Understanding Urine HVA/VMA Ratio on the OAp™ Organic Acids Profile
HVA/VMA Ratio
The Homovanillic acid (HVA) to Vanillylmandelic acid (VMA) ratio, also called the HVA/VMA ratio, on the OAp™ Organic Acids Profile provides critical insights into catecholamine metabolism, reflecting the balance between dopamine breakdown and its conversion to norepinephrine. By analyzing this ratio alongside microbial metabolites and dietary influences, practitioners can gain a comprehensive understanding of their patient’s neurotransmitter health and tailor interventions accordingly.
The HVA/VMA ratio reflects the balance between dopamine and norepinephrine/epinephrine. Catecholamines include dopamine (DA), norepinephrine (NE), and epinephrine (EPI) and play critical roles in neurobehavioral, cardiovascular, and metabolic processes.
Catecholamine Metabolism
The parent amino acid for all of these catecholamines is tyrosine, which can come from diet or the breakdown of phenylalanine. Catecholamine pathways can go to their next product, such as dopamine to norepinephrine, or to their breakdown products, HVA or VMA.
Homovanillic Acid (HVA):
- Dopamine + Dopamine beta-hydroxylase (DBH) + copper + vitamin C → Norepinephrine
- Dopamine + Monoamine oxidases (MAO) + B2 → 3,4-dihydroxyphenylacetic acid (DOPAC) → Catechol-O-methyltransferase (COMT) + SAM → HVA
Vanillylmandelic Acid (VMA):
- Norepinephrine + Phenylethanolamine-N-methyltransferase (PNMT) + SAM (cortisol) → Epinephrine
- Norepinephrine + Catechol-O-methyltransferase (COMT) + SAM → Monoamine oxidases (MAO) + B2 → VMA
- Epinephrine + Catechol-O-methyltransferase (COMT) + SAM → Monoamine oxidases (MAO) + B2 → VMA
Elevated HVA/VMA Ratio:
An elevated HVA/VMA ratio suggests that dopamine is breaking down to HVA instead of converting to norepinephrine. Dopamine is converted to norepinephrine via the DBH enzyme, which is dependent on copper and vitamin C as essential cofactors. If the HVA/VMA ratio is elevated, consider copper supplementation. Zinc supplementation has been reported to reduce GI uptake of copper, particularly at zinc levels attained with supplementation. Monitor the zinc-copper balance.1 Gut bacteria are also known to produce DBH inhibitors such as p-cresol.2 Evaluating gut microbial metabolites may give further insight into the ratio.
The DBH enzyme was noted to be reduced in Alzheimer's disease, autism, cardiovascular disease, and in major depression, though results are not consistent.3,4
Research has found HVA to be higher and 5-HIAA to be lower in participants with functional constipation, which could result in an increased HVA/VMA ratio.5
HVA: Impacts of Diet and Gut Microbial Metabolites
Homovanillic acid has been shown to increase with intestinal bacterial action on polyphenols, such as flavonoids, and on tyrosine. Both polyphenols and tyrosine have phenolic functionality, which bacteria can act on and produce HVA. Phenolic functionality means a compound has a 6-member aromatic ring and a bonded –OH group. Phenol is the simplest polyphenol. Evaluate the Microbial Metabolites section of the OAp Organic Acids Profile.
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HVA is formed as a metabolite of dietary quercetin-based flavonoids when they reach the large intestine. Colonic bacteria release 3,4-dihydroxyphenylacetic acid (DOPAC), which is absorbed into the bloodstream and methylated in the liver to HVA.
- In a double-blind, controlled parallel dietary intervention of phenols and polysaccharides (olive paste), researchers found statistically significant increases in urine levels of HVA with higher polyphenol intake (n=62).6
- Dietary flavanol (such as onions, tomatoes, and tea) intake significantly increased urinary HVA excretion (n=17).7
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Bifidobacterium longum has been found to directly produce HVA and Roseburia intestinalis promoted its growth in animal studies. B. longum directly produced HVA from tyrosine, following the intake of tyrosine-rich foods, such as lean meat, fish, dairy products, and nuts.8
- Research has noted that both tyrosine and phenylalanine can be converted to p-cresol, which can inhibit DBH, leading to increased HVA levels.9
- Evaluate phenylalanine microbial metabolites in the Microbial Metabolite section. 4-hydroxyphenylacetic acid (4-HPA) is a direct precursor of p-cresol.
