Histamine, Histamine Degradation, and Histamine Intolerance

Dr Carrie Decker ND, explores the mechanisms behind the increasingly recognised and better understood intolerance to histamine (1% of population are likely to suffer). Responsible for a wide range of apparently unconnected symptoms, the ingestion of histamine containing foods by someone ill equipped to adequately render the amine neutralised can result in an unpleasant series of functional problems.

Histamine results from the decarboxylation of histidine, and was first described synthetically by Windaus and Vogt in 1907.[1] Dale and Laidlaw over the following years identified that histamine belongs to the biogenic amines, like putrescine, cadaverine, thyramine, spermine and spermidine and the neurotransmitters; catecholamines and indolamines.[2] Biogenic amines can also be found in all living organisms and therefore are also present in various foods like milk, fish, meat, fruits and vegetables.

Histamine intolerance is a symptom complex characterised by reduced Diamine Oxidase (DAO) activity or lack of the enzyme, due to drug interactions, changes in human/microbiome function or gene related insufficiencies. Furthermore an increased availability of histamine can cause intolerance reactions, through ingestion of histamine rich foods, such as fermented or matured foods for example. The location of DAO in the intestinal mucosa, suggests histamine intolerance is likely a gastrointestinal originating disorder.

However, excess histamine, and the symptoms associated with it, are commonly thought of in the context of seasonal allergies. Symptoms such as a runny nose, headaches, hives or itchy skin, increased tendency to asthmatic reactions, and agitation or irritability come to mind. Excessive histamine, via increased mast cell degradation can manifest in a wide variety of symptoms due to its actions on several different receptors in the body. Histamine can be stimulating or inhibiting in its actions, affecting multiple regions of the brain as well as the skin, cardiovascular, digestive, respiratory, reproductive, and immune systems.[3]

Common causes for histamine intolerance include:

1. Inflammatory bowel diseases (or anything that causes damage to the enterocytes – the cells that line the gut)
2. Coeliac disease
3. Intestinal dysbiosis
4. Small Intestinal Bacterial Overgrowth (SIBO)
5. Parasitic infections, like Giardia
6. Leaky gut or increase in intestinal permeability
7. Alcohol or other DAO inhibitors
8. Excess biogenic amines in diet
9. Medications that increase histamine
10. Food allergies
11. Genetic polymorphisms, like MTHFR and others that lower DAO, MAO, ALDH
12. Vitamin cofactor deficiencies – enzymes, like DAO and MAO rely on vitamin co-factors and deficiencies of these can also cause abnormal enzyme activity

The primary pathway by which endogenous histamine is metabolised in the body is via the enzyme histamine methyltransferase (HMT). HMT is present in the cytosol of cells in many tissues including the kidneys, liver, spleen, prostate, ovaries, spinal cord, bronchi, and trachea.[4] HMT is present in the airway tissues which play an important role in degrading histamine and regulating the airway response to histamine.[5] The intermediate products of histamine metabolism via HMT are broken down by the enzymes monoamine oxidase B (MAO B) and aldehyde dehydrogenase (ALDH).1,[6] HMT catalyzes the methylation of histamine in the presence of methyl donors such as S-adenosyl-L-methionine (SAMe).[7] Single nucleotide polymorphisms (SNPs) in any of these enzymes may affect the body’s ability to metabolise and eliminate histamine and the products of its catabolism.[8]

Diamine oxidase (DAO), also known as histaminase, is the main enzyme responsible for the metabolism of ingested histamine. It is found in high levels in the cytoplasm of the gastrointestinal mucosa, and also is produced at high levels in the placenta and kidneys.[9] HMT also is present in the intestinal epithelium, however DAO plays the primary role of histamine breakdown in the intestine, as it is continuously secreted into the intestinal lumen. With gastrointestinal mucosal damage or genetic polymorphisms there may be low levels of DAO and poor breakdown of exogenous histamine.[10],[11] Vitamin B6, vitamin C, and copper are co-factors necessary for the proper function of DAO.[12],[13],[14]

Another potential problem exists because we all have a substantive population of microbes living in our digestive tract.[15] When these populations become imbalanced as in the case of bacterial overgrowth, like SIBO (small intestinal bacterial overgrowth) or yeast overgrowth, the microbes in our gut can also contribute to producing too much histamine as well.[16] Many people who suffer from histamine intolerance have either deficiencies in DAO enzyme production (which breaks down histamine) or it is hypothesized an excess of bacteria and yeast that have become histamine production factories.

