COMPREHENSIVE ORGANIX

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1 Fatty Acid Metabolism Dicarboxylic acids Adipate (H) Suberate (H) Ethylmalonate (H) Carnitine is needed when any of the above markers are elevated. Carnitine is required as a carrier for the transport of fatty acids from the cytosol into the mitochondria for beta-oxidation. This is the dominant pathway used to derive energy from fat, and riboflavin is the necessary cofactor for these enzyme reactions. When carnitine levels are inadequate, the degradation of fatty acids takes place through mega-oxidation, an alternate pathway, which will result in the elevation of any of the above three markers. Adequate vitamin B2 levels are especially important for elevated ethylmalonate, which can result directly from a deficiency of this nutrient. Symptoms Periodic mild weakness, nausea, fatigue, Attention Deficit and Hyperactivity Disorders (ADHD), hypoglycaemia, sweaty feet odour and recurrent infections Action Supplement L-carnitine and vitamin B2. Lysine may also be necessary as it is a precursor for carnitine NB: The use of aspirin can change the interpretation of results for these three markers, as salicylic acid is an inhibitor of fatty acid beta-oxidation. The beta-oxidation enzymes also respond to environmental toxin exposure, with altered lipid metabolism, leading to immune responsiveness and mitochondrial DNA damage. Carbohydrate Metabolism Pyruvate Pyruvate (H) Lactate (H) b-hydroxybutyrate (H) Pyruvate is the anaerobic breakdown product of glucose, which is further converted to acetyl-coa. Pyruvate requires cofactors derived from thiamine, riboflavin, niacin, lipoic acid, and pantothenic acid. Elevated levels of pyruvate may therefore, reflect a failure of the enzymes to convert acetyl-coa due to a functional need for B vitamins, particularly thiamine and pantothenic acid. Under-eating can also lead to elevations. Symptoms Metabolic acidosis, fatty liver associated with alcohol use, encephalopathy associated with alcohol use Action Supplement B1, B2, B3, B5 and lipoic acid NB: Elevations may result from pyruvate supplementation, which has been found to prevent a fatty liver Lactate Lactate, also known as lactic acid, is a principal product of glucose oxidation in skeletal muscle. Lactate accumulates when there is a block in the final stage of energy production, and such a block may result in the inactivation of the citric acid cycle. Elevations are a sign of a potential coenzyme Q10 (CoQ10) deficiency. Symptoms Lethargy, vomiting, abdominal pain, dehydration, hyperventilation, hypotension, cold extremities, cyanosis, tachycardia and cardiovascular disease Action CoQ10 supplementation is effective when lactate is elevated and energy production is interrupted. Also supplement lipoic acid, biotin, vitamins B1, B2, B3, and B5 NB: Both lactate and pyruvate may be elevated by alcohol consumption prior to the urine collection. This effect may be due to the niacin-depleting effect of alcohol. b-hydroxybutyrate Elevations in b-hydroxybutyrate, a common ketone body, may indicate inefficient utilization or mobilization of glucose. Individuals with normal blood glucose response to insulin do not produce high concentrations of ketone bodies because their production of energy from glucose is well controlled. Increased b-hydroxybutyrate is a feature

2 of metabolic acidosis due to the failure of glucose utilisation, as occurs with diabetes. Defects in cytochrome oxidase enzymes of the electron transport system are another reason for elevated hydroxybutyrate. Elevated levels may be formed during fasts or low carbohydrate diets. Symptoms Excessive fatigue on exertion is the most common symptom associated with ketosis Action Supplement chromium and vanadium to support carbohydrate utilisation by improving the action insulin. Support stable blood sugar levels through the diet. Citric Acid Cycle Citrate (H) / (L) Cis-Aconitate (H) / (L) Isocitrate (H) / (L) a-ketogluterate (H) / (L) Succinate (H) / (L) Fumerate (H) Malate (H) Hydroxymethylgluterate (H) / (L) The Krebs or Citric Acid Cycle (CAC) is not only the final common pathway of energy release from food, but is also the source of basic structural molecules that support organ maintenance and neurological function. Conversion of the CAC intermediates is under the control of enzymes that often require vitamin-derived cofactors and minerals for proper functioning. Abnormal spilling of CAC intermediates in urine indicate mitochondrial inefficiencies in energy production. This fundamental pathway is critical for all organ function. Elevated excretion of the compounds involved in the cycle can explain the biochemical basis of excessive fatigue and weakness, which