B3

- a -Ketobutyric acid is produced from cystine, along with hydrogen sulfide (H2S) as a by-product.

- a- Ketobutyric acid is reversibly converted to a- hydroxybutyric acid.

2-Oxoglutaric acid is an organic acid that is important for the proper metabolism of all essential amino acids. It is formed in the Krebs cycle, the energy-producing process that occurs in most body cells.

2-Oxoisocaproic acid (also known as Ketoleucine) is an abnormal metabolite that arises from the incomplete breakdown of branched-chain amino acids.

2-Oxoisocaproic acid is both a neurotoxin and a metabotoxin.

2-Oxoisovaleric acid is an abnormal metabolite that arises from the incomplete breakdown of branched-chain amino acids (=BCAA). 2-Oxoisovaleric acid is a neurotoxin, an acidogen, and a metabotoxin. 

Metabolite of phenylalanine via phenyl pyruvate.

3-Hydroxyisovaleric Acid (3-HIA) is formed from the metabolism of the branched-chain amino acid leucine. Methylcrotonyl-CoA carboxylase catalyzes an essential step in this pathway and is biotin dependent. Reduced activity of this enzyme leads to an alternate pathway of metabolism resulting in 3-hydroxyisovaleric acid.

3-Hydroxypropionic acid (3-HPA) is a major urinary metabolite of propionic acid. Propionic acid is derived from dietary branched-chain amino acids, odd-chain fatty acids, and can be produced in the gut by bacterial fermentation of fiber. The biotindependent enzyme propionyl CoA carboxylase is responsible for metabolizing propionic acid to methylmalonyl CoA, which is subsequently isomerized to succinyl CoA. Decreased activity of this enzyme shunts propionyl CoA into alternative pathways which form 3-HPA.

3-Hydroxyvaleric acid may be products of the condensation of propionyl-CoA with acetyl-CoA catalyzed by 3-oxoacyl-CoA thiolases. An increase amount of 3-hydroxyvaleric acid can be found in methylmalonic acidemia and propionic acidemia. 

4-hydroxyphenyllactate is present in relatively higher concentrations in the cerebrospinal fluid and urine of patients with phenylketonuria (PKU) and tyrosinemia.

A moderate urinary increase in 4-hydroxybutyric acid may be due to intake of dietary supplements containing 4-hydroxybutyric acid, also known as gamma-hydroxybutyric acid. Very high levels may indicate the genetic disorder 3-methylglutaconic aciduria involving succinic semialdehyde dehydrogenase deficiency.

3-Hydroxyphenylacetic acid and 4-hydroxyphenylacetic acid are produced by the bacterial fermentation of amino acids, much like Indoleacetic acid (IAA).

AKA: 4-Hydroxyphenylpyruvate, 4-HPPA

4-hydroxyphenylpyruvic acid is an intermediate in the breakdown of phenylalanine.

4-hydroxyphenylpyruvic acid is converted to homogentisate; a blockage at this step results in increased homogentisate, which can be diagnostic of alkaptonuria.

If the pathway is not blocked, 4-HPPA ends up in the Krebs cycle converted into fumaric acid.

Pyroglutamate (or 5-Oxoproline) is an intermediate in the glutathione metabolism and a marker of glutathione deficiency.

Acetoacetic acid (=acetoacetate) is a ketone body and a weak Beta-keto acid produced from acetyl-CoA in the mitochondrial matrix of hepatocytes.

Elevated in mitochrondrial disorders. Aconitase metabolizes citric and aconitic acids, and is dependent on glutathione.

Dietary fatty acids are metabolized into fuel sources using beta-oxidation. Fatty acid conversion into Acetyl-CoA requires transport across the mitochondrial membrane via the carnitine shuttle. When beta-oxidation is impaired, fats are metabolized using an alternate pathway called omega-oxidation. Omega-oxidation results in elevated levels of dicarboxylic acids such as adipic acid and suberic acid. Impaired beta-oxidation occurs in carnitine deficiency or enzymatic dysfunction due to lack of nutrient cofactors. Vitamin B2 and magnesium play a role in optimizing beta-oxidation.

