Histamine and Histamine Intolerance - PowerPoint Presentation

Histamine and Histamine Intolerance Nutritional Genomics with a Clinical application Presented by SNPed www.snppros.com

HistamineHistamine is released in the body upon mast cell degranulationThere 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 ProductionLess is known about H3 and H4 receptorsH1-H3 receptors are primarily found in the BrainH4 Receptors are found in the peripheryCopyright 2016 Zebra Diagnostics, LLC

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) Copyright 2016 Zebra Diagnostics, LLC 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! Copyright 2016 Zebra Diagnostics, LLC

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. Copyright 2016 Zebra Diagnostics, LLC

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. Copyright 2016 Zebra Diagnostics, LLC

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 Copyright 2016 Zebra Diagnostics, LLC

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 Copyright 2016 Zebra Diagnostics, LLC

The Wide Spread Affects of HistamineTiny 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 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 Copyright 2016 Zebra Diagnostics, LLC

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 (H1) DAO/ABP1: extracellular histamine metabolism (H2) MAO: Extracellular Histamine Metabolism (H2) 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 (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. 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 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 Copyright 2016 Zebra Diagnostics, LLC

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 Copyright 2016 Zebra Diagnostics, LLC

Low Histamine Diet: Foods to Avoid Aged, spoiled and leftover foodThe amino acid histidine degrades to histamineAlcoholFish and shellfish Pickled and canned foods Aged cheesesSmoked meatsBeans Nuts Chocolate/cocoa Citrus Wheat Vinegar Copyright 2016 Zebra Diagnostics, LLC

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

A Review of Histamine Biochemistrywe will discuss several histamine related SNPs including DAO, ABP1, 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: 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 Copyright 2016 Zebra Diagnostics, LLC

ABP1 Cofactors: calcium, copper, oxygen and water Function: degrades extracellular histamine Relevant SNPs: rs10156191 (NSAID sensitivity) rs1049793 (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: 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 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 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 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 rs3741775: Homozygous MAO-A rs6323: Homozygous HNMT rs1050891: heterozygous Associated with chronic urticaria ABP1 rs1049793: Heterozygous Associated with decreased DAO ADH rs617: 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 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. 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 B12 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