can be improved by supplying B-complex vitamins. Since the compounds are related in a cyclical manner, a block at any step can cause accumulations of multiple compounds that precede that step. CoQ10 deficiency can also result in elevated CAC intermediaries, as can antibacterial medication such as gentamicin medication. Low levels of CAC intermediaries can result from insufficient flow of carbon skeletons from amino acids. Aspartic acid is a preferred substrate for the refilling pathway that restores CAC levels of citrate and isocitrate, and can help to increase energy producing intermediates. Citrate Citrate has a broad reference range because citrate levels vary with changes in renal metabolism and acid-alkaline disturbance. The anion properties of citrate are used to balance increased positive ammonia ion excretion. Citrate elevation is therefore a marker of ammonia accumulation due to arginine deficiency. Orotate is an additional sensitive marker for this condition. Amino acid deficiencies, especially methionine and taurine, may result in elevated citrate levels. Symptoms Fatigue and weakness is associated with both high and low levels Action For elevated levels, supplement arginine, lipoic acid, and essential amino acids, especially methionine and taurine. Supplement lipoic acid and magnesium, if gentamicin toxicity is detected. If citrate levels are low, supplement broad-spectrum amino acids and L-aspartic acid. Cis-Aconitate When cis-aconitate is elevated along with citrate and isocitrate, check orotate as all are aspects in renal ammonia clearance, and can indicate an arginine deficiency. Symptoms Fatigue and weakness is associated with both high and low levels Action For elevated levels, supplement arginine and iron. If levels are low, supplement broad-spectrum amino acids Isocitrate When isocitrate is elevated along with citrate and cis-aconitate, check orotate as all are aspects in renal ammonia clearance, indicating an arginine deficiency. Elevated isocitrate and citrate are also signs of increased need for lipoic acid. The enzyme responsible for the conversion of isocitrate to cis-aconitate also requires magnesium and manganese as cofactors. Symptoms Fatigue and weakness is associated with both high and low levels Action For elevated levels, supplement arginine, lipoic acid, magnesium and manganese. If levels are low, supplement broad-spectrum amino acids and L-aspartic acid. 2

3 Alpha Ketogluterate Alpha Ketogluterate (a-kg) is formed by the oxidation of isocitrate and is further oxidised in an energy-releasing step that requires vitamin B1, B2, B3, B5 and lipoic acid as cofactors. Therefore elevations demonstrate these B- vitamin deficiencies. Elevations in a-kg can result from undereating, mitochondrial dysfunction, vitamin B deficiencies, and catabolic breakdown products of glutamic acid, histadine, arginine, proline and glutamine. Levels of a-kg can also serve to mark an aspect of the carbohydrate and fat metabolic relationship. When metabolic conditions such as insulin resistance are present, an inhibition of glutamate dehydroxygenase occurs. Since a-kg is formed from this, mitochondrial a-kg is depleted. Low a-kg is a marker for up-regulated fatty acid synthesis, and increased serum triglycerides. Symptoms & conditions Fatigue and weakness is associated with high levels, while low levels cause elevated serum triglycerides Action For elevated levels supplement vitamins B1, B2, B3, B5 and L-aspartic acid. For low levels supplement a-kg. Succinate The conversion of fumerate to succinate depends on adequate levels of riboflavin, and succinate cannot be used as an energy source if CoQ10 levels are inadequate. Therefore elevated succinate is a marker of CoQ10 and riboflavin deficiencies. When succinate levels drop below normal, leucine and isoleucine are effective precursors that are converted into succinate to assure proper functioning of the CAC. However, adequate levels of vitamin B12 must be ensured, as this conversion is vitamin B12-dependent. Symptoms Fatigue, lassitude, weakness, myocardial and neurological degeneration are associated with both high and low levels Action For elevated levels, supplement CoQ10, vitamin B2 and magnesium. For low levels, supplement L-leucine, L-isoleucine and vitamin B12. Fumerate and malate Fumerate and malate elevations serve as additional markers to substantiate the extent of metabolic interference from CoQ10 deficiency. Elevated malate also could be the result of stimulation of fatty acid synthesis, which is known to inhibit the malate dehydrogenase enzyme. This sign of metabolic resistance to the oxidation of stored fat is seen in patients with low fat, high carbohydrate diets or with the condition hyperinsulinism, known