Order Number: TEST Age: 6 Sex: F MRN: TESTGIRL3. Test Test MD Test Test, NC Zillicoa Street Asheville, NC Genova Diagnostics

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1 63 Zillicoa Street Asheville, NC 2881 Genova Diagnostics Patient: GIRL3 TEST Age: 6 Sex: F MRN: TESTGIRL3 Order Number: Completed: March 28, 26 Received: March 28, 26 Collected: March 28, 26 Test Ward Test Test MD Test Test, NC <= 8.5 <=. 1.7 <= <= <= 8.5 <=. 1.7 <= <= <= <= <=

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6 Patient: SAMPLE PATIENT ID: Page 6 Please note that Beta-ketoglutaric Acid has been removed from the Metabolic Analysis Profile. Beta-ketoglutaric Acid is a minor product of yeast/fungal metabolism. Other markers of yeast dysbiosis continue to be available on the Metabolic Analysis Profile. Commentary is provided to the practitioner for educational purposes, and should not be interpreted as diagnostic or treatment recommendations. Diagnosis and treatment decisions are the responsibility of the practitioner. Analyte Histogram Changes: The shape of the histograms for many of the analytes on this test have changed. The new histograms more accurately reflect the distribution of results for the reference population and for expected, normal levels. No reference range changes have been made. MARKERS CHARACTERISTIC OF INTESTINAL MALABSORPTION AND/OR DYSBIOSIS Three of these chemical markers are formed by yeast/fungal organisms, usually but not necessarily in the gut: arabinose, tartaric acid and citramalic acid. Citramalate can also be formed by anaerobic bacteria. The remaining markers of this section are the result of malabsorption, gut bacterial action, and in some cases, hepatic detoxication of chemicals produced by dysbiotic flora. 2,3 Dihydroxyphenylpropionic acid (DHPPA) is elevated. This organic acid is a byproduct of the bacterial metabolism of phenylalanine, tyrosine, and/or tryptophan. Research has identified various species of Clostridia in the in-vitro production of this compound. Other research on quinoline demonstrates production of DHPPA by Pseudomonas species. Presence of elevated levels of DHPPA in the urine may thus suggest overgrowth of Clostridia and/or Pseudomonas, as well as a degree of malabsorption of aromatic amino acids. A comprehensive stool analysis is suggested. Tartaric Acid is measured to be above the normal range. Widely distributed in fruits, tartaric acid is particularly high in grapes, raisins, and in wine. It may also be found in some soft drinks and baked goods (as "cream of tartar"). Therefore, the elevation of tartaric acid may be due to recent ingestion of higher than usual amounts of some of these foods. In chemical structure, tartaric acid is very similar to malic acid; thus, elevated blood or tissue levels may interfere with malic acid's role in the "malate shuttle", which carries reducing equivalents (protons) into the mitochondria. Aside from dietary sources, elevated urine tartrate can be the result of (intestinal) yeast overgrowth. A stool analysis with microbiology is suggested if dietary sources are ruled out. NEUROTRANSMITTER METABOLITES These metabolites are end products of neurotransmitter metabolism, either the adrenal catecholamines or serotonin (5-HIAA). Abnormal levels correlate with mood swings, mental dysperceptions, anxiety, or depressive disorders. Homovanillic Acid (HVA, or 3-methoxy-4-hydroxyphenylacetic acid) is elevated. HVA is a normal metabolite of dopamine via methylation (requires SAM and a magnesium-activated enzyme), and deamination (requires vitamin B6), and oxidation by monoamine oxidase (MAO) (which uses vitamin B2 as FAD). Infants and male children typically have higher urine HVA than do older children and females. Excessive urine HVA can occur with mental disturbances and with dopaminergic dysfunction. HVA is elevated in urine when the metabolism of dopamine is impaired or dopamine turnover is increased (as may occur with administration of choline or physostigmine).

