INSIDER S GUIDE Urinary porphyrin profiling

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1 Functional Medicine University s Functional Diagnostic Medicine Training Program INSIDER S GUIDE Urinary porphyrin profiling By Ron Grisanti, D.C. & Dicken Weatherby, N.D. Limits of Liability & Disclaimer of Warranty We have designed this book to provide information in regard to the subject matter covered. It is made available with the understanding that the authors are not liable for the misconception or misuse of information provided. The purpose of this book is to educate. It is not meant to be a comprehensive source for the topic covered, and is not intended as a substitute for medical diagnosis or treatment, or intended as a substitute for medical counseling. Information contained in this book should not be construed as a claim or representation that any treatment, process or interpretation mentioned constitutes a cure, palliative, or ameliorative. The information covered is intended to supplement the practitioner s knowledge of their patient. It should be considered as adjunctive support to other diagnostic medical procedures. This material contains elements protected under International and Federal Copyright laws and treaties. Any unauthorized reprint or use of this material is prohibited Functional Medicine Training Program Page1 of 16

2 Contents URINARY PORPHYRIN PROFILING... 3 BIOMARKERS OF TOXIC EFFECTS... 3 WHAT IS THE VALUE OF EVALUATING FOR PORPHYRINS?... 4 SIMPLE ABBREVIATIONS FOR PORPHYRIN PATHWAY INTERMEDIATES... 4 A BRIEF LOOK AT THE HEME PATHWAY... 5 ANALYZING THE PORPHYRIN TEST ENVIRONMENTAL TOXIN- INDUCED PORPHYRINURIAS SYMPTOMS ASSOCIATED WITH PORPHYRINOPATHIES DISEASES AND CONDITIONS ASSOCIATED WITH PORPHYRINOPATHIES SOME DRUGS THAT CAUSE OR EXACERBATE PORPHYRIA (ELEVATION OF TOTAL PORPHYRINS) ENVIRONMENTAL MEDIATORS OF TOXIC PORPHYRIAS FOLLOW UP TESTING: Functional Medicine Training Program Page2 of 16

3 Urinary Porphyrin Profiling Biomarkers of Toxic Effects Toxic chemicals can affect human biochemistry at any level of exposure. Fortunately, the body has mechanisms for transforming, eliminating or compartmentalizing the many toxic chemicals encountered over a lifetime. Functional Medicine Training Program Page3 of 16

4 Nonetheless, these "safety" mechanisms may be inadequate in the modern industrialized society, especially for susceptible people such as the elderly, children, individuals with poor nutritional habits, and others who are physiologically stressed. Recognizing and identifying offending chemicals can present a difficult challenge for the clinician. Many chemicals exert their effect at such low concentrations that they escape direct detection except by very sophisticated laboratory methods. Compartmentalization in tissues, especially brain, that are difficult to access makes routine direct concentration measurements impractical. This where testing for porphyrins shines. Current analytical advances make routine profiling of the multiple intermediates via the Urinary Porphyrin Profiling a powerful tool for assessing toxic effects of heavy metals and some xenobiotics. Porphyrins serve as highly sensitive biomarkers of toxic effects on the heme biosynthetic pathway. Heme is an essential pathway for the proper function of many proteins for oxygen transport, energy production, and detoxification. (Will discuss below in more detail) Elevations of the individual porphyrin species can have a number of causes, including heredity and environmental contact. Chronic exposure to toxic metals, including lead, mercury, arsenic, aluminum, and cadmium commonly leads to patterns of specific porphyrin elevations in the urine often resulting in organ-specific accumulation that compromises target organ physiological function. Heavy metals damage many aspects of metabolism. Similarly, chronic exposure to organic chemicals such as herbicides, pesticides, and industrial and manufacturing by-products can have deleterious impact on the body's biochemistry, which results in the decline of cellular function. The Toxic Effects Porphyrins Profile measures seven porphyrins, total porphyrins, and two ratios to help you differentiate heavy metal toxicity in your patients. According to J.S. Woods from the Department of Environmental Health of the University of Washington, patterns of specific porphyrin elevations in urine may serve as functional fingerprints of toxicity due to specific toxins. What is the Value of Evaluating for Porphyrins? Porphyrins are particularly well suited as biomarkers for two reasons. First, the pathway is highly active, so any disturbance tends to cause rapid and relatively large accumulations of intermediates. Second, the enzymes of the porphyrin-producing pathway are widely distributed in human tissues and some of them are highly sensitive to the presence of various toxins. Simple Abbreviations for Porphyrin Pathway Intermediates Intermediate Abbreviations Functional Medicine Training Program Page4 of 16

