HISTAMINE AND HISTAMINE INTOLERANCE NUTRITIONAL GENOMICS WITH A

HISTAMINE AND HISTAMINE INTOLERANCE NUTRITIONAL GENOMICS WITH A CLINICAL APPLICATION PRESENTED BY SNPED WWW. SNPPROS. COM

HISTAMINE • HISTAMINE IS RELEASED IN THE BODY UPON MAST CELL DEGRANULATION • THERE ARE FOUR HISTAMINE RECEPTORS (H 1 R-H 4 R) • H 1 RECEPTORS ARE FOUND THROUGHOUT THE BODY IN SMOOTH MUSCLE, VASCULAR ENDOTHELIAL CELLS, HEART AND CENTRAL NERVOUS SYSTEM. • H 2 RECEPTORS TRIGGER GASTRIC SECRETION OF HISTAMINE TO REGULATE HCL PRODUCTION • LESS IS KNOWN ABOUT H 3 AND H 4 RECEPTORS • H 1 -H 3 RECEPTORS ARE PRIMARILY FOUND IN THE BRAIN • H 4 RECEPTORS ARE FOUND IN THE PERIPHERY Copyright 2016 Zebra Diagnostics, LLC

H 1 R • FOUND THROUGHOUT THE BODY AND NERVOUS SYSTEM • POSTSYNAPTIC EXCITABILITY AND PLASTICITY • BEHAVIORAL STATE AND REINFORCEMENT (NOVELTY, AROUSAL) • WORKING MEMORY, FEEDING RHYTHMS, ENERGY METABOLISM AND ENDOCRINE CONTROL • DISORDERS OF SLEEP, MOOD, MEMORY, EATING, AND ADDICTION • PAIN AND NEUROINFLAMMATION • EFFECTOR PATHWAYS OF H 1 R INCLUDE PRODUCTION OF ARACHIDONIC ACID (AA), NITRIC OXIDE (NO), AND CGMP • ACTIVATES AMP-KINASE, A CHECKPOINT IN CONTROL OF ENERGY METABOLISM, AND NUCLEAR FACTOR KAPPA B (NF-KB) Copyright 2016 Zebra Diagnostics, LLC Haas, H. L. , Sergeeva, O. A. and Selbach, O. (2008) Histamine in the Nervous System. Physiol Rev. 88, 11831241.

H 1 R • VERY HIGH DENSITY IN NONNEURONAL ELEMENTS INCLUDING GLIA, BLOOD CELLS AND VESSELS • VERY HIGH DENSITY IN BRAIN REGIONS CONCERNED WITH NEUROENDOCRINE, BEHAVIORAL, AND NUTRITIONAL STATE CONTROL, LIKE THE HYPOTHALAMUS, AMINERGIC AND CHOLINERGIC BRAINSTEM NUCLEI, THALAMUS, AND CORTEX • HISTAMINE VIA H 1 R EXCITES NEURONS IN MOST BRAIN REGIONS, INCLUDING BRAIN STEM, HYPOTHALAMUS, AMYGDALA, SEPTUM, HIPPOCAMPUS, OLFACTORY BULB, AND CORTEX. • ALL H 1 R ANTIHISTAMINES FUNCTIONS AS INVERSE AGONISTS, STABILIZING THE RECEPTOR IN ITS INACTIVE STATE—NOTE: THIS DOES NOT CHANGE Copyright 2016 Zebra Diagnostics, LLC ACTUAL HISTAMINE LEVELS!

H 2 R • POSTSYNAPTIC EXCITABILITY AND PLASTICITY • LEARNING AND MEMORY (CONSOLIDATION) • INVOLVED IN PAIN AND NEUROINFLAMMATION • REGULATES NEURONAL PHYSIOLOGY AND PLASTICITY • H 2 R INHIBIT PLA 2 AND RELEASE OF ARACHIDONIC ACID (OPPOSING H 1 R) • H 2 R ANTAGONISTS ARE PRESCRIBED FOR GASTRIC DISORDERS AND HAVE ANTITUMOR ACTIVITY. Copyright 2016 Zebra Diagnostics, LLC