7 Patient: SAMPLE PATIENT ID: Page 7 Dopamine becomes norepinephrine using the enzyme dopamine beta-hydroxylase. This enzyme requires copper for its activation, and oxygen and ascorbic acid as cofactors. Insufficient copper or ascorbate may result in elevated urine HVA, as may other impairments in adrenal catecholamine metabolism. If elevated HVA is due to impaired dopamine-to-norepinephrine metabolism, then epinephrine formation can be slowed or erratic. Individuals with this problem may also present fatigue if the required epinephrine stimulus for glycogenolysis is deficient. ANALYTES CHARACTERISTIC OF CELLULAR ENERGY AND MITOCHONDRIAL FUNCTION These markers are metabolites from four important biochemical pathways in the body, all of which significantly impact the production and availability of energy at the cellular level: glycolysis, the citric acid cycle (Krebs cycle) and both beta-oxidation and omega-oxidation of fatty acids. These analytes provide unique insight into macronutrient catabolism and mitochondrial function in cells. Abnormal levels may be associated with fatigue, malaise, myalgia, headache, muscle weakness, myopathy, hypotonia, or acid-base imbalance. This test is intended to be a diagnostic aid for acquired disorders in these pathways. It is not intended for diagnosis of inborn errors of organic acid metabolism, as this would require extensive molecular genetics testing. However, significantly abnormal findings could be consistent with such inborn errors. If significant abnormalities persist after removal of toxics, supplementation of appropriate nutrients, dietary and hormonal adjustments, and correction of intestinal dysbiosis or infection, it is suggested that the patient be referred to a medical center with capabilities for diagnosis and treatment of congenital metabolic defects. All the measured analytes in this group are within their reference ranges; there are no abnormals. COFACTOR-DEPENDENT AND METABOLITES FROM AMINO ACID CATABOLISM These analytes are formed from essential and protein amino acids via amino group transfer or by other enzymatic transformations. Many are sensitive to vitamin functions as coenzymes and to minerals as enzyme activators. Excesses or deficiencies may lead to various conditions depending upon the particular metabolic imbalance, including fatigue, headaches, myalgias, metabolic acidoses, dietary intolerances, neurological problems, and cognitive disorders. Formiminoglutamic Acid "FIGlu" is elevated in the urine. FIGlu stands for formiminoglutamic acid, a substance produced in body tissue from the dietary amino acid histidine. FIGlu needs tetrahydrofolate (THF), a reduced form of folic acid, to be changed into forms that are metabolically useful. Elevated urine FIGlu can occur with several circumstances. Dietary deficiency of folic acid or severe oxidant stress that limits biologic reduction of folic acid to the THF form can cause this elevation. Histidine as a supplemented nutrient can contribute to urine FIGlu levels, especially if taken in amounts that exceed 5 mg/kg body weight. Metabolism of folic acid can be impaired if vitamin B12 is insufficient or if its metabolism is disordered. So, elevated FIGlu also can mean that some form of B12 or cobalamin is needed. The enzyme that promotes processing of FIGlu and THF requires pyridoxal 5-phosphate as a coenzyme, and vitamin B6 deficiency also may contribute to elevated FIGlu. Finally, there are rare disorders in purine synthesis that impair normal utilization of folate forms that come from

