Histamine Intolerance

Histamine intolerance or HIT can cause a lot of uncomfortable symptoms for individuals who struggle with it. What is histamine? It is a neurotransmitter, produced from an amino acid, histidine, which helps deliver chemical messages to the body. Histamine is critical for important functions such as immune, digestion, blood vessel permeability, muscle contraction, and hormone regulation. It also is an important mediator of allergic reactions. Histamine is an inflammatory mediator bringing immune cells to the site where they are needed. While we need histamine for normal bodily functions, in too great a quantity, it can be a problem.

We have several histamine receptors, H1, H2, H3, H4 that recognize histamine as it goes through the body. H1 is expressed in allergies and inflammation and more specifically, it is expressed in smooth muscles, vascular endothelial cells, the heart, and the central nervous system. [i] H1 and H2 receptors are in the brain and more recently H3 receptors were identified in the central nervous system that inhibit the synthesis and release of histamine.[ii]  

Histamine is a neurotransmitter that keeps your brain active and you awake. That is why antihistamines like Benadryl which block the H3 receptor can often make you sleepy. Long-term, they can also lead to problems with blocking other important neurotransmitters such as dopamine, acetylcholine, and norepinephrine as well as sleep disorders, epilepsy, and cognitive impairment.

H1 and H2 receptors are in the lung and regulate the constriction and dilation of the lung vasculature. H2 is predominantly in the stomach. Of note, H2 is what helps us produce stomach or hydrochloric acid (HCL). For heartburn or reflux, doctors often prescribe H2 blockers which block our ability to produce HCL. This can impact your ability to digest and break down protein.

More recently, H4 has been identified to play a role in colitis, gut ischemia/injury, radiation-induced enteropathy, and allergic gut reactions. In addition, H4 receptors have been implicated in gastrointestinal cancers, visceral pain, and gastric ulcers [iii] Our immune cells have H4 receptors which help us prevent cancer and address infection and in fact, there are histamine receptors on tumor cells.[iv] .

Histamine has both pro-inflammatory and anti-inflammatory effects determined by both the histamine receptor and the cells stimulated. Mast cells are the major producers of histamine in the body in addition to basophils.[v] The body needs to regulate the balance of histamine so it doesn’t overwhelm the body and two enzymes serve this function. Diamine oxidase (DAO) is primarily in the gut, serving to break down histamine. Histamine N-methyl transferase (HNMT) is another enzyme that breaks down histamine. When there is an imbalance between histamine and these two enzymes are either deficient in supply or not active, histamine levels build up in the body.

Overstimulation of histamine and the inability to metabolize histamine can be a problem and lead to histamine intolerance which is often difficult to recognize given the variety of symptoms that can ensue, and because symptoms may occur several hours after exposure to any histamine containing or activating foods or substances. As histamine intolerance (HIT) is challenging to identify, more scientific research is needed to help with diagnosis and management. [vi] It is a pathological process in which the activity of histamine-degrading enzymes is decreased or inhibited and therefore insufficient to inactivate histamine from food and to prevent its passage to the bloodstream. [vii]

Histamine intolerance can result in any of the following symptoms:

Allergy symptoms

• Rhinitis-nasal congestion
• Dyspnea (shortness of breath)
• Itchy, watery eyes
• Reactions to insect stings, chemicals, anesthesia

GI symptoms

• Bloating
• Flatulence
• Diarrhea
• Abdominal Pain
• Constipation
• Abdominal pain

Musculo-Skeletal

• Joint pain

Nervous System

• Migaines
• Headache
• Dizziness
• Loss of consciousness
• Mood swings
• Fatigue

Cardiovascular

• Rapid heart rate
• Hypotonia
• Vascular collapse
• Hypotension
• Water retention

Pulmonary

• Shortness of breath

Reproductive

• Menstrual cramps
• Migraines

Skin

• Pruritis (itch) especially of ears, eyes, nose, and skin
• Urticaria
• Flushing
• Dermatitis
• Swelling
• Hives
• Conjunctivitis (irritated, red, watery eyes)

Gastrointestinal inflammation can be a problem with too much histamine. Diamine Oxidase (DAO) is an important enzyme in your gut that balances or counteracts histamine in your gut that may occur with gut infection, imbalance in the gut microbiome (dysbiosis), food sensitivity, chemical exposure, or eating foods high in histamine. GI inflammation can lead to the production of more DAO. At some point, however, excessive histamine can overwhelm your system. Crohn’s Disease and Celiac Disease often have high histamine.