Citric acid, cis-aconitic acid, and isocitric acid are the first three metabolites in the Krebs Citric Acid energy production cycle, which operates in the mitochondria of your cells. 

Fumarate (together with Succinate and Malate) is used in the body’s metabolic pathway that generates cellular energy – the Citric Acid Cycle.

Glyceric acid is an organic acid that stems from the catabolism of the amino acid serine. Severe elevations in glyceric acid are an indication of a rare inborn error of metabolism known as glyceric aciduria. One form of glyceric aciduria is the result of a defect in the enzyme glycerate kinase which removes glyceric acid from the system. While many case studies have linked this disorder with severe developmental abnormalities, there is some debate as to whether glycerate kinase deficiency is the cause or rather a confounding variable. Another glyceric aciduria is referred to as primary hyperoxaluria type 2 (PH2). This rare genetic condition results in excessive production of oxalates in the system in the form of oxalic acid. Over time, systemic deposition of oxalates in body tissues can occur which is a process known as oxalosis. This disease is characterized by urolithiasis, nephrocalcinosis, and deposition of oxalates in other body tissues.

Urinary hexanoylglycine is a specific marker for the diagnosis of Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. 

Isobutyrylglycine is an acyl glycine. Acyl glycines are normally minor metabolites of fatty acids. However, the excretion of certain acyl glycines is increased in several inborn errors of metabolism.

In certain cases the measurement of these metabolites in body fluids can be used to diagnose disorders associated with mitochondrial fatty acid beta-oxidation.

A two-carbon group from Acetyl-CoA is transferred to oxaloacetate to form citric acid. Citric acid is then converted to isocitric acid through a cis-aconitic intermediate using the enzyme aconitase. Aconitase is an iron-sulfate protein that controls iron homeostasis.

Lactic acid (Lactate) and pyruvic acid are byproducts of glycolysis. Carbohydrates, which contain glucose, are broken down through glycolysis to form pyruvate and two ATP molecules. Pyruvate can also be generated through the catabolism of various amino acids, including alanine, serine, cysteine, glycine, tryptophan and threonine. Magnesium is an important cofactor for a number of glycolytic enzymes necessary to produce pyruvate. Optimally, pyruvic acid is oxidized to form Acetyl-Co-A to be used aerobically via the Krebs Cycle to produce energy. In an anaerobic state, lactic acid is formed instead.

This test measures the level of lactic acid (also known as lactate) in your blood. Lactic acid is the endproduct of the anaerobic metabolism of glucose. The blood lactic acid concentration is affected by its production in muscle cells and erythrocytes and its rate of metabolism in the liver. 

Fumaric acid uses the fumarase enzyme to become malic acid. Malate dehydrogenase catalyzes the conversion of malic acid into oxaloacetate. Two forms of this enzyme exist in eukaryotes. One operates within the mitochondria to contribute to the Citric Acid Cycle; the other is in the cytosol where it participates in the malate/ aspartate shuttle. Riboflavin is an important cofactor for this enzyme and overall mitochondrial energy production and cellular function. At the end of each Citric Acid Cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues.

Malonic acid is found to be associated with malonyl-CoA decarboxylase deficiency, which is an inborn error of metabolism. The name “Malonic” originates from Latin malum, meaning apple. Malonic acid is the archetypal example of a competitive inhibitor: it acts against succinate dehydrogenase (complex II) in the respiratory electron transport chain. 

Methylcitric is an organic acids that reflects decreased activity of the biotin-dependent enzyme propionyl-CoA carboxylase.

