2-Hydroxyhippuric Acid

2-Hydroxyhippuric acid, or salicyluric acid, is a metabolite derived from the conjugation of glycine with salicylate, a process influenced by the body’s detoxification systems and gut microbiota activities.

 Commonly recognized as a uremic toxin, its presence is significant in the study of metabolic pathways and xenobiotics in humans. 

This compound plays a crucial role in binding metal ions, which is indicative of its importance in metal-related toxicity and potential therapeutic applications.

Recent studies have highlighted its elevated levels in the urine of autistic children with atopic dermatitis (AD), suggesting heightened metabolic or detoxification activities involving salicylic acid in these individuals. T

his finding points to a possible link between 2-hydroxyhippuric acid and gastrointestinal issues commonly observed in autism, raising questions about its broader implications in metabolic disorders and microbiota functions.

What is 2-Hydroxyhippuric Acid?  [1., 4., 6., 8.]

2-Hydroxyhippuric acid, also known as salicyluric acid, is a uremic toxin and a metabolite of xenobiotics in humans.  The production of 2-Hydroxyhippuric Acid is closely linked to the body’s detoxification mechanisms.

It is formed through the conjugation of glycine with salicylate, notably influenced by microbiota activities and metabolic processes in the body, and has been observed in studies involving Saccharomyces cerevisiae and certain plants. 

This compound's interactions, particularly in complex systems involving dimethyltin(IV) at varying pH levels, highlight its significant role in binding metal ions, which is crucial in understanding its behavior in biological systems and its potential implications in biomedical research on metal-related toxicity and therapeutic mechanisms.

2-Hydroxyhippuric Acid and Autism [6.]

In a study exploring the gut microbiota and urinary organic acids in autistic children with and without atopic dermatitis (AD), 2-hydroxyhippuric acid was one of the organic acids analyzed. 

It was found in higher concentrations in the urine of children with AD compared to those without AD.  Specifically, the level of 2-hydroxyhippuric acid was 1.438 ± 2.057 mmol/mmol creatinine in the AD group, compared to 0.616 ± 0.414 mmol/mmol creatinine in the control group, which was statistically significant (P = 0.048). 

This suggests an increased metabolic processing or detoxification activity involving salicylic acid in children with AD, which could be linked to the gastrointestinal issues commonly reported in individuals with autism.

What Are Organic Acids?  [3., 5.]

Organic acids are organic compounds with acidic properties.  They include a variety of functional groups like carboxyl, phenol, enol, and thiol, with carboxylic acids having the strongest acidity.

Organic acids are considered weak acids, with those containing phenol, enol, alcohol, or thiol groups being even weaker.  

Their structures vary in terms of carbon chain types—aromatic, aliphatic, alicyclic, heterocyclic—saturation, substitutions, and the number of functional groups. 

These acids play critical roles in metabolic and catabolic pathways, notably in the tricarboxylic acid cycle inside mitochondria, which is central to energy production in eukaryotes.  They are also pivotal in determining the sensory properties of fruits and vegetables.

Organic Acid Disorders  [2., 9.]

Organic acid disorders are inherited metabolic conditions that affect the enzymes or transport proteins essential for the breakdown of amino acids, lipids, or carbohydrates. They are marked by the excessive excretion of non-amino organic acids in urine, primarily due to defects in specific enzymes involved in amino acid breakdown that cause buildup of organic acids in tissues.

Conditions can manifest as inborn metabolic disorders of organic acids and amino acids, urea cycle anomalies, and mitochondrial respiratory chain deficiencies.

These disorders are typically passed down through autosomal recessive inheritance.  They often present in newborns with symptoms like vomiting and lethargy, progressing to more severe neurological symptoms. 

Early diagnosis and intervention are critical and can improve outcomes. Diagnostic methods include urine organic acid analysis via gas chromatography-mass spectrometry (GC/MS). 

Current treatments focus on managing symptoms and preventing complications, although definitive therapies are still under research.  Treatment focuses may include dietary management, detoxifying harmful metabolites, and in severe cases, organ transplantation. 

Continuous monitoring and management are essential for managing symptoms and preventing complications.

Organic Acids and the Microbiome  [5.]

Increasingly, research highlights new relationships between the microbiome and human health.  Many organisms that comprise the microbiome produce organic acids that can then be tested for additional diagnostic capability.  

Certain organic acids in urine like hippuric acid, benzoic acid, and indoleacetic acid are metabolites produced by gut bacteria from the breakdown of amino acids, dietary polyphenols, and other substances. 