Another risk factor is food intolerance. According to the National Institute of Allergy and Infectious Diseases based in the USA, a food intolerance occurs when; 1, your body lacks a particular enzyme to digest nutrients, 2, nutrients are too abundant to be digested completely, or 3, a particular nutrient cannot be digested properly. Adverse symptoms may occur when foodstuffs containing items one is intolerant to are consumed. A common example is lactose intolerance, associated with deficiency of the enzyme lactase necessary to digest lactose sugars. Histamine intolerance is another intolerance characterized by being unable to efficiently metabolise food or drug originating histamine, and because of this experience histamine-mediated symptoms.

Clinically there is a wide array of possible manifestations of excess histamine or histamine intolerance. The non-specific symptoms associated with excess histamine may involve the central nervous system (CNS), gastrointestinal tract, cardiovascular system, respiratory tract, skin, and reproductive system.1,10 CNS symptoms may include headaches, insomnia, agitation, dizziness, anxiety, depression, and panic disorder. Gastrointestinal symptoms may include pain, bloating, diarrhea, and gastroesophageal reflux. Cardiovascular symptoms may include changes in blood pressure, palpitations, and other heart rhythm disorders. Respiratory and airway symptoms may include a cough, respiratory distress, asthmatic symptoms, sneezing, and phlegm. Symptoms of the skin and mucosa may include hives, itching, redness, and swelling of the skin or lips and tongue similar to an anaphylactic reaction. Women may experience reproductive symptoms including dysmenorrhea and headaches associated with the menstrual cycle. 1,10

Histamine levels in food vary considerably, and levels increase with maturation or fermentation. For this reason foods that contain high levels of histamine include fermented meats, aged cheeses, alcoholic beverages (especially red wine), and sauerkraut.[17],[18] Histamine levels in foods also increase the longer foods are stored as it is a process of microbial fermentation and spoilage. Foods and medications can also have a histamine releasing action, or act to inhibit the breakdown of histamine. Foods which may lead to the release of histamine include citrus, strawberries, papaya, nuts, tomatoes, spinach, chocolate, pork, egg white, crustaceans, fish, and food additives and spices. A wide variety of medications also may inhibit the breakdown of histamine.1

A key observation is that serum activity of DAO is significantly lower in individuals with suspected histamine intolerance.^[19] In these individuals, it was also found that serum DAO activity level increased with adherence to a low-histamine diet – an inverse relationship of clinical value. The main symptoms these subjects experienced involved the skin, gastrointestinal tract, respiratory system, and eyes, which were also improved by following a low-histamine diet. From these findings, a test has been developed to assess for histamine intolerance by assessing serum or plasma DAO activity level.19

Other ways to investigative if histamine intolerance is an issue is with the usage of a diet diary, possibly combined with histamine avoidance and provocation testing. As supplements which contain the enzyme DAO which breaks down food sourced histamine exist, investigations also could include consumption of high histamine foods both with and without the supplementation of DAO to see if symptoms diminish with the enzyme use. Testing for tryptase, which is released from mast cells along with histamine when they are activated, could be assessed in conjunction with a 24-urine collect of histamine. This would not directly provide information about histamine degradation but would shed light on if high levels of histamine are an issue.

