Hompes MethodLesson 29 –

Organic Acids – Part Four

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B-Vitamins

• In the last lesson we looked at how a whole selection of organic acid markers can provide us with an understanding of a person’s B vitamin status:

– α-ketoisovalerate

– α-ketoisocaproate

– α-keto-β-methylvalerate

– Xanthurenate

– β-Hydroxyisovalerate

– Methylmalonate

– Formiminoglutamate

B-Vitamins

• Remember that the B vitamins are also heavily involved with sugar metabolism, so when you see them pop up in different sections of the organic acids test, it’s pretty clear that B-vitamins are going to be helpful in that person’s programme.

Neurotransmitter Metabolism

• B vitamins are also heavily involved in the next section of the organic acids profile, in which we’re able to get a window into neurotransmitter metabolism.

Neurotransmitter Metabolism

• A neurotransmitter is a substance that enables nerve impulses (action potentials) to travel from nerve to nerve so the cells can communicate with each other. They impact mood, personality and behaviour, amongst other things (including digestion).

Neurotransmitter Metabolism

• I recommend several books for a full and complete discussions on neurotransmitters:– The Mood Cure - Julia

Ross

– The Edge Effect – Eric Braverman

– Why Isn’t My Brain Working? – DatisKharrazian

Neurotransmitter Metabolism

• Neurotransmitters interact with hormones and their activity is affected by toxins, inflammation and autoimmune situations, as well as nutritional deficiencies.

Neurotransmitter Metabolism

• Tests are available to look at neurotransmitter levels per se – usually in urine – though controversy exists regarding the best way to do the tests and how accurate they actually are.

• We are currently exploring all the different options with a view to developing work in this area, and also developing a specific advanced training module that fits in with an advanced hormone balance training module.

Neurotransmitter Metabolism

• The four primary neurotransmitters are:

– Acetylcholine – learning and memory

– Dopamine – pleasure and reward

– Serotonin – happy and joyful

– GABA – calm and relaxed

Neurotransmitter Metabolism

• The organic acids panel provides some information regarding the metabolism of the serotonin and dopamine pathways, but not the acetylcholine and GABA pathways.

Vanilmandelate and Homovanillate

• Vanilmandelate, also known as vanilmandelic or vanillyl-mandelic acid (VMA), is the main metabolite of the catecholamines, epinephrine, and norepinephrine. Homovanillate (HVA) is the main metabolite of dopamine that appears in urine.

Vanilmandelate and Homovanillate

• Low urinary levels of VMA and HVA have been associated with low CNS levels of these neurotransmitters. Symptoms associated with this condition include depression, sleep disturbances, anxiety, and fatigue.

Vanilmandelate and Homovanillate

• Elevated levels of VMA and HVA signal an increased rate of synthesis and degradation in normal tissue or abnormal production by tumor tissue. Neuroblastictumors frequently cause a profound elevation in VMA, which may be expressed as the VMA/HVA ratio.

Vanilmandelate and Homovanillate

• In the absence of such disease processes, increased catecholamine synthesis results from the synergism of pituitary adrenocorticotropic hormone and adrenal cortisol. This constitutes the widely recognized chronic stress response that manifests as heightened sympathetic reactions to stress.

Vanilmandelate and Homovanillate

• Just as an important aside, the catecholamines are:

– Adrenaline / epinephrine

– Noradrenaline / norepinephrine

• They are very important in our discussion of the stress response, which as I’ve said previously is much more than just cortisol.

Vanilmandelate and Homovanillate

• Vanilmandelate (VMA) is the breakdown product of both epinephrine and norepinephrine. Elevated levels indicate a high turnover of these fight or flight neurotransmitters. Phenylalanine and tyrosine are the amino acid precursors. Reducing stress and/or supplementing with calming herbs or compounds may help.