H 3 R • PRESYNAPTIC TRANSMITTER RELEASE AND PLASTICITY • NUMEROUS CNS FUNCTIONS, COGNITION, EMOTION, LEARNING, AND MEMORY • BLOOD-BRAIN BARRIER CONTROL • DISORDERS OF SLEEP MOOD, MEMORY, EATING, AND ADDICTION • INVOLVED IN PAIN AND NEUROINFLAMMATION • CONTROLS THE RELEASE OF OTHER BIOGENIC AMINES, ACETYLCHOLINE, GLUTAMATE, GABA, AND PEPTIDERGIC SYSTEMS. • LOSS OF H 3 R FUNCTION CAUSES BEHAVIORAL STATE ABNORMALITIES, REDUCED LOCOMOTION, METABOLIC SYNDROME WITH HYPERPHAGIA, LATE-ONSET OBESITY, INCREASED INSULIN AND LEPTIN LEVELS, AND AN INCREASED SEVERITY OF NEUROINFLAMMATORY DISEASES. Copyright 2016 Zebra Diagnostics, LLC

H 4 R • CHEMOTAXIS (MOVEMENT OF AN ORGANISM IN RESPONSE TO CHEMICAL STIMULUS • SIMILAR TO H 3 RS BUT IS EXPRESSED IN PERIPHERAL CELLS AND TISSUES (BLOOD, SPLEEN, LUNG, LIVER, AND GUT). ALSO MAY BE PRESENT IN PARTS OF BRAIN. • PROMISING DRUG TARGET IN INFLAMMATION Copyright 2016 Zebra Diagnostics, LLC

PHARMACOLOGICAL INTERVENTIONS • H 1 BLOCKERS: ZYRTEC, ALLEGRA, CLARITIN, BENADRYL, XYZAL AND HYDROXYZINE • H 2 BLOCKERS: ZANTAC, PEPCID, AND TAGAMET • MAST CELL STABILIZERS: CHROMOLYN SODIUM AND KETOTIFEN • QUERCETIN IS A NATURAL MAST CELL STABILIZER Copyright 2016 Zebra Diagnostics, LLC

THE WIDE SPREAD AFFECTS OF HISTAMINE TINY HISTAMINE IS RESPONSIBLE FOR A STAGGERING NUMBER OF BIOLOGICAL EFFECTS, WHICH VARY BASED ON RECEPTOR, CELL LOCATION, AND TARGET CELL. (DIAGRAM ADAPTED FROM MAINTZ 2007 AM J CLIN NUTR 85: 1185– 96) Copyright 2016 Zebra Diagnostics, LLC

HISTAMINE ISSUES • HISTAMINE IS A MAJOR NEUROTRANSMITTER • CONTROLS SLEEP/WAKE CYCLE (HENCE DROWSINESS WITH H 1 BLOCKERS) • REGULATES RELEASE OF HCL VIA ACTIVATION OF PROTON PUMP IN PARIETAL CELLS • PLAYS A ROLE IN INNATE AND ACQUIRED IMMUNITY, ALLERGY AND INFLAMMATION, IMMUNOMODULATION REGULATING T-CELL FUNCTIONS, AND AUTOIMMUNITY. • PAIN AND NEUROINFLAMMATION • INCREASES MOTOR PERFORMANCE, BALANCE AND COORDINATION • IMPACTS NEUROENDOCRINE CONTROL Copyright 2016 Zebra Diagnostics, LLC • BEHAVIORAL STATE, BIOLOGICAL RHYTHMS, BODY WEIGHT, ENERGY METABOLISM, THERMOREGULATION, FLUID BALANCE, STRESS AND REPRODUCTION

HISTAMINE ISSUES • REGULATES FEEDING, DRINKING AND BODY TEMPERATURE • REGULATES WATER BALANCE • INHIBITS THE HYPOTHALAMUS-PITUITARY-THYROID AXIS • REGULATES IMMUNITY AND BLASTOCYST IMPLANTATION DURING PREGNANCY, GONADAL DEVELOPMENT DURING EMBRYOGENESIS, LACTATION, AND ADULTHOOD SEX STEROID METABOLISM • CONTROLS APPETITE, FEEDING RHYTHMS AND ENERGY METABOLISM • MEDIATES ITCH AND PAIN Haas, Helmut L. et al. “Histamine in the Nervous System. ” Physiol. Rev. 88: 1183 -1241, 2008. Copyright 2016 Zebra Diagnostics, LLC