as Syndrome X. Symptoms Symptoms include fatigue and weakness. With low levels, the fatigue is often relieved by protein intake Action High fumerate levels require CoQ10, while low fumerate levels require L-tyrosine and L-phenylalanine. High malate levels require CoQ10 and while levels require broad spectrum amino acids. Hydroxymethylglutarate Hydroxymethylglutarate (HMG) is the metabolic precursor of both cholesterol and CoQ10. Low levels of HMG therefore, reflect inadequate synthesis and a possible deficiency of CoQ10. High levels of HMG can also reveal inhibition in the synthesis of CoQ10. Although this may seem paradoxical, simultaneously low serum CoQ10 and low HMG suggest CoQ10 inadequacy, which may be associated with both low and high levels of HMG: the rationale being that a block in the pathway inhibits the formation of HMG, producing low levels in the urine, while a block subsequent to the formation of HMG produces high levels. Symptoms Fatigue and weakness is associated with both high and low levels Action Supplement CoQ10 NB: Statin cholesterol-lowering drugs reduce synthesis of CoQ10, which may result in elevated HMG in urine 3

4 B Complex markers a-ketoisovalerate (H) a-keto-b-methylvalerate (H) b-hydroxyisovalerate (H) a-ketoisocaproate (H) Xanthurenate (H) a-ketoisovalerate, a-ketoisocaproate, a-keto-b-methylvalerate All of the compounds placed in this category are metabolic intermediates in the degradation of amino acids. When hepatic or small intestinal enzymes remove the amino groups from the branch chain amino acids, valine, leucine and isoleucine, the above products are formed. Because of the specificity of individual enzymes utilising the vitaminderived coenzymes, discrete patterns of elevated excretion of specific intermediates signal functional deficiencies of individual vitamins. These include vitamin B1, B2, B3, B5 and lipoic acid. Symptoms Fatigue, irritation, poor memory, sleep disturbance, anorexia, abdominal discomfort, and constipation Action Supplement vitamins B1, B2, B3, B5 and lipoic acid NB: Patients taking the hydrolipidemic agent clofibrate may have a diminished sensitivity to these makers Xanthurenate This marker of tryptophan metabolism requires vitamin B6 as a cofactor. Elevated xanthurenate may be found even when there is no challenge with extra tryptophan. In such cases, the insufficiency of vitamin B6 is able to interfere with the normal conversion of dietary tryptophan. Although the excretion of both xanthurenate and kynurenate (neurotransmitter metabolism marker) are increased when vitamin B6 is insufficient, xanthurenate is the principal product that appears. This is due to the further metabolism of kynurenate to citric acid cycle intermediaries in the liver. Symptoms and conditions High homocysteine, seborrheic dermatosis, anaemia, convulsions (infants), and peripheral neuropathy Action Supplement both vitamin B6 (pyridoxine) and pyridoxine-5-phosphate b-hydroxyisovalerate Elevated b-hydroxyisovalerate levels will only appear if there is a biotin deficiency. This can be caused by lack of biotin-rich foods, excess avidin (from raw egg whites) or genetic enzyme variations. Overuse of antibiotics can also contribute to a biotin insufficiency by lowering beneficial bacteria in the gut, which help to produce biotin. The carboxylase enzymes, which require biotin as a cofactor, have critical roles in major pathways for the utilization of energy from amino acids, the synthesis of fatty acids for cell membrane replacement and the maintenance of blood glucose via gluconeogensis. Biotin deficiencies of various degrees can develop in normal pregnancies and in patients on long-term anticonvulsant therapy. Symptoms Alopecia, seborrhoeic dermatitis, skin rash, brittle nails, candidiasis, unusual odour to urine, immune deficiencies, muscle weakness, multiple carboxylase deficiency (an inherited disorder), developmental delay, truncal ataxia, convulsions, loss of language development, tremors, and gait disturbance Action Supplement biotin, consume biotin-rich foods, including eggs, fish, milk, whole grain cereals, legumes, cruciferous vegetables, white and sweet potatoes. If deficiency is due to dysbiosis, supplement a probiotic. Methylation markers Methylmalonate (H) Formiminoglutamate (H) Methylmalonate Methlymalonate (MMA) is produced during the breakdown of valine into energy-yielding products using vitamin B12. A lack of vitamin B12 therefore impairs this conversion, as well as the one where methionine is recovered from homocysteine. This can lead to an accumulation of homocysteine and MMA. Such biochemical impairment helps explain the fatigue resulting from vitamin B12 deficiency and the rapid improvement of symptoms these individuals experience with administration of intramuscular vitamin B12. Other causes that may result in elevated levels include alcohol, gut dysbiosis and ageing (loss of intrinisic factor). 4