5 Uroporphyrin Heptacarboxyporphyrin Hexacarboxyporphyrin Pentacarboxyporphyrin Precoproporphyrin Coproporphyrin I Coproporphyrin II Uro Hepta Hexa Penta Precopro Copro I Copro II A Brief Look at the Heme Pathway The highly regulated heme pathway consists of eight enzyme-driven reactions. Reactions begin and end inside the mitochondria, with intervening steps carried out in the cytosol. When porphyrinogens build up, they are easily oxidized to porphyrins that appear in urine. Functional Medicine Training Program Page5 of 16

6 Toxicants like heavy metals and organic xenobiotics bind to one or more enzymes to produce specific patterns of urinary porphyrin elevation. Oxidized porphyrins that accumulate in the body become additional toxicants that cause further tissue degradation. Heme is required at the active sites of oxygen-binding, oxygen-utilizing and oxidizing systems, hemoglobin (and myoglobin), cytochromes, and mitochondrial electron carriers and is synthesized in most human tissues (pre-dominantly liver and bone marrow) by a pathway with intermediates called porphyrinogens. The first reaction in heme biosynthesis (1) takes place in the mitochondrion and involves the condensation of 1 glycine and 1 succinylcoa by the pyridoxal phosphate-containing enzyme, d-aminolevulinic acid synthase (ALA synthase). Functional Medicine Training Program Page6 of 16

7 This reaction is both the rate-limiting reaction of heme biosynthesis, and the most highly regulated reaction. Mitochondrial d-aminolevulinic acid (ALA) is transported to the cytosol, where ALA dehydratase (2) (also called porphobilinogen synthase or hydroxymethylbilane synthase) dimerizes 2 molecules of ALA to produce the pyrrole ring compound porphobilinogen. Functional Medicine Training Program Page7 of 16

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9 The next step (3) in the pathway involves the head-to-tail condensation of 4 molecules of porphobilinogen to produce the linear tetrapyrrole intermediate, hydroxymethylbilane. The enzyme for this condensation is porphobilinogen deaminase (PBG deaminase). This enzyme is also called uroporphyrinogen I synthase. Functional Medicine Training Program Page9 of 16

10 Hydroxymethylbilane has two main fates. The most important is regulated, enzymatic conversion to uroporphyrinogen III, the next intermediate on the path to heme. This step is mediated by a holoenzyme comprised of uroporphyrinogen synthase plus a protein known as uroporphyrinogen III cosynthase. Genetic defects that cause increased ALA synthase activity or decreased uroporphyrinogen I synthase activity lead to the disease known as acute intermittent porphyria, which is diagnosed by the excretion of excess porphobilinogen (a condition that is not obvious from the color of the urine). Genetic defects in enzymes beyond hydroxymethylbilane in the biosynthetic pathway result in the accumulation of excess hydroxymethylbilane, leading to an alternative non-enzymatic cyclization. In erythropoietic uprotoporphyria, bone marrow uroporphyrinogen III cosynthase is only present at about 30% of the normal level; the result is that massive amounts of Type I uroporphyrinogen and its highly colored oxidation products are found in the urine and deposited in a variety of tissues, including teeth and bones. In the cytosol, the acetate substituents of uroporphyrinogen (normal uroporphyrinogen III or abnormal uroporphyrinogen I) are all decarboxylated by the enzyme uroporphyrinogen decarboxylase (4). The resultant products have methyl groups in place of acetate and are known as coproporphyrinogens, with coproporphyrinogen III being the, important, normal intermediate in heme synthesis. Coproporphyrinogen III is transported to the interior of the mitochondrion, where 2 propionate residues are decarboxylated, yielding vinyl substituents on the 2 pyrrole rings (5). Functional Medicine Training Program Page10 of 16

11 The colorless product is protoporphyrinogen IX. In the mitochondrion, protoporphyrinogen IX is converted to protoporphyrin IX (structure shown below) by protoporphyrinogen IX oxidase (6). The oxidase reaction requires molecular oxygen and results in the loss of 6 protons and 6 electrons, yielding a completely conjugated ring system, which is responsible for the characteristic red color to hemes. The final reaction (7) in heme synthesis also takes place in the mitochondrion and involves the insertion of the iron atom into the ring system generating heme b. The enzyme catalyzing this reaction is known as ferrochelatase. The enzymes ferrochelatase, ALA synthase and ALA dehydratase (a sulfhydryl containing enzyme) are highly sensitive to inhibition by heavy metal Functional Medicine Training Program Page11 of 16