HISTAMINE ISSUES • HISTAMINE ISSUES ARE INCREDIBLY COMMON • RANGE FROM HAY FEVER AND ASTHMA, TO GASTROINTESTINAL ISSUES AND MAST CELL ACTIVATION DISORDERS (MCAD) • DEGRADATION RELIES ON THREE MAJOR ENZYMES • HMNT: INTRACELLULAR HISTAMINE METABOLISM (H 1) • DAO/ABP 1: EXTRACELLULAR HISTAMINE METABOLISM (H 2) • MAO: EXTRACELLULAR HISTAMINE METABOLISM (H 2) Copyright 2016 Zebra Diagnostics, LLC

HISTAMINE INTOLERANCE • HISTAMINE INTOLERANCE MAY OCCUR WHEN THERE ARE SNPS TO THE ENZYMES DIAMINE OXIDASE (DAO) AND AMILORIDE BINDING PROTEIN I (ABP 1). • SYMPTOMS INCLUDE: • GASTROINTESTINAL COMPLAINTS, MIGRAINES, FATIGUE, DIZZINESS, RUNNY NOSE, FLUSHING, ASTHMA AND HIVES • INTERESTINGLY, ELEVATED HISTAMINE CAN INHIBIT DAO WHICH CAUSES INCREASED HISTAMINE INTOLERANCE. Copyright 2016 Zebra Diagnostics, LLC

HISTAMINE AND NEUROTRANSMITTERS • DECREASES GABA LEVELS • INCREASES NOREPINEPHRINE AND EPINEPHRINE • GLYCINE INHIBITS A SUBPOPULATION OF HISTAMINERGIC NEURONS (HENCE SEDATIVE EFFECT) • DECREASES SEROTONIN VIA H 3 R ACTIVATION • INHIBITS DOPAMINE • SINCE HISTAMINE IS MAJOR WAKE-PROMOTING NEUROTRANSMITTER IN THE CNS IT CAN CAUSE SLEEP DISORDERS. • GABAERGIC NEURONS ARE EXCITED THROUGH H 1 R IN THE SUBSTANTIA NIGRA AND VENTRAL TEGMENTUM. • FOR THIS REASON ATIVAN (AND OTHER ANXIETY MEDICATIONS) OFTEN HAS AN ANTI-HISTAMINE EFFECT. Copyright 2016 Zebra Diagnostics, LLC • HISTAMINE MAY BE A DANGER RESPONSE SIGNAL PROMOTING ANXIETY

HISTAMINE AND HORMONES • HISTAMINE GREATLY IMPACTS NEUROENDOCRINE CONTROL (BEHAVIORAL STATE, BIOLOGICAL RHYTHMS, BODY WEIGHT, ENERGY METABOLISM, THERMOREGULATION, FLUID BALANCE, STRESS AND REPRODUCTION) • STIMULATES SECRETION OF ADRENOCORTICOTROPIC HORMONE (ACTH) WHICH THEN INCREASES CORTISOL LEVELS • INVOLVED IN ESTROGEN-INDUCED LH SURGES IN FEMALES (MEDIATED BY GNRH) • INHIBITORY EFFECT ON RELEASE OF GROWTH HORMONE AND TSH • HISTAMINE DECREASES TRH RELEASE AND TSH PLASMA LEVELS THROUGH H 2 R IN BOTH HYPOTHALAMIC AND PITUITARY TARGETS. • SYSTEMIC L-THYROXINE USE, ALONG WITH RISES IN T 3 AND T 4 INCREASES CORTICAL 5 -HT AND HISTAMINE CONTENT, WHEREAS CARIMAZOLE (RX FOR HYPERTHYROIDISM) LOWERS HISTAMINE, GLUTAMATE, AND 5 HT LEVELS, SUGGESTING A T 3/T 4 MEDIATED NEGATIVE FEEDBACK ON TRH PRODUCTION BY HISTAMINE. • POTENT STIMULUS FOR Copyright 2016 Zebra Diagnostics, LLC AVP AND OXYTOCIN RELEASE

LOW HISTAMINE DIET: FOODS TO AVOID • AGED, SPOILED AND LEFTOVER FOOD • THE AMINO ACID HISTIDINE DEGRADES TO HISTAMINE • AGED CHEESES • SMOKED MEATS • BEANS • NUTS • ALCOHOL • CHOCOLATE/COCOA • FISH AND SHELLFISH • CITRUS • PICKLED AND CANNED FOODS • WHEAT • VINEGAR Copyright 2016 Zebra Diagnostics, LLC