Vanilmandelate and Homovanillate

• Supplementing with tyrosine or phenylalanine may increase production. If levels are low it may indicate that these products are no longer being made due to adrenal exhaustion. Supplementing with needed amino acids and co-factors may help to increase levels. Co-factors include iron, tetrahydrobiopterin(BH4), vitamin B6, magnesium, and copper. Checking cortisol levels can help determine treatment.

Vanilmandelate and Homovanillate

• Homovanillate (HVA) is the breakdown product of dopamine. Its amino acid precursors are phenylalanine and tyrosine. Elevated levels indicate a high turnover. If levels are low it may indicate that these products are no longer being made due to adrenal exhaustion. Supplementing tyrosine or phenylalanine and co-factors may help to increase levels. If VMA is elevated and HVA is low it may indicate a need for copper.

Vanilmandelate and Homovanillate

Metametrix Organix Interpretive Guide

Vanilmandelate and Homovanillate

• The essential amino acid phenylalanine breaks down to tyrosine.

• Tyrosine is used in the production of thyroid hormones, melatonin in skin, and the neurotransmitters, dopamine, norepinephrine, and epinephrine.

• These neurotransmitters are further broken down and excreted.

• Dopamine is excreted as homovanillate, and norepinephrine and epinephrine are excreted jointly as vanilmandelate.

• High levels of these products in the urine identify a high turnover; low levels may indicate inadequate production.

Vanilmandelate and Homovanillate

• Intervention options for low HVA and VMA:

– Protein intake?

– Digestive efficiency?

• Tyrosine / phenylalanine

• Vitamin B6

• Copper – careful as can be toxic

• Iron – careful as can be toxic– For Fe and Cu, a full evaluation is needed before

recommending supplementation.

Vanilmandelate and Homovanillate

• Intervention options for high HVA and VMA:

– A thorough evaluation of physiological stressors is needed (nutrition, bugs, toxins, nutrient deficiencies, mental/emotional stress). Gradual unloading of physiological stress will be needed.

5-Hydroxyindoleacetate

• 5-Hydroxyindoleacetate (5-HIA) is the breakdown product of the neurotransmitter serotonin. 5-Hydroxytryptophan (5-HTP) is an intermediate in the production of serotonin (you may have heard of 5-HTP as a nutritional supplement).

5-Hydroxyindoleacetate

• The compound 5-HIA is measured as a marker of serotonin metabolism. When 5-HIA is elevated, it indicates higher than normal turnover of serotonin with potential depletion of tryptophan or a high turnover due to antidepressants such as serotonin re-uptake inhibitors (Prozac, Zoloft, etc.).

5-Hydroxyindoleacetate

The serotonin pathway requires certain nutritional compounds for optimal function – tryptophan, BH4, B6, B2 and copper.

Metametrix Organix Interpretive Guide

Kynurenate, Quinolinate, Picolinate

• While tryptophan makes serotonin, it can also go down another pathway to kynurenate, quinolinateand picolinate. These steps are B6 dependent. Xanthurenate has been used as a marker of need for B6. Quinolinate is a product of inflammation and is seen with oxidative stress, infections, or autoimmune disorders.

Kynurenate, Quinolinate, Picolinate

Metametrix Organix Interpretive Guide

Kynurenate, Quinolinate, Picolinate

http://www.metametrix.com/files/learning-center/leifm/book-Laboratory-Evaluations-in-Molecular-Medicine.pdf

Kynurenate, Quinolinate, Picolinate

• In general, the pathway in which kynurenic, xanthurenic, and quinolinic acids are formed from L-tryptophan serves the following functions:

– Clearance of excess L-tryptophan

– Maintenance of nicotinic acid levels

– Regulation of peripheral pain perception by CNS neurons

– Enhancing macrophage defense functions

Kynurenate, Quinolinate, Picolinate

• Quinolinate production is a link between the immune system and the brain. Chronic stimulation of the immune response causes release of interferon gamma by macrophages. Interferon gamma (IFN-γ) induces increased production of the enzyme, indoleamine-2,3-dioxygenase, that starts the pathway of tryptophan conversion to QUIN.

