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The nutri-genomic impact on histamine metabolism.

Histamine is a 5-carbon nitrogenous substance that has an immune-modulatory role most known for the "allergic reaction." Histamine is well documented in other conditions such as Meniere's disease, irritable bowel syndrome and headaches. The endogenous production of histamine comes from the decarboxylation of the amino acid histidine via the pyridoxal-5'-phosphate (vitamin B6) dependent enzyme histidine decarboxylase. There are also many foods that contain appreciable levels of histamine and avoidance may be part of treatment for certain patients. It is the author's opinion that the histaminic response is grossly discounted in clinical practice when the patient presents without anaphylactic symptomatology. This is most likely due to the multiple systems involved and the seemingly random presentation as well as disorganized timing of symptoms. Most patients with over activation of histamine degranulation go decades, some even their entire lives, without finding answers. (1)

L-Histidine + [H.sup.+] [??](HDC) [??] Histamine + C[O.sub.2]

Mast cells, basophils, neurons and enterochromaffin cells carry out synthesis of histamine. Some bacteria have the ability to stimulate the histamine response independent of IgE mediation--the bacteria themselves or endotoxins seem to trigger basophil, leukocytes and mast cell degranulation. An example is Human Parvo Virus B19 and its production of erythemous rash, arthropathy and respiratory distress. Due to its versatile binding capacity histamine is suspected to be involved in over 20 physiologic functions. (2)

Mast cells may have the greatest impact on histaminic load of an individual. Mast cells are a type of B cell that is created in the bone marrow and part of the immune system. Mast cells contain both histamine and heparin, along with some other immune-proteins. Much of mast cell's fame comes from the allergic reaction. When an allergen is introduced to the system it triggers an IgE response. Immunoglobulin E and the antigen bind together. This complex attaches to the mast cell, which causes degranulation. Degranulation essentially is the release of intracellular proteins, in this case; histamine. If this process is exaggerated it could lead to anaphylaxis. Histamine also regulates the expression of certain inflammatory cytokines such as IL-6 and IL-8 and is an integral part of the inflammatory and immune cascade. There are 2 main forms of mast cell activation: primary and secondary. Primary activation relates to genetic defects in c-Kit and PDGFRA which lead to mastocystosis and eosinophilic leukemia, respectively (1, 3) Secondary activation is much more common and results from the crosslinking and aggregation of IgE, IgG, immune-proteins, hormones as well as physical and emotional stressors.

Clinical signs of an over abundance of sustained histamine load are, but not limited to:

1. Sclerosing of the outer border of the tympanic membrane

2. Positional tachycardia with or without hypotension

3. Dermatographism

4. Vasomotor instability

5. Diffuse rashes or uticaria

Given the sporadic and diffuse nature of presentation, it is important for the clinician to take a thorough history and not just information surrounding the presenting complaint. It may not be surprising to find out that patients experiencing elevated histamine have not felt well since their early teens or adolescent years.

Histamine works on 4 major receptors in the body: H1, H2, H3, H4. The following are the major tissue locations:

* H1- located in vascular tissue, smooth muscles and in the CNS

* H2- found in the gastric epithelium (parietal cells) and the airways

* H3- expressed in central nervous system- regulation of neurotransmission

* H4- found in bone marrow and is involved with regulating the immune response

Metabolism of histamine is mostly dependent on one-carbon metabolism via histamine N-methyltransferase (H-NMT) and deamination via diamine oxidase (DAO). H-NMT is found in the cystosol and appears to respond to intracellular histamine utilizing the methyl donor S adenosyl-L-methionine or SAMe. (4) H-NMT is responsible for most, if not all, deactivation of histamine in the central nervous system. DAO enzyme has not been isolated in central nervous tissue.

Diamine oxidase is responsible for extracellular deactivation of histamine such as dietary histamine. (4) Many patients with DAO defects or deficiencies will experience gastrointestinal dysfunction when consuming foods higher in histamine. Those signs can be stomach cramping, nausea, diarrhea and pain. DAO has also been seen to reduce migraines in those patients who were deficient in DAO activity.

Enzyme Polymorphisms and Histamine Metabolism

As with most conditions--genetics play a large role in the development and progression of disease. It is important to note that a specific genetic profile is not an absolute for manifestation of disease. There must be environmental factors that trigger these genetics to be expressed or overburden enzymes to a point that exposes their weakness. For example: A patient with a polymorphism for DAO may not experience negative symptomology unless they were to consume foods high in histamine such as cured pork products. Deficiencies in nutrient cofactors will also expose functional weakness of those enzymes predisposed to dysfunction due to genetic defects.