HISTAMINE SNYTHESIS AND METABOLISM HISTAMINE • H Copyright 2016 Zebra Diagnostics, LLC Helmut L. Haas et al. Physiol Rev 2008; 88: 1183 -1241 © 2008 by American Physiological Society

A REVIEW OF HISTAMINE BIOCHEMISTRY WE WILL DISCUSS SEVERAL HISTAMINE RELATED SNPS INCLUDING DAO, ABP 1, MAO-A, HNMT, AND ADH. Copyright 2016 Zebra Diagnostics, LLC

DAO • DIAMINE OXIDASE • COFACTOR: RIBOFLAVIN (FAD) • FUNCTION: EXTRACELLULAR HISTAMINE DEGRADATION (GASTROINTESTINAL SYSTEM) • INHIBITED BY HIGH HISTAMINE • RELEVANT SNPS: RS 2070586, RS 2111902, RS 3741775 • CONSIDER A LOW HISTAMINE DIET • MAY SUPPLEMENT DAO (HISTAMINE BLOCK, HISTDAO, DAOSIN, ETC. )—ALWAYS DERIVED FROM PIGS AVOID IF SENSITIVE/ALLERGIC TO PORK Copyright 2016 Zebra Diagnostics, LLC

ABP 1 • COFACTORS: CALCIUM, COPPER, OXYGEN AND WATER • FUNCTION: DEGRADES EXTRACELLULAR HISTAMINE • RELEVANT SNPS: • RS 10156191 (NSAID SENSITIVITY) • RS 1049793 (DECREASED DAO, INCREASED ULCERATIVE COLITIS SYMPTOMS) Copyright 2016 Zebra Diagnostics, LLC

MAO-A • MONOAMINE OXIDASE-A • COFACTOR: RIBOFLAVIN (FAD) • FUNCTION: CATALYZES THE DEAMINATION OF THE AMINES DOPAMINE, SEROTONIN, EPINEPHRINE, NOREPINEPHRINE • METABOLIZES THE XENOBIOTIC AMINES: HETEROCYCLIC AMINES (MEAT), TYRAMINES, AND HISTAMINE • CONNECTED TO TRYPTOPHAN VIA METHYLATION; LOOK AT UAA Copyright 2016 Zebra Diagnostics, LLC

HNMT • HISTAMINE N-METHYLTRANSFERASE • COFACTOR: SAM • FUNCTION: DEGRADES INTRACELLULAR HISTAMINE • RELEVANT SNPS: • RS 11558538 AND RS 1801105 (ASTHMA, ATOPIC DERMATITIS) • RS 1050891 (ADHD, CHRONIC UTICARIA) • ONCE PAST HMNT, INTRACELLULAR HISTAMINE MUST THEN MOVE THROUGH MAO (FAD COFACTOR) AND DAO (FAD COFACTOR) • INHIBITED BY VIRUSES Copyright 2016 Zebra Diagnostics, LLC

ADH • ALCOHOL DEHYDROGENASE • COFACTORS: ZINC, VITAMIN C, NAD, AND THIAMINE • FUNCTION: FINAL ENZYME REQUIRED FOR BOTH EXTRACELLULAR AND INTRACELLULAR HISTAMINE DEGRADATION • NOT VERY HIGHLY POLYMORPHIC EXCEPT IN ASIAN POPULATIONS Copyright 2016 Zebra Diagnostics, LLC

CASE STUDY • DD IS A 47 -YEAR-OLD FEMALE WITH A HISTORY OF EHLERS-DANLOS SYNDROME (HYPERMOBILITY TYPE), GERD, URTICARIA AND UNSPECIFIED AUTOIMMUNE DISEASE. • SHE HAS BEEN PRESCRIBED ATIVAN FOR OCCASIONAL ANXIETY. • SHE COMPLAINS OF RANDOM GI DISTURBANCES SUCH AS DIARRHEA, BLOATING AND REFLUX. • SHE REPORTS THAT SHE FEELS BETTER WHEN EATING VEGETARIAN MEALS. • OFTEN AFTER EATING SHE HAS SNIFFLING, COUGHING, HEADACHE, NAUSEA, ITCHY/SWOLLEN EYES, AND SOMETIMES DIARRHEA. Copyright 2016 Zebra Diagnostics, LLC