Kynurenate, Quinolinate, Picolinate

• Since the gut is a primary point of chronic inflammatory signal induction via interferon gamma, there is reason to suspect that QUIN elevation may indicate both inflammatory bowel conditions and neuronal degeneration. Within the brain, the hippocampus is an area rich in NMDA receptors and it is very sensitive to the neurotoxic effects of QUIN.

Kynurenate, Quinolinate, Picolinate

• If you see elevated quinolinate levels, suspect inflammation that’s likely the result of infections:

– Bacterial infection

– Viral infection

– Fungal and parasitic infections

– Meningitis

– Autoimmune diseases

– Septicemia

– Congenital hyperammonemia

Kynurenate, Quinolinate, Picolinate

• Elevated xanthurenate and kynurenate are worthy of B6

supplementation.

• Elevated quinolinate is worthy of exploration – why is QUIN elevated? – What infections could be involved?

– What does a GI test say?

– What do the Organix dybiosis markers look like?

– Lyme disease?

– Viral infection?

– Oral infection?

Picolinate

• For some reason, the lab literature doesn’t cover picolinate (neither the interpretive guide or the Lab Evaluations Manual). I found some information in an old Designs For Health Interpretation Guide for a combo test panel designed by my friend Laurent Bannock.

Picolinate

• Picolinate elevations are also caused by inflammatory processes induced by the immune system. High protein diets can increase production of picolinate whereas polyunsaturated fatty acids divert the flow through the kynurenin pathway to quinolinate. In cases of elevated urinary picolinate, supplemental mineral-picolinate salts may be contributing sources.

Picolinate

• Because picolinate is a marker of inflammation, the obvious remedy is to find the reasons for the inflammation and deal with them. It may be prudent to reduce red meat intake. Supplements that can assist include:

– Antioxidants (C, E, lipoic acid)

– Omega-3 fatty acids

Neurotransmitters & Stress

• Ultimately, this all comes down to:

Too much bad stuff in the body

+

inadequate good stuff

=

Stress

=

altered physiology

Neurotransmitters - Sample Report 1

Neurotransmitters - Sample Report 1

Oxidative Stress

• It’s noteworthy that the two sample reports also exhibit high levels of oxidative stress. Generally, higher levels of physiological stress will increase the amount of oxidative stress and damage, which is where we’ll now turn our attention.

Oxidative Stress

• Remember that oxidative stress goes hand in hand with inflammation. These two processes underlie symptom and disease development. Removing bad stuff and replacing good stuff should theoretically reduce inflammation and oxidative stress.

Oxidative Stress

Oxidative Stress

Oxidative Stress

• P-Hydroxyphenyllactate (HPLA) is a metabolite of tyrosine and a marker of cell turnover. It may be useful for studying disorders of tyrosine metabolism, including inborn errors of metabolism, and liver disease. Elevated HPLA is associated with tumor growth and leukemia. HPLA is also a marker of hepatic encephalopathy in patients with hepatic cirrhosis.

Oxidative Stress

• HPLA is an important regulator of normal and malignant cell growth, and it appears to mediate the cancer promoting effects of estrogen. Thus, high urinary HPLA signals an increased tissue growth response that may be associated with neoplastic disease or increased growth of normal tissue.

Oxidative Stress

• Elevated levels of HPLA result in a dramatic decrease of ascorbic acid (vitamin C) concentration in the liver, adrenal glands, and blood. High doses of ascorbic acid (100 mg/kg body weight daily) were shown to arrest or significantly inhibit the excretion of HPLA in patients with hemoblastoses and nephroblastoma.

http://www.metametrix.com/files/learning-center/leifm/book-Laboratory-Evaluations-in-Molecular-Medicine.pdf

Oxidative Stress

• When considering oxidative stress and explaining it to clients I find it helpful to imagine a pinball machine. You fire off the pinball and off it goes, bouncing around everywhere in a completely uncontrolled fashion. It bumps into things and causes damage (oxidative damage).