5 Symptoms and conditions Anaemia, fatigue, gastrointestinal disorders, dysbiosis, elevated homocysteine, ischaemic heart disease, stroke and deep vein thrombosis (DVT) Action Methylmalonate, formiminoglutamate and a-hydroxybutyrate are all possible indicators of high homocysteine, and any combination of these may require serum homocysteine levels to be checked. If only MMA is elevated, supplement vitamin B12. Stop alcohol intake and treat any dysbiosis, if necessary. Formiminoglutamate Formiminoglutamate (FIGLU) is an intermediate in the degradation of the amino acid histidine. Folic acid is the cofactor required by the enzyme that converts FIGLU into glutamic acid. Therefore an elevation of FIGLU occurs in the later stages of folate deficiency. FIGLU excretion has been used as a measure of the influence of drugs or alcohol on functional folate status. Since humans cannot synthesise folate, it must be provided by the diet, and poor dietary intake of folate-rich foods or excessive intake of processed foods, will increase the chances of an insufficiency. Impaired absorption, oral contraception, pregnancy, inadequate utilisation due to a metabolic block, increased demand/ excretion or increased destruction of folate, genetic enzyme defects and alcoholism can all also contribute to folate insufficiency. In addition, vitamin C protects folate from oxidative destruction, therefore low dietary vitamin C can have a negative impact on folate status. Symptoms and conditions Inhibition of DNA synthesis, impaired cell division, cervical dysplasia, breast cancer (53% higher risk with folate deficiency), heart disease, stroke, DVT, neural tube defects, megaloblastic anaemia, thrombotic events in Crohns patients due to high homocysteine levels, and pancreatic cancer associated with cigarette smoking Action Methylmalonate, formiminoglutamate and a-hydroxybutyrate are all possible indicators of high homocysteine, and any combination of these may require homocysteine levels to be checked. If FIGLU only is elevated, folic acid supplementation is required and alcohol intake should be stopped. Neurotransmitter Metabolism Markers Vanilmandelate (H) / (L) 5-Hydroxyindoleacetate (H) / (L) Quinolinate (H) Homovanillate (H) / (L) Kynurenate (H) Vanilmandelate Vanilmandelate (VMA) is the main metabolite of the catecholamines, epinephrine and norepinephrine. Low levels of VMA have been associated with low levels of these neurotransmitters, and may reflect adrenal exhaustion or an essential amino acid deficiency. Elevated levels may result from increased rate of catecholamine synthesis that results from heightened sympathetic reactions to stress, and myocardial injury. Chronic elevations can deplete levels of the amino acid, tyrosine. Additionally, elevations can result from certain pharmacological drugs and herbs including, ma huang, ephedra, pseudoephedrine, caffeine and decongestants. Symptoms Elevated levels may result in hypertension, headaches, muscle aches, digestive disturbances, decreased immunity, cold hands, anxiety and sleep disturbances. Low levels can result in depression, sleep disturbances, anxiety and fatigue Action Identify sources of stress (emotional and physical) and decrease where possible. Decrease stimulants and ensure adequate protein intake and digestion. Supplementation of L-tyrosine may be necessary with high levels and low levels of VMA. The relationship of tyrosine to epinephrine also gives rise to the anti-hypertensive role of tyrosine. Homovanillate Homovanillate (HVA) is the main metabolite of dopamine, and low levels of HVA have been associated with low levels of this neurotransmitter in the central nervous system. Elevated levels can result from an increased rate of synthesis and degradation in normal tissue, essential amino acid deficiency, medication for Parkinson s disease (L- Dopa), copper deficiency, cocaine use and amphetamine use. Low levels can result from chronic stress and antipsychotic drugs. Symptoms High levels can cause agitation, delirium, psychosis, and tyrosine depletion. Low levels can result in depression, sleep disturbances, anxiety and fatigue and Parkinson s symptoms Action Ensure adequate protein intake and digestion. Address stress levels. 5