Other names: Methylmalonic Acid or MMA

Methylmalonic acid (MMA) is a substance produced in very small amounts and is necessary for human metabolism and energy production. In one step of metabolism, vitamin B12 promotes the conversion of methylmalonyl CoA (a form of MMA) to succinyl Coenzyme A. If there is not enough B12 available, then the MMA concentration begins to rise, resulting in an increase of MMA in the blood and urine. The measurement of elevated amounts of methylmalonic acid in the blood or urine serves as a sensitive and early indicator of vitamin B12 deficiency.

N-Valerylglycine (also known as N-Pentanoylglycine) is an acyl derivative of Glycine. The presence of N-Valerylglycine (among other metabolites) in urine is used in medicine to diagnose inborn errors of metabolism (such as mitochondrial fatty acid b-oxidation defects) through the use of liquid chromatography coupled with tandem mass spectrometry.

Phenylacetic acid (PAA) is produced by the bacterial metabolism of phenylalanine. Several bacterial strains are known to produce PAA, including Bacteroidetes and Clostridium species. Dietary polyphenols may also contribute to PAA elevation.

Phenyllactic acid is a metabolite of phenylalanine.

Phenylpyruvic acid is a keto-acid that is an intermediate or catabolic byproduct of phenylalanine metabolism. It has a slight honey-like odor. 

Propionylglycine is a N-acylglycine obtained by formal condensation of the carboxy group of propionic acid with the amino group of glycine. It has a role as a human urinary metabolite. It is functionally related to a propionic acid. It is a conjugate acid of a propionylglycinate. 

Lactic acid and pyruvic acid are byproducts of glycolysis. Carbohydrates, which contain glucose, are broken down through glycolysis to form pyruvate and two ATP molecules. Pyruvate can also be generated through the catabolism of various amino acids, including alanine, serine, cysteine, glycine, tryptophan and threonine.92 Magnesium is an important cofactor for a number of glycolytic enzymes necessary to produce pyruvate.93 Optimally, pyruvic acid is oxidized to form Acetyl-Co-A to be used aerobically via the Krebs Cycle to produce energy. In an anaerobic state, lactic acid is formed instead.

Increased urinary products of the omega fatty acid metabolism pathway may be due to carnitine deficiency, fasting, or increased intake of triglycerides from coconut oil, or some infant formulas.

Dietary fatty acids are metabolized into fuel sources using beta-oxidation. Fatty acid conversion into Acetyl-CoA requires transport across the mitochondrial membrane via the carnitine shuttle.80 When beta-oxidation is impaired, fats are metabolized using an alternate pathway called omega-oxidation. Omega-oxidation results in elevated levels of dicarboxylic acids such as adipic acid and suberic acid. Impaired beta-oxidation occurs in carnitine deficiency or enzymatic dysfunction due to lack of nutrient cofactors. Vitamin B2 and magnesium play a role in optimizing beta-oxidation.

Succinate (or succinic acid) is an important metabolite that is involved in several chemical processes in the body.

Succinylacetone (SA) is used for the diagnosis and monitoring of patients with tyrosinemia type I (Tyr I). Succinylacetone is exclusively elevated in blood and urine of patients with tyrosinemia type I . As urinary Succinylacetone concentration is much higher than blood, Succinylacetone is usually tested in urine samples.

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.

- Thymine is one of the five bases used to build nucleic acids.
- It is also known as 5-methyluracil or by the abbreviations T or Thy.
- Thymine is found in DNA, where it pairs with adenine via two hydrogen bonds. In RNA, thymine is replaced by uracil.

Trans-Cinnamoylglycine is one component of the Acylglycines panel.

Acylglycines are an important class of metabolites that are used in the diagnosis of several organic acidurias and mitochondrial fatty acid oxidation disorders.

The pyrimidine metabolites are markers of folate metabolism. The two markers are uracil and thymine. Folate acts as a methyl donor in converting uracil to thymine.

Elevated values of uracil suggest folic acid deficiency. Folate is needed to convert uracil to thymine by methylation.