Transcript Histamine and Histamine Intolerance

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 (H1R-H4R)
• H1 RECEPTORS ARE FOUND THROUGHOUT THE BODY IN SMOOTH MUSCLE, VASCULAR
ENDOTHELIAL CELLS, HEART AND CENTRAL NERVOUS SYSTEM.
• H2 RECEPTORS TRIGGER GASTRIC SECRETION OF HISTAMINE TO REGULATE HCL PRODUCTION
• LESS IS KNOWN ABOUT H3 AND H4 RECEPTORS
• H1-H3 RECEPTORS ARE PRIMARILY FOUND IN THE BRAIN
• H4 RECEPTORS ARE FOUND IN THE PERIPHERY
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H1R
• 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 H1R 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)
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Haas, H.L., Sergeeva, O.A. and Selbach, O. (2008) Histamine in the Nervous System. Physiol Rev. 88, 1183-1241.
H1R
• 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 H1R EXCITES NEURONS IN MOST BRAIN REGIONS, INCLUDING BRAIN STEM,
HYPOTHALAMUS, THALAMUS, AMYGDALA, SEPTUM, HIPPOCAMPUS, OLFACTORY BULB,
AND CORTEX.
• ALL H1R ANTIHISTAMINES FUNCTIONS AS INVERSE AGONISTS, STABILIZING THE RECEPTOR
IN ITS INACTIVE STATE—NOTE: THIS DOES NOT CHANGE ACTUAL HISTAMINE LEVELS!
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H2R
• POSTSYNAPTIC EXCITABILITY AND PLASTICITY
• LEARNING AND MEMORY (CONSOLIDATION)
• INVOLVED IN PAIN AND NEUROINFLAMMATION
• REGULATES NEURONAL PHYSIOLOGY AND PLASTICITY
• H2R INHIBIT PLA2 AND RELEASE OF ARACHIDONIC ACID (OPPOSING H1R)
• H2R ANTAGONISTS ARE PRESCRIBED FOR GASTRIC DISORDERS AND HAVE ANTITUMOR ACTIVITY.
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H3R
• 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 H3R 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.
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H4R
• CHEMOTAXIS (MOVEMENT OF AN ORGANISM IN RESPONSE TO CHEMICAL STIMULUS
• SIMILAR TO H3RS 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
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PHARMACOLOGICAL INTERVENTIONS
• H1 BLOCKERS: ZYRTEC, ALLEGRA, CLARITIN, BENADRYL, XYZAL AND HYDROXYZINE
• H2 BLOCKERS: ZANTAC, PEPCID, AND TAGAMET
• MAST CELL STABILIZERS: CHROMOLYN SODIUM AND KETOTIFEN
• QUERCETIN IS A NATURAL MAST CELL STABILIZER
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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)
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HISTAMINE ISSUES
• HISTAMINE IS A MAJOR NEUROTRANSMITTER
• CONTROLS SLEEP/WAKE CYCLE (HENCE DROWSINESS WITH H1 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
• BEHAVIORAL STATE, BIOLOGICAL RHYTHMS, BODY WEIGHT, ENERGY METABOLISM, THERMOREGULATION,
FLUID BALANCE, STRESS AND REPRODUCTION
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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.
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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 (H1)
• DAO/ABP1: EXTRACELLULAR HISTAMINE METABOLISM (H2)
• MAO: EXTRACELLULAR HISTAMINE METABOLISM (H2)
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HISTAMINE INTOLERANCE
• HISTAMINE INTOLERANCE MAY OCCUR WHEN THERE ARE SNPS TO THE ENZYMES DIAMINE
OXIDASE (DAO) AND AMILORIDE BINDING PROTEIN I (ABP1).
• SYMPTOMS INCLUDE:
• GASTROINTESTINAL COMPLAINTS, MIGRAINES, FATIGUE, DIZZINESS, RUNNY NOSE, FLUSHING,
ASTHMA AND HIVES
• INTERESTINGLY, ELEVATED HISTAMINE CAN INHIBIT DAO WHICH CAUSES INCREASED HISTAMINE
INTOLERANCE.
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HISTAMINE AND NEUROTRANSMITTERS
• DECREASES GABA LEVELS
• INCREASES NOREPINEPHRINE AND EPINEPHRINE
• GLYCINE INHIBITS A SUBPOPULATION OF HISTAMINERGIC NEURONS (HENCE SEDATIVE EFFECT)
• DECREASES SEROTONIN VIA H3R ACTIVATION
• INHIBITS DOPAMINE
• SINCE HISTAMINE IS MAJOR WAKE-PROMOTING NEUROTRANSMITTER IN THE CNS IT CAN CAUSE SLEEP
DISORDERS.