12 poisoning. Indeed, a characteristic of lead poisoning is an increase in ALA in the circulation in the absence of an increase in porphobilinogen. In addition to iron, this final phase of metal incorporation inserts cobalt and/or magnesium into the protoporphyrin ring to produce heme, cobalamin and, in plants, chlorophyll, respectively. These complex organometallic structures are sometimes called the pigments of life. Analyzing the Porphyrin Test Porphyrins appear elevated in urine when the cellular pathway for heme synthesis is blocked by natural or man-made toxicants or when genetic disorders that affect the enzymes of the porphyrin pathway are present. When confounding variables are absent, the analytes and ratios of the Porphyrin Profile allow discrimination of certain types of toxic effects. Heavy Metals Aluminum Arsenic Mercury Lead Porphyrinurias + + Heptacarboxyporphyrin (+) Hexacarboxyporphyrin (+) Pentacarboxyporphyrin (+) + Precoproporphyrin ++ Coproporphyrin I + + Coproporphyrin III Precopro/Uro I & III + Copro I/Copro III + Organotoxins Hexachlorobenzene Methyl chloride Dioxin Polyvinylchloride Polybrominated biphenyl Porphyrinurias Heptacarboxyporphyrin (+) (+) (+) Hexacarboxyporphyrin (+) (+) (+) Pentacarboxyporphyrin Precoproporphyrin Coproporphyrin I Coproporphyrin III Precopro/Uro I & III Copro I/Copro III Functional Medicine Training Program Page12 of 16

13 The green pluses (+) show the typical pattern of elevated porphyrins. The double red pluses (++) show dominant elevations. Blue pluses enclosed in parathesises indicate alternate patterns that may appear. Calculated total porphyrins levels are generally elevated in the severe types of any condition that produce porphyrias. Aminolevulinic acid (ALA) and zinc protoporphyrin are other porphyrin pathway intermediates elevated in lead toxicity and iron deficiency, respectively. Environmental Toxin- Induced Porphyrinurias Environmental Toxin Arsenic Mercury Lead Hexachlorobenzene Methyl chloride Dioxin Polyvinylchloride Coproporphyrins Urinary Porphyrin Elevation (or as noted)* Uroporphyrins Pentacarboxyporphyrin Coprophyrin I High Copro I:III ratio Precoproporphyrin PenAminolevulinic acid (ALA) Coproporphyrin III Coproporphyrin I (sometimes) Zinc protoporphyrintacarboxyporphyrin Coproporphyrin (total) Aminolevulinic acid (ALA) Coproporphyrin III Coproporphyrin I (sometimes) Zinc protoporphyrin Uroporphyrins Coproporphyrins Uroporphyrins Coproporphyrins Coproporphyrins (Uroporphyrins) Symptoms Associated with Porphyrinopathies Chronic elevation of porphyrins causes tissue degeneration due to their secondary toxic effects. However, many conditions that manifest as less severe patterns of elevation may not be associated with such direct porphyrin toxicity. Symptoms in patients with these conditions are highly variable. Primary Complaints Associated Symptoms Condition Exacerbated by Acute porphyrias Neurologic presentations due to hepatic accumulations: Acute abdominal pain Nausea Vomiting Constipation Seizures Headaches Difficulty in concentration; Personality changes; Weakness Muscle and joint aches; Unsteady gait Poor coordination Numbness Low carbohydrate diets (skipped meals); Intake of alcoholic beverages; Medications, including sulfadrug antibiotics, barbiturates, estrogen, birth control pills; Functional Medicine Training Program Page13 of 16