6 5-Hydroxyindoleacetate Catabolic breakdown of serotonin leads to the excretion of 5-hydroxyindoleacetate (5-HIA). Elevated levels of this metabolite may result from the use of serotonin-specific re-uptake inhibitors (SSRI) or increased release of serotonin from either the CNS or digestive tract. A very high 5-HIA can lead to depletion of the essential amino acid precursor, L-tryptophan, which is required for the synthesis of serotonin. Symptoms Low levels can result in depression, fatigue, insomnia, decreased gut motility (constipation) and ADHD. Elevated levels may result in depression and stunted growth Action When 5-HIA levels are low, increase consumption of tryptophan-rich foods including turkey, bananas, low fat milk, lentils and eggs. The supplement 5-hydroxytryptophan (5-HTP) can increase tryptophan and levels, and can be given when levels are low, unless individual is taking prescription antidepressant/ anxiety medication. NB: Ethanol consumption can lower 5-HIA levels Kynurenate Kynurenate (KYNA) is a specific biochemical marker of vitamin B6 status and is produced during the catabolism of the amino acid tryptophan. Vitamin B6, in the form of pyridoxal-5-phosphate (P-5-P) is required for this reaction, and an elevation of KYNA therefore indicates a vitamin B6 insufficiency. KYNA is a precursor to the quinolinate (QUIN), both of which have well documented effects in the central nervous system. KYNA antagonises QUIN as a brain modulator, having preferential binding affinity for N-methyl-D-aspartate (NMDA) receptors. The activity of P-5-P in this pathway, may account for vitamin B6 s neuroprotective effects, and even transient deficits in vitamin B6 levels can result in significant shifts in brain physiology. KYNA can also help to decrease pain perception. Symptoms and conditions Increased pain perception, active disease in relapsing-onset of MS Action Supplement vitamin B6 (P-5-P) Quinolinate QUIN production serves as a link between the immune system and the brain. The conversion of tryptophan to QUIN, is stimulated by immune responses, which cause the release of interferon-gamma by macrophages. 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 disease and neuronal degeneration. QUIN is a powerful antagonist of the NMDA receptors, eliciting a heightened response, which greatly accelerates neurological degeneration. In inflammatory diseases, a high QUIN: KYNA ratio increases the risk of neurotoxicity. In addition, bacterial, viral, parasitic and fungal infections can all result in increased QUIN levels. Symptoms and conditions Bacterial, viral, parasitic or fungal infections, IBD, neuronal degeneration, insomnia, learning difficulties in children, Chronic Fatigue Syndromes (especially the immune mediated form) and increased pain perception Action Identify source of inflammation/ immune stimulation and treat where possible. Supply antioxidants especially vitamin C, vitamin E and lipoic acid Oxidative Damage and Antioxidant Markers p-hydroxyphenyllactate (H) 8-Hydroxy-2-deoxyguanosine (H) p-hydroxyphenyllactate p-hydroxyphenyllactate (HPLA) is a metabolite of the amino acid, tyrosine, that acts as part of the cell signalling mechanisms for apoptosis. It stimulates pro-oxidant production and is also associated with carcinogenesis. Very high urinary levels of HPLA can signal normal tissue growth or that associated with neoplastic disease, or result from inborn errors of metabolism. Elevated levels of this marker result in a dramatic decrease of vitamin C concentration in the liver, adrenal glands, and blood. Symptoms and conditions Early onset of ageing-related symptoms, cancer, leukaemia and hepatic encephalopathy Action Tissue-saturating levels of vitamin C should be considered in patients with elevated levels of HPLA. Other antioxidants, such as vitamin E, lipoic acid, and CoQ10 may be beneficial 6

7 8-Hydroxy-2-deoxyguanosine 8-Hydroxy-2-deoxyguanosine (8-OHdG) is a useful marker for indicating the rate of damage to DNA induced by oxidative stress. The formation of 8-OHdG is sufficiently sensitive to reveal even mild elevations of reactive oxygen species. 8-OHdG levels can rise naturally with age, or in adults with mild hypercholesterolaemia and/or hypertension. Enhanced oxidative damage in human lung tissue due to cigarette smoking can also cause 8-OhdG levels to rise. The oxidative damage to DNA indicated by high 8-OhdG levels may be caused by chronic psychological stress, perceived overwork, smoking, hypercholesterolaemia, hypertension, chronic inflammation, chronic liver disease, diabetes, air pollution, smoking, irradiation, thermal injury, toxicity induced by toxic metals, solvents, pesticides and drugs. Action Supply antioxidants including vitamin C, vitamin E, flavanoids and other antioxidants as necessary. If oxidative burden due to decreased hepatic detoxification, support glutathione synthesis by providing organic sources of sulphur such as n-acetylcysteine (NAC). Identify and reduce other causes of increased oxidative challenge, such as