• GABAERGIC NEURONS ARE EXCITED THROUGH H1R IN THE SUBSTANTIA NIGRA AND VENTRAL TEGMENTUM.
• FOR THIS REASON ATIVAN (AND OTHER ANXIETY MEDICATIONS) OFTEN HAS AN ANTI-HISTAMINE EFFECT.
• HISTAMINE MAY BE A DANGER RESPONSE SIGNAL PROMOTING ANXIETY
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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 H2R IN BOTH HYPOTHALAMIC AND PITUITARY
TARGETS.
• HISTAMINE DECREASES TRH RELEASE AND TSH PLASMA LEVELS THROUGH H2R IN BOTH HYPOTHALAMIC AND PITUITARY TARGETS.
• SYSTEMIC L-THYROXINE USE, ALONG WITH RISES IN T3 AND T4 INCREASES CORTICAL 5-HT AND HISTAMINE CONTENT, WHEREAS
CARIMAZOLE (RX FOR HYPERTHYROIDISM) LOWERS HISTAMINE, GLUTAMATE, AND 5-HT LEVELS, SUGGESTING A T3/T4 MEDIATED
NEGATIVE FEEDBACK ON TRH PRODUCTION BY HISTAMINE.
• POTENT STIMULUS FOR AVP AND OXYTOCIN RELEASE
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LOW HISTAMINE DIET: FOODS TO AVOID
• AGED, SPOILED AND LEFTOVER FOOD
• THE AMINO ACID HISTIDINE DEGRADES
TO HISTAMINE
• AGED CHEESES
• SMOKED MEATS
• BEANS
• ALCOHOL
• NUTS
• FISH AND SHELLFISH
• CHOCOLATE/COCOA
• PICKLED AND CANNED FOODS
• CITRUS
• WHEAT
• VINEGAR
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HISTAMINE SNYTHESIS AND METABOLISM
HISTAMINE
• H
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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, ABP1,
MAO-A, HNMT, AND ADH.
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DAO
• DIAMINE OXIDASE
• COFACTOR: RIBOFLAVIN (FAD)
• FUNCTION: EXTRACELLULAR HISTAMINE DEGRADATION (GASTROINTESTINAL SYSTEM)
• INHIBITED BY HIGH HISTAMINE
• RELEVANT SNPS: RS2070586, RS2111902, RS3741775
• CONSIDER A LOW HISTAMINE DIET
• MAY SUPPLEMENT DAO (HISTAMINE BLOCK, HISTDAO, DAOSIN, ETC.)—ALWAYS DERIVED FROM PIGS
AVOID IF SENSITIVE/ALLERGIC TO PORK
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ABP1
• COFACTORS: CALCIUM, COPPER, OXYGEN AND WATER
• FUNCTION: DEGRADES EXTRACELLULAR HISTAMINE
• RELEVANT SNPS:
• RS10156191 (NSAID SENSITIVITY)
• RS1049793 (DECREASED DAO, INCREASED ULCERATIVE COLITIS SYMPTOMS)
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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
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HNMT
• HISTAMINE N-METHYLTRANSFERASE
• COFACTOR: SAM
• FUNCTION: DEGRADES INTRACELLULAR HISTAMINE
• RELEVANT SNPS:
• RS11558538 AND RS1801105 (ASTHMA, ATOPIC DERMATITIS)
• RS1050891 (ADHD, CHRONIC UTICARIA)
• ONCE PAST HMNT, INTRACELLULAR HISTAMINE MUST THEN MOVE THROUGH MAO (FAD
COFACTOR) AND DAO (FAD COFACTOR)
• INHIBITED BY VIRUSES
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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
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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.
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CASE STUDY—EHLERS-DANLOS
• EHLERS-DANLOS SYNDROME (EDS) IS A GENETIC CONNECTIVE TISSUE
DISORDER
• COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, 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
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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
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CASE STUDY—GENETICS
• DAO RS3741775: HOMOZYGOUS
• MAO-A RS6323: HOMOZYGOUS
• HNMT RS1050891: HETEROZYGOUS
• ASSOCIATED WITH CHRONIC URTICARIA
• ABP1 RS1049793: HETEROZYGOUS
• ASSOCIATED WITH DECREASED DAO
• ADH RS617: WILD TYPE
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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 ABP1 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.
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REMEMBER THE
HISTAMINE
PATHWAYS
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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 B12 AS TOLERATED
• HNMT REQUIRES PROPER METHYLATION TO FUNCTION
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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
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