Low HVA/VMA Ratio:
A lower HVA/VMA ratio suggests that the conversion of dopamine to norepinephrine is happening as expected. Since the HVA is not detectable at the very low end if the HVA result is below its detection limit (<dl), the HVA/VMA ratio cannot be calculated and is listed as N/A.
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Author Betsy Redmond, Ph.D., MMSc, RDN
Dr. Redmond has 30 years experience in nutrition with a focus on functional laboratory assessment, research and application. She is a registered dietitian-nutritionist, with a Masters' degree in clinical nutrition from Emory University and a PhD in nutrition from the University of Georgia. Dr. Redmond is the past president of Dietitians in Integrative and Functional Medicine and the recipient of the Excellence in Practice award...
The opinions expressed in this presentation are the author's own. Information is provided for informational purposes only and is not meant to be a substitute for personal advice provided by a doctor or other qualified health care professional. Patients should not use the information contained herein for diagnosing a health or fitness problem or disease. Patients should always consult with a doctor or other health care professional for medical advice or information about diagnosis and treatment.
References:
- EFSA Scientific Committee; More SJ, Bampidis V, Benford D, Bragard C, Halldorsson TI, Hernández-Jerez AF, Bennekou SH, Koutsoumanis K, Lambré C, Machera K, Mullins E, Nielsen SS, Schlatter JR, Schrenk D, Turck D, Younes M, Boon P, Ferns GA, Lindtner O, Smolders E, Wilks M, Bastaki M, de Sesmaisons-Lecarré A, Ferreira L, Greco L, Kass GEN, Riolo F, Leblanc JC. Re-evaluation of the existing health-based guidance values for copper and exposure assessment from all sources. EFSA J. 2023 Jan 17;21(1):e07728. doi: 10.2903/j.efsa.2023.7728.
- DeWolf WE Jr, Carr SA, Varrichio A, Goodhart PJ, Mentzer MA, Roberts GD, Southan C, Dolle RE, Kruse LI. Inactivation of dopamine beta-hydroxylase by p-cresol: isolation and characterization of covalently modified active site peptides. Biochemistry. 1988 Dec 27;27(26):9093-101.
- Cross AJ, Crow TJ, Perry EK, Perry RH, Blessed G, Tomlinson BE. Reduced dopamine-beta-hydroxylase activity in Alzheimer's disease. Br Med J (Clin Res Ed). 1981 Jan 10;282(6258):93-4.
- Hamner MB, Gold PB. Plasma dopamine beta-hydroxylase activity in psychotic and non-psychotic post-traumatic stress disorder. Psychiatry Res. 1998 Feb 27;77(3):175-81.
- Chojnacki J, Popławski T, Kaczka A, Romanowska N, Chojnacki C, Gąsiorowska A. Assessment of Urinary Dopamine and Serotonin Metabolites in Relation to Dysbiosis Indicators in Patients with Functional Constipation. Nutrients. 2024 Sep 4;16(17):2981.
- Conterno, L., et al., Measuring the impact of olive pomace enriched biscuits on the gut microbiota and its metabolic activity in mildly hypercholesterolaemic subjects. Eur J Nutr, 2019. 58(1): p. 63-81.
- Combet E, Lean ME, Boyle JG, Crozier A, Davidson DF. Dietary flavonols contribute to false-positive elevation of homovanillic acid, a marker of catecholamine-secreting tumors. Clin Chim Acta. 2011 Jan 14;412(1-2):165-9.
- Zhao M, Ren Z, Zhao A, Tang Y, Kuang J, Li M, Chen T, Wang S, Wang J, Zhang H, Wang J, Zhang T, Zeng J, Liu X, Xie G, Liu P, Sun N, Bao T, Nie T, Lin J, Liu P, Zheng Y, Zheng X, Liu T, Jia W. Gut bacteria-driven homovanillic acid alleviates depression by modulating synaptic integrity. Cell Metab. 2024 May 7;36(5):1000-1012.e6.
- Zheng Y, Bek MK, Prince NZ, Peralta Marzal LN, Garssen J, Perez Pardo P, Kraneveld AD. The Role of Bacterial-Derived Aromatic Amino Acids Metabolites Relevant in Autism Spectrum Disorders: A Comprehensive Review. Front Neurosci. 2021 Oct 21;15:738220.