The following enzymes are known to contribute or have a direct role in metabolism of histamine: monoamine oxidase (MAO), di amine oxidase (DAO), and histamine N-methyl transferase, aldehyde dehydrogenase. (4, 5, 6, 7, 8, 9) Each of these enzymes play specific roles. (Note: this list is not all-inclusive, but serves as references of those enzymes that seem to have the strongest influence). Histamine metabolism needs to be looked at from a global standpoint. Supporting one enzyme could cause downstream overburden of another enzyme. The most commonly overlooked enzyme in histamine breakdown is aldehyde dehydrogenase, as we will discuss.

The following will concentrate on the genetic connections of mast cell activation and/or histamine breakdown. There are 2 main categories we will look at--genes that code for proteins/enzymes and the nutrients that those enzymes depend on for optimal function. We are interested in both the enzymes level of function; whether it's up or down regulated, as well as the products or fuel for that enzyme.

For example: Aldehyde dehydrogenase is involved in breaking down aldehydes. Aldehydes are those chemicals in perfumes that give them their distinct smell; molds also give off aldehydes. Someone who is sensitive to those smells may have 1 of 3 scenarios.

1. A genetic defect in aldehyde dehydrogenase, causing upstream metabolites to increase (aldehydes)

2. A deficiency in molybdenum (a rare earth mineral); which is the "fuel" for the enzyme

3. Or a combination of 1 and 2, which would be the worse case scenario.

The following outlines the major metabolic pathways of histamine. This is not all-inclusive as histamine is regulated and broken down in many pathways.

Histamine Regulation

The following will concentrate on the enzymes that can affect BH4 levels and its relationship to histamine; Methyltetrahydrafolate reductase (MTHFR), dihydropteridine reductase, dihydrofolate reductase (DHFR), and quinoid dihydropteridine reductase (QDPR) heavily influence BH4 (tetrahydrobiopterin) synthesis and recycling. The detailed reactions of each of these enzymes are not the subject of this article, but single nuclear polymorphisms or cofactor deficiencies could lead to poor tetrahydrobiopterin (BH4) status.

Tetrahydrobiopterin is an essential cofactor in the biosynthesis of catecholamines, serotonin and melatonin. As it pertains to histamine control, BH4 is important cofactor to nitric oxide synthase. NOS have the ability to regulate mast cell degranulation. It is also proposed that nitric oxide synthase may also protect mast cells from activation induced cell death. It is worthy of note that you can have a genetic defect to NOS as well as MTHFR 1298 making this a potent combination for rogue mast cell activation. C-reactive protein above 0.5 mg/L has been shown to be a beneficial surrogate marker for NOS deficiency.

Histamine Degradation

Diamine oxidase or DAO is responsible for breaking down dietary histamines and to a lesser extent, endogenous histamine. (10) The enzyme is dependent on a couple basic vitamins and minerals: vitamin B6, vitamin C, copper." It is released by the intestinal mucosa where it interacts with the foods we eat. It can later be transported into the blood stream via the lymphatics.

Long chain fatty acids such as olive oil can increase the secretion of DAO into the lymphatic system, possibly mitigating the effects of dietary histamine. In one rat study, carbohydrates and protein had no effects on the release of DAO into the lymphatic system. (12) Long chain fatty acids produced the greatest response. This would be another notch in the "benefit belt" of the higher fat diets such as Mediterranean and paleo-style. In the absence of any genetic defect, a highly active DAO enzyme creates natural waste products such as acetaldehyde, ammonia, and hydrogen peroxide which themselves can cause their own negative health consequences.

Histamine + [O.sub.2] + [H.sub.2]0 [??](DAO) [??] Imidazole acetaldehyde +N[H.sub.3] + [H.sub.2][0.sub.2]

DAO in mammals is found in highest concentration in the small and large bowel, as well as placenta and kidneys. It is worthy of note; those females who feel much better when they are pregnant should be evaluated

for body burden of histamine. Placental tissues increase DAO activity, which may explain their reduction of symptoms. Decreased DAO activity has been correlated to inflammatory diseases such as ulcerative colitis, irritable bowel syndrome and migraines. (4) DAO is commercially available. The author recommends starting with the lowest dose and working your way up to what is believed to be therapeutic. Many patients may experience a reaction similar to that of a "HERX" reaction in microbial necrosis.

Histamine-N-Methyl Tranferase (H-NMT) is found in the cytosol and is dependent on the availability of S-adenosyl-L-methionine as a methyl donor. CNS scavenging of histamine is carried out by H-NMT since DAO is not found within brain tissues. H-NMT is also found in the periphery, in such tissues as kidney, liver, ovaries, spleen, spinal cord, and pulmonary cells and is responsible for the degradation of intracellular histamine.