These acids provide insights into gut health and metabolic functions.  For example, elevated levels of certain acids may indicate gut dysbiosis or specific metabolic imbalances, such as phenylketonuria. 

Some organic acids known to be produced by the microbiome include: 

Benzoic Acid (BA): 

Produced from phenylalanine and polyphenol metabolism by intestinal bacteria. High levels in urine can indicate glycine deficiency or liver dysfunction.

Hippuric Acid (HA):

Formed in the liver by conjugation of benzoic acid with glycine. Elevated levels may indicate exposure to environmental toxins like toluene.

Phenylacetic Acid (PAA) and Phenylpropionic Acid (PPA): 

These acids result from phenylalanine metabolism by gut bacteria. High urinary levels can suggest dysbiosis or disorders like phenylketonuria. PAA is also associated with depression markers.

4-Hydroxybenzoic Acid (4-HBA) and 4-Hydroxyphenylacetic Acid (4-HPAA): 

Derivatives of tyrosine metabolism. 4-HBA is linked to catechin (green tea) metabolism, and 4-HPAA is useful in diagnosing small bowel diseases related to bacterial overgrowth.

3-Hydroxyphenylpropionic Acid (3-HPPA): 

A metabolite from dietary polyphenols like proanthocyanidins, indicative of robust bacterial metabolism in the intestines.

3,4-Dihydroxyphenyl Propionic Acid (3,4-DHPPA): 

Produced from dietary quinolones by clostridial species, with high levels suggesting an overgrowth.

3-Indoleacetic Acid (IAA): A breakdown product of tryptophan by gut bacteria such as Bifidobacterium and Bacteroides. Elevated levels are seen in conditions like phenylketonuria or dietary changes.

These organic acids are important markers in clinical diagnostics, helping to monitor metabolic disturbances, gut microbiota balance, and exposure to environmental toxins.

Their presence and concentration are influenced by diet, gut microbiota composition, and overall metabolic health, making them valuable indicators in clinical settings for assessing both metabolic and gastrointestinal conditions.

Organic Acid Testing in Functional Medicine

Organic Acid Testing in Functional Medicine

In functional medicine, organic acid testing is utilized to evaluate a patient's metabolic function through a simple urine test. This testing can identify metabolic imbalances that may affect a patient’s mood, energy, and overall health. 

Testing provides insights into nutrient deficiencies, dietary habits, toxic exposures, and gut microbiome activity. 

The results assist practitioners in customizing treatment plans to address specific metabolic dysfunctions and improve health outcomes. 

Additionally, it helps in assessing the impact of microbial metabolism and the efficiency of the Krebs Cycle, aiding in personalized healthcare.

Lab Testing for 2-Hydroxyhippuric Acid

Test Information, Sampling Methods and Preparation

Laboratory testing for organic acids including 2-Hydroxyhippuric Acid is typically done in urine, although it can also be tested in blood.  Testing may be ordered to diagnose an inborn metabolic disorder, or to assess metabolic function and gastrointestinal health in a functional medicine setting.  

Urine samples may be collected in a clinical setting; they can also be collected at home.  Some labs recommend or require a first morning void sample, to provide a concentrated sample.  

Interpreting 2-Hydroxyhippuric Acid Results

Optimal Range for 2-Hydroxyhippuric Acid Testing

Generally, falling within reference ranges for organic acids is recommended, although for many of these organic acids, a level towards the lower end of the reference range is considered optimal.  

It is essential to consult with the laboratory company used for their recommended reference range for 2-Hydroxyhippuric Acid.  Organic acids are typically reported in units per unit of creatinine.  

Clinical Significance of Elevated Levels of 2-Hydroxyhippuric Acid

Elevated levels of 2-Hydroxyhippuric Acid are commonly associated with increased salicylate metabolism and/or xenobiotic exposure.  It may also indicate an overgrowth of salicylate-producing bacteria in the microbiome.  

Clinical Significance of Low Levels of 2-Hydroxyhippuric Acid

Low levels of 2-Hydroxyhippuric Acid are not considered clinically relevant.  

2-Hydroxyhippuric Acid Related Biomarkers and Comparative Analysis

2-Hydroxyhippuric Acid is typically tested along with other organic acids to gain deeper insights into metabolic pathways and physiological processes.

Organic acids that may be tested as part of a panel include: 

‍2-Hydroxybutyric Acid: this acid is a marker for insulin resistance and increased oxidative stress.