14 Tingling of arms and legs; Fluid retention; Rapid heart rate; High blood pressure; Increased sweating; Intermittent fever Exposure to toxic chemicals Non-acute porphyrias Cutaneous presentations (photosensitivity) due to bone marrow accumulations: Pigmentation Changes in facial hair Fragile skin Rashes Blistering Dark-colored urine (especially after its exposure to sunlight), and above symptoms may be present All of the above Skin symptoms made worse by exposure to sunlight. Copper or brass jewelry exacerbates reaction Primary Complaints Associated Symptoms Condition Exacerbated by Neurologic presentations: Abdominal pain; nausea; vomiting; constipation; seizures Cutaneous presentations: Changes in skin pigmentation; changes in facial hair; fragile skin; rashes; blistering Headaches; difficulty in concentration; personality changes; weakness; muscle and joint aches; unsteady gait; poor coordination; numbness; tingling of arms and legs; fluid retention; rapid heart rate; high blood pressure; increased sweating; intermittent fever Dark-colored urine (especially after its exposure to sunlight), and above symptoms may be present Low carbohydrate diets (skipped meals); intake of alcoholic beverages; medications, including sulfa-drug antibiotics, barbiturates, estrogen, birth control pills; exposure to toxic chemicals Above factors, and skin symptoms made worse by exposure to sunlight. Copper or brass jewelry exacerbates reaction Diseases and Conditions Associated with Porphyrinopathies Infectious diseases Mononucleosis Acute poliomyelitis Liver diseases Cirrhosis Active chronic hepatitis Toxic and infectious hepatitis Fatty liver Alcoholic liver syndromes Drug injury Cholestasis Cholangitis Biliary cirrhosis Malignancies Hepatocellular tumors Hepatic metastases Pancreatic carcinoma Functional Medicine Training Program Page14 of 16

15 Pregnancy Carbohydrate fasting Lymphomatosis Hematologic diseases Hemolytic, sideroachrestic, sideroblastic and aplastic anemias Ineffective erythropoiesis (intramedullary hemolysis) Pernicious anemia Thalassemia Leukemia Erythroblastosis Disturbance of iron metabolism Myocardial infarction Diabetes mellitus Hereditary tyrosinemia Hereditary hyperbilirubinemias Bronze baby syndrome Hemosiderosis Idiopathic and secondary Iron deficiency anemia Dubin Johnson syndrome Rotor s syndrome Erythrohepatic protoporphyria Some Drugs That Cause or Exacerbate Porphyria (Elevation of Total Porphyrins) Drugs that can affect test measurements include the following: Antipyrine Amidopyrine Aminoglutethimide Barbiturates Carbamazepine Carbromal Chloropropramide Chloral hydrate Danazol Dapsone Diclofenac Diphenylhydantoin Ergot preparations Ethanol (acute) Ethclorvynol Ethinamate Glutethimide Griseofulvin Isopropylmeprobamate Mephenyltoin Meprobamate Methylprylon N-butylscopolammaonium bromide Nitrous oxide Novobiocin Phenylbutazone Primadone Pyrazolone preparations Succinimides Sulfonthylmethane Sulfonmethane Synthetic estrogens Progestins Tolazamide Tolbutamide Trimethadone Valproic acid Functional Medicine Training Program Page15 of 16

16 Environmental Mediators of Toxic Porphyrias Hexachlorobenzene exposure in adults results in cutaneous photosensitivity and porphyrinuria. However, in infants, exposure results in high mortality and neurotoxicity (convulsions) without porphyrinuria. Aluminum inhibits some heme synthetic enzymes and has been implicated in causing porphyria in chronic hemodialysis patients, whom are often aluminum overloaded. Lead intoxication causes signs and symptoms similar to acute intermittent porphyria including abdominal pain, constipation and vomiting. The following include additional environmental mediators of toxic porphyrias: Hexachlorobenzene PAHs 2,4,5-T PCBs Carbon tetrachloride 2,4-D Chlordane Chloroform DDT/DDE Diazinon Dioxins/ /TCDD Vinyl chloride Formaldehyde Halothane Methyl chloride Organochlorine pesticides Organophosphates Paint fumes Pesticides Phenoxyacetic herbicides Solvents such as xylene Follow Up Testing: Patients testing mildly positive on the urinary porphyrins test should be followed up with more specific testing such as toxic element testing of chelation-challenged urine for a differential diagnosis. Tests that assay toxic metals directly in biological samples are essential for confirming whether the toxicity symptoms are caused by a metal. When a significant toxic element metabolic impact is seen in the porphyrin pathway, other functional tests may show abnormalities related to the metabolic perturbations of the toxicant on metabolic pathways governed by enzymes sensitive to toxic effects of the element. Then, treatments may be designed to deal with specific causes and efficacy of treatment can be indicted by correction of the porphyrinuria. Functional Medicine Training Program Page16 of 16