Histamine + S-Adenosyl-methionine (SAM) [??] (HNMT) [??] N-Methylhistamine + S-Adenosyl-homocysteine(SAH)

Mitochondrial monoamine oxidase (MAO) has the capacity break it down histamine, due to its structure. MAO's primary role is in the metabolism of neurotransmitters but its impact of histamine breakdown cannot be ignored. The health of the patient's mitochondria and overall oxygen status needs to be evaluated since MAO is located in the mitochondrial membrane of most cells.

The author has found that some patients with obvious histamine overload respond very poorly to anti-histamine treatments. Further investigation would reveal deficiencies in cofactors or direct defects of aldehyde dehydrogenase (ALDH). Degradation of histamine through H-NMT or DAO/MAO will produce 3-methylimidazol acetaldehyde and imidazole acetaldehyde. Both of these metabolites will need to be processed through ALDH. Xenobiotics such as bacteria and yeast will also produce acetaldehyde. Neurotransmitter and alcohol degradation will also result in aldehydes. It is easy to see how this enzyme can become overburdened. Supplementation with cofactors like molybdenum and vitamin B6 has proven to be beneficial. Often the patient will be started on molybdenum and B-vitamins prior to any anti-histamine protocol to avoid adverse reactions.

In the authors opinion, before administering a treatment based off of a genetic profile it would be prudent to perform a thorough consultation and examination to rule out any active infections and/or mitochondrial dysfunction due to their paramount influence over the activation and regulation of the entire genome. Also, in the absence of genetic defects one should also be examined for cofactor deficiencies as these could mimic the effects of genetic defects, even in the absence of single nucleotide polymorphisms.

Rogue mast cell response and histamine overload has been seen in clinical practice, yet often discounted due to seemingly unrelated symptoms. The highly migratory and ambiguous symptomatology of histamine body burden has made it difficult in the past to concentrate efforts on its reduction. With the current wave of affordable nutri-genomic testing, some of your patient's symptoms should no longer remain a mystery. Re-thinking those hard to treat or non-responsive cases with histamine on your differential diagnostic list may make things clearer.

by: Brett Wisniewski, DC, DACBN

References

(1.) Afrin, L. Presentation, Diagnosis, and Management of Mast Cell Activation Syndrome.

(2.) Noszal, B.; Kraszni, M.; Racz, A. (2004). "Histamine: fundamentals of biological chemistry". In Falus, A.; Grosman, N.; Darvas, Z. Histamine: Biology and Medical Aspects. Budapest: SpringMed. pp. 15-28. ISBN 380557715X

(3.) Gotlib J, Cools J. Five years since the discovery of FIPIL1-PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias. Feukemia. 2008; 22: 1999-2010.

(4.) Laura Maintz, Thomas Bieber, Natalija Novak. Histamine Intolerance in Clinical Practice. Dtsch Arztebl 2006; 103(51-52): A 3477-83

(5.)Silla Santos MH. Biogenic amines: their importance in foods. Int J Food Microbiol 1996; 29: 213-31.

(6.) Bieganski F, Kusche J, Feussner KD, Hesterberg R, Richter H, Lorenz W. Human intestinal diamine oxidase: substrate specificity and comparative inhibitor study. Agents Actions 1980; 10: 108-10.

(7.) Bieganski T, Kusche J, Feussner KD, Hesterberg R, Richter H, Lorenz W. The importance of human intestinal diamine oxidase in the oxidation of histamine and/or putrescine. Arch Immunol Ther Exp (Warsz) 1980; 28: 901-6.

(8.) Bieganski T, Kusche J, Lorenz W, Hesterberg R, Stahlknecht CD, Feussner KD. Distribution and properties of human intestinal diamine oxidase and its relevance for the histamine catabolism. Biochim Biophys Acta 1983; 756: 196-203.

(9.) Bieganski T. Biochemical, physiological and pathophysiological aspects of intestinal diamine oxidase. Acta Physiol Pol 1983; 34: 139-54.

(10.) Sattler J, Hafner D, Klotter HI, Lorenz W, Wagner PK. Food-induced histaminosis as an epidemiological problem: plasma histamine elevation and haemodynamic alterations after oral histamine administration and blockade of diamine oxidase (DAO). Agents Actions 1988; 23: 361-5.

(11.) Johnston CS. The antihistamine action of ascorbic acid. Subcell Biochem 1996; 25: 189-213

(12.) Wollin, Armin, Xiaolin Wang, and Patrick Tso. "Nutrients regulate diamine oxidase release from intestinal mucosa." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 275.4 (1998): R969-R975.
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Author:Wisniewski, Brett
Publication:Original Internist
Date:Sep 1, 2015
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