environmental toxin exposure, excess alcohol consumption and cigarette smoking Detoxification Indicators 2-Methylhippurate (H) Glucarate (H) Sulphate (H) / (L) Orotate (H) Pyroglutamate (H) a-hydroxybutyrate (H) 2-Methylhippurate 2-Methylhippurate is a by-product from the detoxification of the common solvent, xylene. Xylene is oxidised via the hepatic P450 oxidase enzymes and then conjugated with glycine during Phase II detoxification. Xylene can be found in new paint, paint thinners, building products, fuel and exhaust fumes, dry cleaning fluid, new cars, new carpets, industrial degreasers and solvents. Accumulation of toxins such as xylene can result in increased oxidative stress. Action Avoid source of xylene exposure and supplement glycine Orotate When there is insufficient capacity for detoxifying the load of ammonia via the urea cycle, the synthesis of orotate is stimulated. Increased orotate production is a sensitive indicator of arginine deficiency. Most of the symptoms that develop following arginine deprivation can largely be accounted for by a decreased efficiency of ammonia detoxification and reduced formation of nitric acid. In addition, magnesium is required for orotate metabolism and high levels should alert one to a significant possibility of intracellular magnesium insufficiency. Orotate is very sensitive to anything that can elevate ammonia, including intestinal bacterial ammonia production or excess meat intake. Symptoms and conditions Hyperammonaemia, poor growth, poor coordination and lethargy. Symptoms of an arginine deficiency can include coronary artery disease, angina, hypertension, impaired insulin production and possible hair loss. Symptoms of a magnesium deficiency can include nausea, vomiting, hypotension, weakness, confusion and anxiety Action Decrease protein intake and treat any gut dysbiosis if appropriate. Supply arginine and magnesium NB: When orotate is high, check citrate, cis-aconitate and isocitrate, as all are aspects of ammonia clearance Glucarate Glucarate is an overall indicator of hepatic detoxification, including liver enzyme induction (Phase I) and glucoronidation (Phase II). Decreased glucarate is an indicator of reduced overall hepatic function, while elevated glucarate levels signal hepatic enzyme induction due to potentially toxic exposures. A variety of toxins can upregulate detoxification, including drugs, food components, gut microbial metabolites, xenobiotics (pesticides, herbicides, fungicides, petrochemicals, alcohol, polycyclic aromatic hydrocarbons, nitrosamines, heterocyclic amines), steroid hormones and fat-soluble vitamins. Symptoms and conditions Oxidative stress, fatigue, headaches, muscle pain, mood disorders, poor exercise tolerance and CFS. Action Identify and reduce source of toxic exposure 7

8 a-hydroxybutyrate a-hydroxybutyrate (AHB) is the byproduct of the final step in the conversion of methionine via homocysteine to cysteine, and is a marker of hepatic glutathione synthesis. Elevated levels of AHB occur due to toxin-stimulated upregulated of detoxification, including both the sulphation and glucuronidation pathways. These toxins can include intestinal microbial byproducts, xenobiotics and pharmaceutical drugs, especially acetominophen. Smoking, poor diet, and lack of exercise can also lead to elevated AHB. Symptoms and conditions Any diseases associated with increased glutathione demand, such as muscular dystrophy, macular degeneration, diabetes, emphysema, hepatic cirrhosis, respiratory distress syndromes, Parkinson s disease, autistic spectrum disorders, radiation poisoning and extreme endurance training Action Supply sources of organic sulphur for glutathione synthesis including NAC, L-methionine, taurine, whey protein isolate, and alpha-lipoic acid. NAC is preferable to methionine in patients with elevated homocysteine levels, unless adequate folic acid and vitamin B12 are supplied Pyroglutamate Pyroglutamate is a metabolite produced from the transport of amino acids in renal tubules where glutathione is its carrier. This pathway conserves amino acids at the expense of glutathione, therefore elevated pyroglutamate indicates glutathione wasting and possible amino acid deficiencies especially glycine. Elevations may also indicate mitochondrial inefficiency Symptoms and conditions Any diseases that increase glutathione demand as above Action Supply sources of organic sulfur for glutathione synthesis including NAC, L-methionine, taurine, whey protein isolate, and alpha-lipoic acids. NAC is preferable to methionine in patients with elevated homocysteine levels, unless adequate folic acid and vitamin B12 are supplied Sulphate The sulphation pathway forms part of Phase II hepatic detoxification and