Treatment strategies for individuals who experience histamine intolerance include avoidance of foods with high levels of histamine, avoidance of histamine releasing substances, avoidance of medications that inhibit DAO or HMT, supplementation of the DAO enzyme with meals that contain histamine, and/or the use of antihistamines or natural substances that support the breakdown of histamine. A combination of these strategies may be most effective, as absolute avoidance of histamine is not feasible for most individuals. If genetic testing shows that polymorphisms in DAO exist, long-term supplementation with this enzyme may be appropriate in order to mediate the systemic health consequences of excess histamine.

References

[1] Windaus A, Vogt W. Synthese des Imidazolyl-athylamins. Ber. Dtsch. Chem. Ges. 1907;40:3691–3695. (No Abstract Available)

[2] Dale HH, Laidlaw PP. The physiological action of β-iminazolylethylamine. J. Physiol. 1911;41:318–344 View Full Text

[3] Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007 May;85(5):1185-96. View Full Text

[4] Schwelberger HG. Histamine N-methyltransferase (HNMT) enzyme and gene. In: Falus A, editors. Histamine: biology and medical aspects. Budapest, Hungary: SpringMed Publishing, 2004: 53-9.

[5] Yamauchi K, et al. Structure and function of human histamine N-methyltransferase: critical enzyme in histamine metabolism in airway. Am J Physiol. 1994 Sep;267(3 Pt 1):L342-9. View Abstract

[6] Schayer RW. The metabolism of histamine in various species. Br J Pharmacol Chemother. 1956 Dec;11(4):472-3. View Full Text

[7] Boudíková-Girard B, Scott MC, Weinshilboum R. Histamine N-methyltransferase: inhibition by monoamine oxidase inhibitors. Agents Actions. 1993 Sep;40(1-2):1-10. View Abstract

[8] García-Martín E, García-Menaya J, Sánchez B, Martínez C, Rosendo R, Agúndez JA. Polymorphisms of histamine-metabolizing enzymes and clinical manifestations of asthma and allergic rhinitis. Clin Exp Allergy. 2007 Aug;37(8):1175-82. View Abstract

[9] Biegański T, et al. Distribution and properties of human intestinal diamine oxidase and its relevance for the histamine catabolism. Biochim Biophys Acta. 1983 Mar 31;756(2):196-203. View Abstract

[10] D’Agostino L, Ciacci C, Daniele B, Barone MV, Sollazzo R, Mazzacca G. Postheparin plasma diamine oxidase in subjects with small bowel mucosal atrophy. Dig Dis Sci. 1987 Mar;32(3):313-7. View Abstract

[11] Maintz L, et al. Association of single nucleotide polymorphisms in the diamine oxidase gene with diamine oxidase serum activities. Allergy. 2011 Jul;66(7):893-902. View Abstract

[12] Kovacova-Hanuskova E, Buday T, Gavliakova S, Plevkova J. Histamine, histamine intoxication and intolerance. Allergol Immunopathol (Madr). 2015 Aug 1. View Abstract

[13] Johnston CS. The antihistamine action of ascorbic acid. Subcell Biochem. 1996;25:189-213. View Abstract

[14] Martner-Hewes PM, et al.Vitamin B-6 nutriture and plasma diamine oxidase activity in pregnant Hispanic teenagers. Am J Clin Nutr. 1986 Dec;44(6):907-13. View Abstract

[15] Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007 Oct 18;449(7164):804-10. View Full Text

[16] Kyriakidis DA, Theodorou MC, Tiligada E. Histamine in two component system-mediated bacterial signaling. Front Biosci (Landmark Ed). 2012 Jan 1;17:1108-19. View Abstract

[17] Silla Santos MH. Biogenic amines: their importance in foods. Int J Food Microbiol. 1996 Apr;29(2-3):213-31. View Abstract

[18] Bodmer S, Imark C, Kneubühl M. Biogenic amines in foods: histamine and food processing. Inflamm Res. 1999 Jun;48(6):296-300.View Abstract

[19] Mušič E, Korošec P, Šilar M, Adamič K, Košnik M, Rijavec M.. Serum diamine oxidase activity as a diagnostic test for histamine intolerance. Wien Klin Wochenschr. 2013 May;125(9-10):239-43. View Abstract