Medications can block DAO and the body’s ability to break down histamine. The female menstrual cycle is also involved with DAO. If you have headaches during your menstrual cycle, your DAO levels are lower than the rest of your cycle, meaning that you may have some issues with histamine. A week before menses, you can try eating a low histamine diet if migraines or other high histamine symptoms occur during your period.

Mold exposure stimulates mast cell release of histamine and mold hypersensitivity can occur with chronic toxic mold exposure.[viii]

Food and Nutritional deficiencies can lead to histamine issues. Lack of nutrients can decrease the body’s ability to break down histamine. Mast cells are cells that support the immune response. They have receptors on their surface, and when they bind with food antigens this causes the mast cell to release histamine.

• Specific vitamins help balance histamines. Vitamin C stabilizes the cell membrane of mast cells. Copper helps with production of DAO. Vitamin B6 is important of metabolism of histamines.
• Food Sensitivities can lead to increased histamine and have multiple causes and effects. It can be challenging to figure out whether you have a food intolerance, food allergy, and food sensitivity. Mast Cell Activation Syndrome (MCAS) where mast cells are chronically releasing histamine can be activated by food sensitivities and mold.
• Gluten-Sensitivity also can lead to increased histamine. There also is an association between migraine, celiac disease, non-celiac gluten sensitivity (NCGS), and the activity of DAO. (research article). NCGS causes inflammation which decreases DAO, leading to histamine build up and symptoms of histamine intolerance.
• Diet: Foods can be histamine rich, histamine releasing foods, or inhibit DAO. You can eliminate or avoid these foods to reduce symptoms of histamine intolerance.
  • High histamine foods: Histamine can build up in aged food. The older the food the more likely they contain more histamine. That is why low histamine diets include fresh food. Aged cheeses, fermented foods, alcohol, chocolate, spinach, eggplant are examples of high histamine foods. Certain strains of lactobacillus or probiotics high in lactobacillus can increase histamine.
  • Histamine-releasing foods: Not high in histamine, but trigger histamine release. Alcohol, tomatoes, wheat germ, bananas, pineapple, mushrooms, beans, nuts, food additives are examples. Sulfites commonly found in wines can activate histamine or nitrites in preserved meats.
  • Foods that inhibit DAO: Alcohol, fermented drinks, energy drinks, and green tea can decrease DAO.
  • Alcohol– Unfortunately, alcohol adds not only to histamine production, but also affects DAO levels and that is why it is reflected in all categories.
  • Foods that support DAO and avoid histamine response: Organic, fresh meat and fish as well as non-citrus organic fruit, eggs, dairy substitutes such as almond milk. Fresh avocados, coconut and olive oil are good sources of fat. Tulsi tea is made from Holy Basil, a natural anti-histamine.
• Supplements: These can stabilize mast cells and histamine release.
  • Vitamin C: Natural anti-histamine and helps to stabilize mast cells.
  • N-Acetylcysteine (NAC): Helps with preventing histamine release
  • Stinging Nettle: Helps with environmental allergens as well as stabilizing immune cells.
  • Quercetin: Stabilizes mast cells and histamine response. Quercetin is also able to reduce redness, itching, and inflammation of damaged skin.[ix]
  • Higher doses of vitamin C (5 grams) and quercetin (4-5 grams), spread over the day can help to stabilize significant histamine reactions.

There are many supplement products containing a number of these ingredients to support healthy histamine levels.

• Testing: These tests can help identify immune system issues and sensitivity or allergy
  • Food allergy testing (IgE)-More your immune system is sensitized, the more likely you will develop more allergies. Need to test more than the typical foods.
  • Delayed hypersensitivity testing-Food and chemical testing for foods and chemicals you are sensitive to.
  • Diamine Oxidate Levels
  • Histamine Levels
  • Micronutrient testing to see if key nutrients are low
  • Eosinophil count

In my practice, I use urine testing to measure histamine, DAO levels as well as other tests to uncover other potential hidden metabolic stressors. Urine testing for histamine is a relatively newer approach.[x] The DAO: Histamine Ratio helps to identify where the possible imbalances in DAO and histamine levels are. For example, when the ratio between the two is high it suggests there is enough DAO enzyme available in our gut for histamine degradation, or that there is a relatively low level of free histamine in our system. When the ratio is low it suggests there is insufficient DAO enzyme available to degrade the relative amount of free histamine. This helps to guide recommendations.