is used for the biotransformation of many drugs, steroid hormones, phenolic and other compounds. Severe depletion of organic sulphur levels will cause simultaneous high pyroglutamate and low sulphur excretion in urine. High pyroglutamate with normal sulphate indicates inadequate organic sulphur sources for production of cysteine required for glutathione synthesis. Normal urinary pyroglutamate with low sulphate levels can occur in individuals with impaired sulphate activation. Rapid replenishment of hepatic sulphate can only be accomplished with organic sulphur such as NAC or methionine. Symptoms Any diseases that increase glutathione demand as above Action Supply sources of organic sulphur for glutathione synthesis including NAC, L-methionine, taurine, whey protein isolate, and alpha-lipoic acids. NAC is preferable to methionine in patients with elevated homocysteine levels, unless adequate folic acid and vitamin B12 are supplied Intestinal Dysbiosis Benzoate (H) Phenylpropionate (H) Indican (H) Hippurate (H) p-hydroxybenzoate (H) Tricarballylate (H) Phenylacetate (H) p-hydroxyphenylacetate (H) Urinary markers have a high predictive ability for measuring abnormal overgrowth of unfavourable microflora in the small intestine. These distinct microbial toxins and metabolic products can affect multiple organs when the GI tract becomes leaky due to inflammation and damage to the gut mucosa. Causes of general dysbiosis can include low levels of hydrochloric acid in the stomach, widespread use of antacids, repeated use of antibiotics, carbohydrate malabsorption, alcohol abuse, use of NSAIDS or corticosteroid and excessive stress levels. 8 Symptoms and conditions associated with dysbiosis include diarrhoea, constipation, steatorrhoea, abdominal distention/ pain, IBS, IBD, Coeliac disease, food allergies/ intolerance, carbohydrate intolerance, skin disorders (urticaria, rashes, acne, psoriasis, eczema), cognitive deficits, decreased vitamin B12 absorption, headaches, arthralgias, myalgias, fatigue, CFS, ASD, autoimmune disorders, recurrent sinusitis, recurrent vaginal yeast/ bladder infections and cystic fibrosis.

9 Benzoate and Hippurate Bacterial deamination of the amino acid, phenylalanine, produces benzoate, which is conjugated with glycine in the liver to form hippurate. Glycine and pantothenic acid are limiting factors in this process. Therefore elevated benzoate is a marker of inadequate levels of these nutrients and inefficient glycine conjugation. Benzoic acid is also used as a preservative in processed food such as pickles and lunchmeat and occurs naturally in cranberries. This should be taken into account when interpreting results. Action Supplement glycine, panthothenic acid, and probiotics. As sugars and amino acids in diet can be used for microbial growth, limit intake of refined sugars and protein Phenylacetate and Phenylpropionate Intestinal bacterial action on phenylalanine causes the appearance of phenylacetate and phenylpropionate in urine. These markers should only be present in background concentrations in healthy subjects without bacterial overgrowth. Action Supplement probiotics. As sugars and amino acids in diet can be used for microbial growth, limit intake of refined sugars and protein p-hydroxybenzoate and p-hydroxyphenylacetate Tyrosine from dietary protein is the parent compound from which p-hydroxyphenylacetate and p-hydroxybenzoate are formed. These products are not the result of normal human metabolism but are produced by bacteria and protozoa that can populate the gut. P-hydroxyphenylacetate has been found useful in detecting small bowel disease associated with Giardia Lamblia, Proteus Vulgaris and Clostridium difficile infections, as well as lactose intolerance and low secretory IgA levels. High antibiotic use, especially those that act on aerobic bacteria such as neomycin, can encourage the growth of anaerobic bacteria and protozoa. Strains of E. coli can produce p-hydroxybenzoate from glucose and further investigation followed by antibiotic treatment should be considered. Action Antibiotics, including metronidazole (Clostridia or Giardia) or trimethoprim-sulphamethoxazole (Proteus) may be indicated. As sugars and amino acids in diet can be used for microbial growth, limit intake of refined sugars and protein. Supplement probiotics and vitamin C Indican Bacteria in the upper bowel produce enzymes that convert tryptophan into indican. An elevated level of indican is therefore, an indicator of upper bowel bacterial overgrowth. Such an overgrowth has been reported for some patients with adult Coeliac disease. Oral antibiotics can reduce indican excretion, which is also reduced when the gut is populated with Lactobacillus salivarius, plantarum, and