CASE STUDY—EHLERS-DANLOS • EHLERS-DANLOS SYNDROME (EDS) IS A GENETIC CONNECTIVE TISSUE DISORDER • COL 1 A 1, COL 1 A 2, COL 3 A 1, COL 5 A 2, TNXB • ASSOCIATED WITH LOOSE/HYPERMOBILE JOINTS, PAIN, SCOLIOSIS/KYPHOSIS, FRAGILE SKIN, EASY BRUISING, DYSAUTONOMIA, GERD, HIATAL HERNIA, INTESTINAL PERMEABILITY • VASCULAR EDS MAY CAUSE AORTIC DISSECTION • EDS IS CAUSED BY A DEFECT IN THE STRUCTURE, PRODUCTION OR PROCESSING OF COLLAGEN OR PROTEINS THAT INTERACT WITH COLLAGEN. • DIAGNOSED BY GENETIC TESTING AND BEIGHTON SCALE Copyright 2016 Zebra Diagnostics, LLC

CASE STUDY—ORGANIC ACIDS • VANILMANDELATE (VMA): 5. 3 H • INCREASED NOREPINEPHRINE AND EPINEPHRINE CATABOLISM • HOMOVANILATE (HVA): 7. 1 H • INCREASED DOPAMINE CATABOLISM • P-HYDROXYPHENYLLACTATE: 0. 39 FH • MARKER FOR OXIDATIVE STRESS AND VITAMIN C NEED • D-ARABINITOL: 78 H • INCREASES WITH CANDIDA INFECTION Copyright 2016 Zebra Diagnostics, LLC

CASE STUDY—GENETICS • DAO RS 3741775: HOMOZYGOUS • MAO-A RS 6323: HOMOZYGOUS • HNMT RS 1050891: HETEROZYGOUS • ASSOCIATED WITH CHRONIC URTICARIA • ABP 1 RS 1049793: HETEROZYGOUS • ASSOCIATED WITH DECREASED DAO • ADH RS 617: WILD TYPE Copyright 2016 Zebra Diagnostics, LLC

CASE STUDY—BRINGING IT ALL TOGETHER • DD’S GENETICS ARE THE PERFECT STORM FOR HISTAMINE INTOLERANCE. • PRESENCE OF A HOMOZYGOUS DAO SNP, COMBINED WITH HOMOZYGOUS MAO-A, HETEROZYGOUS ABP 1 AND HETEROZYGOUS HNMT SEVERELY IMPAIR HER ABILITY TO CATABOLIZE HISTAMINE. • EDS MEANS THAT INTESTINAL PERMEABILITY/LEAKY GUT ARE LIKELY. COMBINED WITH INCREASED HISTAMINE WHICH DESTROYS THE GUT, THIS WILL LEAD TO FOOD SENSITIVITIES AND DYSBIOSIS. • CANDIDA PRODUCES ALCOHOL WHICH MUST GO THROUGH ADH. THIS FURTHER TAXES THIS ENZYME WHICH IS ALSO IMPORTANT FOR HISTAMINE BREAKDOWN. Copyright 2016 Zebra Diagnostics, LLC

REMEMBER THE HISTAMINE PATHWAYS Copyright 2016 Zebra Diagnostics, LLC

CASE STUDY—INTERVENTION • LOW HISTAMINE DIET • DAO SUPPLEMENT SUCH AS DAOSIN MAY BE USED WITH HIGH HISTAMINE FOODS • VITAMIN C: 500 MG QID • RIBOFLAVIN: 400 MG OID • FAD IS THE COFACTOR FOR DAO, MAO • ZINC CARNOSINE: 75 MG BID • QUERCETIN DIHYDRATE: 500 MG QID • ANTIFUNGALS SUCH AS NYSTATIN, OIL OF OREGANO, CAPRYLIC ACID, ETC. • METHYL B 12 AS TOLERATED • HNMT REQUIRES PROPER METHYLATION TO FUNCTION Copyright 2016 Zebra Diagnostics, LLC

UPCOMING WEBINARS • MITOCHONDRIAL HEALTH AND DISEASE PART 2: (CW) DEC 21 • NEUROTRANSMITTER SERIES PART 1 (JP) JAN 11 • VITAMIN D: GENETICS, LABORATORY EVALUATIONS AND DISEASE (CW) JAN 18 • NEUROTRANSMITTER SERIES PART 2 (JP) FEB 1 • NUTRIENT SPECIFIC SNPS (CW) FEB 15 • DYSBIOSIS: GENETICS AND FUNCTIONAL TESTING (JP) MARCH 1 Copyright 2016 Zebra Diagnostics, LLC