Summary: Histamine intolerance can result in a wide range of symptoms and often may progressively worsen if not addressed. Working with a practitioner who can identify histamine intolerance and provide a low histamine diet as well as address underlying causes of histamine intolerance whether they are food sensitivities, gut pathogens, leaky gut, or other causes can help bring balance histamine and DAO. The overall goal is to reduce the causes of inflammation, thereby alleviating symptoms.

References:

Osborn, Peter. Histamine and Seasonal Allergy Crash Course. November 1, 2021. https://www.youtube.com/watch?v=NkpV-vEsd3c.

Davis, Reed. Histamine Intolerance. Functional Diagnostic Nutrition.

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[i] Thangam EB, Jemima EA, Singh H, Baig MS, Khan M, Mathias CB., Church MK., Saluja R. The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets. Frontiers in Immunology. VOLUME9, 2018. https://www.frontiersin.org/article/10.3389/fimmu.2018.01873.  DOI=10.3389/fimmu.2018.01873   

[ii] Parsons ME, Ganellin CR. Histamine and its receptors. Br J Pharmacol. 2006 Jan;147 Suppl 1(Suppl 1):S127-35. doi: 10.1038/sj.bjp.0706440. PMID: 16402096; PMCID: PMC1760721.

[iii] Deiteren A, De Man JG, Pelckmans PA, De Winter BY. Histamine H₄ receptors in the gastrointestinal tract. Br J Pharmacol. 2015 Mar;172(5):1165-78. doi: 10.1111/bph.12989. Epub 2015 Jan 12. PMID: 25363289; PMCID: PMC4337694.

[iv] Branco ACCC, Yoshikawa FSY, Pietrobon AJ, Sato MN. Role of Histamine in Modulating the Immune Response and Inflammation. Mediators Inflamm. 2018 Aug 27;2018:9524075. doi: 10.1155/2018/9524075. PMID: 30224900; PMCID: PMC6129797.

[v] Borriello F, Iannone R, Marone G. Histamine Release from Mast Cells and Basophils. Handb Exp Pharmacol. 2017;241:121-139. doi: 10.1007/164_2017_18. PMID: 28332048.

[vi] Comas-Basté O, Sánchez-Pérez S, Veciana-Nogués MT, Latorre-Moratalla M, Vidal-Carou MDC. Histamine Intolerance: The Current State of the Art. Biomolecules. 2020 Aug 14;10(8):1181. doi: 10.3390/biom10081181. PMID: 32824107; PMCID: PMC7463562.

[vii] Kovacova-Hanuskova E, Buday T, Gavliakova S, Plevkova J. Histamine, histamine intoxication and intolerance. Allergol Immunopathol (Madr). 2015 Sep-Oct;43(5):498-506. doi: 10.1016/j.aller.2015.05.001. Epub 2015 Aug 1. PMID: 26242570.

[viii] Kritas SK, Gallenga CE, D Ovidio C, Ronconi G, Caraffa Al, Toniato E, Lauritano D, Conti P. Impact of mold on mast cell-cytokine immune response. J Biol Regul Homeost Agents. 2018 Jul-Aug;32(4):763-768. PMID: 30043558.

[ix] Maramaldi G, Togni S, Pagin I, et al. Soothing and anti-itch effect of quercetin phytosome in human subjects: a single-blind study. Clin Cosmet Investig Dermatol. 2016;9:55-62. Published 2016 Feb 26. doi:10.2147/CCID.S98890

[x] Comas-Basté O, Latorre-Moratalla ML, Bernacchia R, Veciana-Nogués MT, Vidal-Carou MC. New approach for the diagnosis of histamine intolerance based on the determination of histamine and methylhistamine in urine. J Pharm Biomed Anal. 2017 Oct 25;145:379-385. doi: 10.1016/j.jpba.2017.06.029. Epub 2017 Jul 5. PMID: 28715791.