Oxidative Stress

• Sustained inflammatory responses cause increased production of reactive oxygen species (ROS). When local antioxidant protection fails to keep reactive oxygen species in check, there are molecular consequences for every class of structural molecule.

Oxidative Stress

• 8-Hydroxy-2’-deoxyguanosine (8-OHdG) is a product of oxidative damage to DNA. It is recognized as a useful marker in estimating DNA damage induced by oxidative stress. Oxidative DNA damage is common in various forms of chronic liver disease ,suggesting a link between chronic inflammation and hepatocarcinogenesis.

Oxidative Stress

• Why would the liver be chronically inflamed?

– Bad foods

– Bad bugs

– Bad toxins

– Plus inadequate levels of antioxidants, amino acids and other protective nutrients.

Oxidative Stress

• The antioxidant protection in young children was evaluated by urinary 8-OHdG. 8-OHdG formation is sufficiently sensitive to reveal even mild chronic effects of ROS. The association of cancer with chronic psychological stress and perceived overwork may be via the formation of 8-OHdG.

http://www.metametrix.com/files/learning-center/leifm/book-Laboratory-Evaluations-in-Molecular-Medicine.pdf

Oxidative Stress

• Increases in 8-OHdG with cigarette smoking is associated with aging and enhancement of oxidative damage in human lung tissues. 8-OHdG levels rise with age in adults with mild hypercholesterolemia or/and mild hypertension.

Oxidative Stress

• Lower levels of antioxidants may predispose to oxidative stress, which is manifested by higher levels of 8-OHdG. Levels of 8-OHdG were significantly higher in atherosclerotic patients and vitamin C levels were significantly lower. This oxidative stress may promote and worsen atherosclerosis.

Oxidative Stress

• Exposure to organochlorines does not result in elevated 8-OHdG, indicating that the genotropiceffects of this compound are exerted through mechanisms other than ROS formation. A similar conclusion may be reached regarding moderate alcohol consumption, which seems to have the overall effect of reducing DNA damage, as shown by the decrease in 8-OHdG levels.

Oxidative Stress

• Diabetics tend to have higher urinary 8-OHdG excretion than healthy controls and the levels are related to the severity of tubulointerstitial lesions. Oxidative stress may contribute to the progression of tubulointerstitial injury in patients with diabetic nephropathy.

http://www.metametrix.com/files/learning-center/leifm/book-Laboratory-Evaluations-in-Molecular-Medicine.pdf

Oxidative Stress

• Remember that you can also measure oxidative stress / damage by assessing TBARS and lipid peroxides in urine, as we discussed in the Toxins and Detoxification module.

Oxidative Stress - Interventions

• Determine why there’s an excess of oxidation.

– Too much bad stuff (e.g. H. pylori, arsenic, mercury…even iron); lack of sleep, over exercise; blood sugar issues

• Do the investigative work; get the basics right!

– Too little good stuff (antioxidants):

• Vitamin C – 2g or more /day (buffered)

• Vitamin A

• Vitamin E

• Bioflavonoids

• CoQ10

Stress!

• “Stress” requires changes in metabolism to keep up with higher energy demands. It’s not just life & death stress, or exercise that causes this. It’s chronic stress, too. People can be running away from saber-toothed tigers 24/7!

http://4.bp.blogspot.com/-SPOYBjpatIE/UGcSbHsHPgI/AAAAAAAAAGM/MDK1wyAGtqU/s1600/b

aby+saber+tooth+tiger+picture.jpg

Stress!

Don’t just give supplements and expect miracles.

Thank You!

• Thanks a million for tuning in. I appreciate your time and I appreciate you choosing me as one of your teachers. In the next lesson we’ll review how the Organic Acids profiles can assist in ascertaining information on detoxification and gut function, whilst looking at the full test report layout.