‍2-Hydroxyphenylacetic Acid: derived from phenylalanine metabolism, this acid is used as a biomarker in various metabolic assessments.

‍3-Hydroxybutyric Acid: a ketone body produced during fat metabolism, indicative of carbohydrate deprivation or ketogenic conditions.

3-Hydroxyisovaleric Acid: an organic acid that accumulates in leucine catabolism disorders, often elevated in maple syrup urine disease.

3-Indoleacetic Acid: a metabolite of tryptophan, it is significant in the study of serotonin pathways and plant growth regulation.

‍4-Hydroxybenzoic Acid: a derivative of tyrosine metabolism, it is linked to catechin (green tea) metabolism and may be produced by some intestinal bacteria.

‍4-Hydroxyphenyllactic Acid: a metabolite associated with disorders of tyrosine metabolism.

4-Hydroxyphenylacetic Acid: a breakdown product of tyrosine, used in diagnosing disorders involving the degradation of aromatic amino acids.

5-Hydroxyindoleacetic Acid: the main metabolite of serotonin, used as a marker in the diagnosis of carcinoid syndrome.

‍Adipic Acid: a dicarboxylic acid that can also be formed metabolically in humans through the oxidation of certain fatty acids.

a-Keto-b-Methylvaleric Acid: an intermediate in isoleucine metabolism, which can accumulate in certain metabolic disorders.

a-Ketoisocaproic Acid: an intermediate in the metabolism of leucine, elevated in maple syrup urine disease

a-Ketoisovaleric Acid: a breakdown product of valine metabolism, also linked to maple syrup urine disease.

a-Ketoglutaric Acid: a key intermediate in the citric acid cycle, essential for energy production and nitrogen transport.

‍Benzoic Acid: produced from phenylalanine and polyphenol metabolism by intestinal bacteria. High levels in urine can indicate glycine deficiency or liver dysfunction.

Cis-Aconitic Acid: an intermediate in the tricarboxylic acid cycle, formed by the dehydration of citric acid.

Citric Acid: a central compound in the citric acid cycle, crucial for energy production in cells.

Ethylmalonic Acid: this acid accumulates in ethylmalonic encephalopathy and is involved in fatty acid metabolism.

Fumaric Acid: an intermediate in the tricarboxylic acid (TCA) cycle, participating in energy production through its conversion to malate and subsequent participation in the generation of ATP.

Homovanillic Acid: a major metabolite of dopamine, used as a marker to monitor dopamine levels.

Hippuric Acid: formed from the conjugation of benzoic acid and glycine; elevated levels can indicate exposure to certain environmental toxins.

Hydroxymethylglutarate: an intermediate in leucine metabolism, also associated with disorders of ketogenesis and ketolysis.

Isocitric Acid: an isomer of citric acid and an important part of the citric acid cycle, pivotal in cellular energy production.

Kynurenic Acid: a product of tryptophan metabolism, known for its role as a neuroprotective agent.

Lactic Acid: produced from pyruvate via anaerobic metabolism, an indicator of hypoxia and strenuous exercise.

Malic Acid: a dicarboxylic acid found in fruits, and involved  in the citric acid cycle.

Methylmalonic Acid: an indicator of Vitamin B12 deficiency, it accumulates when the vitamin is deficient.

‍Methylsuccinic Acid: a dicarboxylic acid often involved in alternative pathways of fatty acid metabolism.

Orotic Acid: involved in the metabolism of pyrimidines, abnormalities in its levels can indicate metabolic disorders.

Pyroglutamic Acid: an uncommon amino acid derivative that can accumulate in glutathione synthesis disorders.

Pyruvic Acid: a key intersection in several metabolic pathways; its levels are crucial for assessing cellular respiration and metabolic function.

‍Quinolinic Acid: a neuroactive metabolite of the kynurenine pathway, elevated levels are associated with neurodegenerative diseases.

Suberic Acid: a dicarboxylic acid that is a biomarker in adipic aciduria, often studied in relation to fatty acid oxidation disorders.

Succinic Acid: a four-carbon dicarboxylic acid that plays a central role in the Krebs cycle, crucial for energy production.

Tricarballylic Acid: an organic acid that can inhibit aconitase in the citric acid cycle and is sometimes associated with glyphosate exposure.

Vanillylmandelic Acid: a metabolite of epinephrine and norepinephrine, used as a marker for neuroblastoma and other catecholamine-secreting tumors.

Order Organic Acids Testing

Click here to compare testing options and order organic acid testing.