8 Patient: SAMPLE PATIENT ID: Page 8 FIGlu and THF. Abnormal levels of uric acid, succinylpurines, inosine or adenosine may be investigated if FIGlu levels remain elevated despite folate, cobalamin, pyridoxine and antioxidant therapy. Elevated FIGlu can be coincident with homocystinuria and predisposition to cardiovascular disease. In children, elevated FIGlu and folate and/or vitamin B12 dysfunctions may be associated with mental retardation, autism, growth failure and seizures. Folate and/or vitamin B12 insufficiencies can be secondary to gastrointestinal disorders or poor quality diet, and deficiencies of both have been noted in elderly populations. Glutaric Acid is measured to be high. This organic acid is formed from the essential amino acids lysine (primarily) and tryptophan, via alpha ketoadipic acid (AKAA) and glutaryl-coa. Glutaric acid is elevated when glutaryl CoA metabolism is impaired, such as when needed nutrient cofactors are missing. Glutaryl-CoA is dehydrogenated to form glutaconyl-coa and then crotonyl-coa using a FAD-dependent dehydrogenase enzyme; the FAD (from riboflavin) becomes FADH2. Glutaric aciduria may have negligible manifestations if mild, but if the dehydrogenase is notably weak, then severe symptoms can be experienced beginning in infancy and childhood with general neurological deterioration, spasticity and mental retardation. Glutaric acid can be very elevated in the rare case of multiple acyl-coa dehydrogenase dysfunction. The resulting glutaric aciduria type II can lead to metabolic acidosis, hypoglycemia, hypotonia, nausea and diarrhea, and frequently the individual has a "sweaty feet" or foul odor. Poor weight gain and frequent regurgitation of food are seen in children. In glutaric aciduria type II, adipic, lactic, and beta-hydroxybutyric (BHBA) acids are also elevated. This more general enzyme impairment is postulated to be a weakness in mitochondrial electron transfer. Glutaric acid excess may or may not be helped by supplementation of riboflavin, mitochondrial support nutrients, or CoQ1. Pyroglutamic Acid (5-oxoproline) is measured to be elevated. Pyroglutamic acid primarily arises during the "gamma-glutamyl cycle" which splits glutathione (GSH) into cysteinylglycine and a gamma-glutamyl moiety. The gamma-glutamyl part attaches to another amino acid or short-chain peptide, or joins with an element (essential mineral) for transport across a membrane or into a cell. The enzyme gamma-glutamylcyclotransferase finishes the transport function by splitting off what was carried and changing the gamma-glutamyl part into pyroglutamic acid. The pyroglutamic acid is then used to make glutathione by converting back to glutamic acid (by 5 oxyprolinase, ATP, and Mg), combining with cysteine (by gamma glutamylcysteine synthetase, ATP, and Mg), and finally combining with glycine (by glutathione synthetase, ATP, and Mg). Inadequacies of magnesium, ATP, cysteine, or glycine can therefore be rate-limiting, resulting in elevated pyroglutamic acid and deficient GSH. Elevations in pyroglutamic acid can also occur from ingestion of protein powder supplements, "hydrolyzed" protein, and infant formulas. Markedly high urinary levels of pyroglutamic acid (pyroglutamic aciduria) may result from (genetic) weakness in the last step, glutathione synthetase. This causes gamma-glutamylcysteine to accumulate; the cycle is short circuited, beneficial nutrient transport does not occur, and the cyclotransferase enzyme splits gamma-glutamylcysteine into cysteine and pyroglutamic acid. Episodic, mild to severe pyroglutamic aciduria can be of dietary origin, coming from partially or completely hydrolyzed protein supplements, such as found in some powdered infant formulas or protein powder supplements. There may or may not be associated problems. A mild pyroglutamic aciduria may occur from rate-limitation in glutathione synthesis due to magnesium insufficiency. Glutathione and/or N-acetyl cysteine supplementation may be beneficial, depending upon the body's ability to transport it to areas of need. Severe

9 Patient: SAMPLE PATIENT ID: Page 9 pyroglutamic aciduria of genetic origin is rare, is expressed in infancy and features jaundice, hemolysis, psychomotor retardation, and neurological degeneration. INTERPRETATION AT A GLANCE Please note: The preceding dosage suggestions are designed for adults. Please adjust them accordingly (downward) for children. Homovanillic Acid is measured to be high. Possible Conditions Possible Remedies Confirming Tests Copper/ascorbate inadequacy Copper 2-4 mg/d, RBC or hair element analysis, Vitamin C 25-2 mg/d Vitamin analysis Cholinergic excess Change supplements or medications Review supplements/medication for cholinergic function Dopamine utilization disorder As prescribed by neurologist Neurological exam

0091 Organix Comprehensive Profile - Urine

0091 Organix Comprehensive Profile - Urine Accession #: Order #: Reference #: Patient: Date of Birth: Age: Sex: Date Collected: Date Received: Telephone: Fax: Organix Interpretation Organix Interpretive Guide is downloadable at: www.metametrix.com/files/test-menu/interpretive-guides/organix-ig.pdf