casei species. Indican testing can differentiate pancreatic insufficiency from biliary stasis as the cause of steatorrhoea. Patients with steatorrhoea due to pancreatic insufficiency show a rise of indican from low to normal when treated with pancreatic enzymes, but urinary indican levels do not rise in patients with steatorrhoea not due to pancreatic insufficiency nor in normal subjects who receive pancreatic enzymes. Increased indican levels correlate with enteric protein loss and can indicate incomplete protein digestion, and may be used as a marker of protein digestive inadequacy. This is often a complication of cirrhosis of the liver. Even patients with normal intestinal bacteria can show increased indican when they fail to digest dietary protein properly. Action Repopulate gut with Lactobacillus strains other than acidophilus, including L. salivarius, L. plantarum, and L. casei. As sugars and amino acids in diet can be used for microbial growth, limit intake of refined sugars and protein Tricarballylate Tricarballyalate is produced by a strain of aerobic bacteria, and has a high affinity for magnesium, causing decreased intestinal absorption of this mineral. To a lesser degree, zinc and calcium may also be bound, resulting in reduced levels of these minerals. A high carbohydrate diet may be responsible for elevated levels of tricarballylate. Action Supplement magnesium and probiotics. Initiate a restricted carbohydrate diet 9

10 L. acidophilus / General bacteria D-Lactate (H) D-Lactate Although Lactobacillus acidophilus and other lactic acid-producing strains of bacteria are usually beneficial, certain individuals can develop an overgrowth. This results in elevated levels of D-lactate. If there are multiple elevations of bacterial markers there is likely to be a general bacterial overgrowth, including L. acidophillus strains. If no other bacterial markers are elevated, the overgrowth may be due to excess supplementation, carbohydrate malabsorption/ high intake thereof, or excessive antibiotic use. It is more common in patients who have undergone jejunoileostomy. Action Discontinue all supplementation of lactic acid-producing bacteria. Antibiotic therapy may be warranted when D-Lactate is high, alternatively use non-lactobacillus species including bifidobacter species. As sugars and amino acids in diet can be used for microbial growth, limit intake of refined sugars and protein if dysbiosis present. Stop alcohol completely Clostridial Species Dihydroxyphenylpropionate (H) Dihydroxyphenylpropionate The metabolite, dihydroxyphenylpropionate (DHPP), is strongly associated with Clostridia. This organism is frequently the cause of traveller s diarrhoea, but its by-products may produce other symptoms. Clostridial species are particularly susceptible to displacement by the favourable organism Saccharomyces boulardii, which is a non-colonising 'probiotic' yeast supplement. Action Supplement saccharomyces boulardii, and probiotics. Antibiotics including metronidaxole (Flagyl), can also reduce levels of clostridial species. Other considerations include herbs such as goldenseal, citrus seed extract, garlic, uva ursi, aloe vera, and olive leaf extract. As sugars and amino acids in diet can be used for microbial growth, limit intake of refined sugars and protein if dysbiosis present Yeast / Fungal D Arabinitol D-Arabinitol (H) Although some degree of yeast overgrowth is common in normal GI tracts, candida infections are of widest clinical concern due to transmission or direct invasion of the GI and GU tracts. These species of yeast have the ability to rapidly overwhelm the immune response in hospitalised patients, producing disseminated candidiasis. D- arabinitol is a metabolite of most pathogenic candida species, in vitro and in vivo. It is a 5-carbon sugar alcohol that can be produced from enzyme activity on the sugar, arabinose, by candida yeast species. Therefore measuring D-arabinitol allows prompt diagnosis of invasive candidiasis. Action Treatment with antifungal medication including nystatin, fluconazole (diflucan) or itraconazole (sporanox). Antifungal herbs include tannelbit, goldenseal, citrus seed extract, garlic, uva ursi, aloe vera, olive leaf extract, oregano, capyrllic acid and undecylenic acid. Dietary intervention is essential. Stop alcohol and eliminate sugars 10

11 Interpretation Report for Organix Profile Note: Vitamin & Mineral requirements for cofactors are shown in light blue boxes. Elevations of metabolites before these steps indicate functional deficiencies of the nutrients. Compounds reported in Organix Profile are printed in red INDIVIDUAL WELLBEING diagnostic laboratories Parkgate House 356 West Barnes Lane New Malden Surrey KT3 6NB tel: fax: