What is histamine?
Histamine is a signaling molecule that is used by your brain and also by your entire body (Anderson, 2023). Histamine is a biogenic amine that occurs to various degrees in many foods. Histamine (2-[4-imidazolyl]ethylamine) was discovered in 1910 by Dale and Laidlaw. It was identified as a mediator of anaphylactic reactions in 1932 (Maintz and Novak 2007).
Histamine is synthesized by the pyridoxal phosphate (vitamin B-6)–containing l-histidine decarboxylase (HDC) from the amino acid histidine (Maintz and Novak 2007).
It is synthesized by:
- mast cells
- basophils
- platelets
- histaminergic neurons
- enterochromaffin cells
Histamine is stored intracellularly in vesicles and released on stimulation and is a potent mediator of numerous biologic reactions.
Histamine is well known for triggering the degranulation of mast cells by crosslinking of the FcεRI receptor by specific allergens.
However, several other non-immune triggers can also activate mast cells such as:
- neuropeptides
- complement factors (ie, C3a and C5a)
- cytokines
- hyperosmolarity
- lipoproteins
- adenosine
- superoxidases
- hypoxia
- chemical and physical factors (eg, extreme temperatures, traumas)
- alcohol
- certain food and drugs
How does histamine exert its effects?
Histamine exerts its effects by binding to its 4 receptors. These are common in histamine intolerance.
These include(Moriguchi and Takai 2020).:
histamine 1 receptor (H1R): Histamine H1 receptor (H1R) is globally expressed in various tissues, including bronchial smooth muscle cells and vascular smooth muscle cells. When histamine binds to H1R, it elicits airway contraction, vascular relaxation, vascular permeabilization and mucosal secretion. Consequently, the type I immediate allergic responses emerge, including bronchial asthma and anaphylaxis (Moriguchi and Takai 2020).
HRH1 has been associated with multiple processes, including memory, learning, circadian rhythm, and thermoregulation. HRH1 has also been known to contribute to the pathophysiology of allergic diseases such as atopic dermatitis, asthma, anaphylaxis and allergic rhinitis.
The protein encoded by the HRH1 gene mediates the contraction of smooth muscles, the increase in capillary permeability due to contraction of terminal venules, the release of catecholamine from adrenal medulla, and neurotransmission in the central nervous system.
histamine 2 receptor (H2R)- Found mostly in the stomach, gastric ECL cells secrete histamine upon stimulation with gastrin and acetylcholine. Thereafter, secreted histamine binds to the histamine H2 receptor (H2R) in parietal cells and activates gastric acid secretion from parietal cells. A series of studies have shown that histamine exerts immunomodulatory activity through H2R signaling. For instance, histamine represses the release of histamine itself from basophils and mast cells represses the proliferation of lymphocytes, diminishes neutrophil infiltration and suppresses cytokine production from macrophages through H2R (Moriguchi and Takai 2020)
histamine 3 receptor( H3R)- The histamine H3 receptor (H3R) functions as an inhibitory auto receptor at the presynaptic membrane of neurons in the central nervous system and inhibits neuronal release of histamine and other neurotransmitters, including glutamate, γ‐aminobutyric acid (GABA), dopamine, noradrenaline and acetylcholine (Moriguchi and Takai 2020). In the central nervous system in the brain, histamine regulates arousal and cognition through the activity of H3R. Based on this activity, pitolisant, a potent H3R antagonist, has recently been approved for the treatment of sleep disorders (Moriguchi and Takai 2020).
The function of H3R in the inflammatory response has been described in nervous systems. It was reported that H3R participates in neurogenic control of blood–brain permeability and inflammatory response, and thereby eliminates excessive inflammation in the CNS.
histamine 4 receptor (H4R) – The HRH4 gene encodes a histamine receptor that is predominantly expressed in hematopoietic cells. This protein is thought to play a role in inflammation, and allergy responses.
The histamine H4 receptor (H4R) is mainly expressed in immunocompetent cells, including mast cells, eosinophils, monocytes, dendritic cells and T cells, and H4R promotes immune cell chemotaxis and allergic and inflammatory responses (Moriguchi and Takai 2020). H4R antagonists have been shown to have anti‐inflammatory and anti‐allergic efficacy in preclinical models of asthma, colitis, dermatitis and arthritis (Moriguchi and Takai 2020).
What does histamine do?
It can cause common mechanisms seen in histamine intolerance:
- increased vascular permeability
- mucus secretion
- tachycardia
- alterations of blood pressure
- arrhythmias
- stimulates gastric acid secretion and nociceptive nerve fiber
In addition, histamine has been known to play various roles in neurotransmission, immunomodulation, hematopoiesis, wound healing, day-night rhythm, and the regulation of histamine- and polyamine-induced cell proliferation and angiogenesis in tumor models and intestinal ischemia (Maintz and Novak 2007).
Below is a representation of various symptoms exerted by different histamine receptors.
How is histamine metabolized?
Histamine can be metabolized in 2 ways: by oxidative deamination by DAO (former name: histaminase) or by ring methylation by histamine-N-methyltransferase (HNMT). Which enzyme is acting on histamine depends on the localization of histamine.
In healthy persons, dietary histamine can be rapidly detoxified by amine oxidases. For patients with histamine intolerance, this pathway may be often dysregulated.
Diamine oxidase (DAO) is the main enzyme for the metabolism of ingested histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator release (Maintz and Novak 2007).
The DAO protein is stored in plasma membrane–associated vesicular structures in epithelial cells and is secreted into the circulation on stimulation. Therefore, it has been proposed that DAO may be responsible for scavenging extracellular histamine (eg, after ingestion of histamine-rich food) after mediator release.
In mammals, DAO expression is restricted to specific tissues; the highest activities are shown for small bowel and colon ascendens and for placenta and kidney (Maintz and Novak 2007). Lower DAO activity has been discussed as a potential indicator of intestinal mucosa damage in inflammatory and neoplastic diseases and in persons undergoing chemotherapy.
Conversely, HNMT, the second most important enzyme inactivating histamine, is a cytosolic protein, which can convert histamine only in the intracellular space of cells. HNMT is widely expressed in human tissues; the greatest expression is in kidney and liver, followed by spleen, colon, prostate, ovary, spinal cord cells, bronchi, and trachea. HNMT is regarded as the key enzyme for histamine degradation in the bronchial epithelium.
The two enzymes (DAO and HNMT) do not seem to compete for the substrate, although they have a similar affinity for histamine and they are expressed in some overlapping tissues (Maintz and Novak 2007). HNMT has a slightly higher affinity for histamine (Maintz and Novak 2007).
Nutrients
Various nutrients are important for the proper functioning of enzymes. In the image below, you can see the nutrients that are cofactors for various histamine metabolizing enzymes. Many patients with histamine intolerance are low in these nutrients.
These include the following cofactors:
- DAO-zinc, Vitamin C, B6 and copper, B2, B1 and magnesium
- HDC– B6 and folate
- HMNT– SAMe, also B12, B9 and minerals molybdenum, Copper, selenium and zinc, Vitamin A and Vitamin D
- MAO-B: B2, but also B6, Magnesium and vitamin C
- Aldehyde dehydrogenase– Zinc, Vit C, B5, NAD, B1
Also, as the image demonstrates, various conditions can change how these enzymes function.
For example, DAO is downregulated by mucosal damage, alcohol and certain medications. HDC is downregulated by catecholamines, inflammation, benzene, LPS, infections, bacteria and high histamine in the diet.
What is histamine intolerance?
Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine, is a disorder associated with an impaired ability to metabolize ingested histamine that was described at the beginning of the 21st century (Comas-Basté, Sánchez-Pérez et al. 2020).
Histamine intolerance results from a disequilibrium of accumulated histamine and the capacity for histamine degradation. The main enzyme for metabolism of ingested histamine is diamine oxidase (DAO). An impaired histamine degradation based on a reduced DAO activity and the resulting excess of histamine may cause numerous symptoms mimicking an allergic reaction.
Underlying conditions for increased histamine availability may be due to endogenous histamine overproduction caused by: (Maintz and Novak 2007)
- Allergies
- Mastocytosis
- Certain histamine containing bacteria
- gastrointestinal bleeding
- increased exogenous ingestion of histidine or histamine by food or alcohol.
Other biogenic amines, such as putrescine, may also be involved in displacing histamine from its mucosal mucine linkage, which results in an increase of free absorbable histamine in circulation. However, the main cause of histamine intolerance is an impaired enzymatic histamine degradation caused by genetic or acquired impairment of the enzymatic function of DAO or HNMT (both of which I can test for genetically).
Gastrointestinal diseases with altered enterocytes also may cause decreased production of DAO. Yet another cause can be competitive inhibition of histamine degradation of DAO by other biogenic amines, alcohol, or certain drugs such as amitriptyline- commonly prescribed medication for IC.
Acquired histamine intolerance may be transient and therefore reversible after the elimination of causes, such as by discontinuing DAO-blocking drugs. DAO inhibits the transepithelial permeation of exogenous histamine- impaired DAO activity results in increased enteral histamine uptake with consequent increased plasma histamine concentrations and corresponding symptoms. Increased amounts of histamine metabolites may also inhibit HNMT, the second enzyme metabolizing histamine (Maintz and Novak 2007).
Interestingly, histamine intolerance seems to be acquired mostly through the impairment of DAO activity caused by gastrointestinal diseases or through the inhibition of DAO. However, there are high individual variations in the expression of DAO in the gut and the association of SNPs in the DAO gene with gastrointestinal diseases. This provides evidence for a genetic predisposition in a subgroup of patients with histamine intolerance.
Clinical picture of histamine intolerance
Basal plasma histamine concentrations of 0.3 to 1.0 ng/mL are considered normal (52). Exceeding the individual histamine tolerance gives rise to concentration-dependent histamine-mediated symptoms.
Typical symptoms of histamine intolerance include :
- gastrointestinal disorders
- sneezing
- rhinorrhea and congestion of the nose
- headache
- dysmenorrhea
- hypotonia
- arrhythmias
- urticaria
- pruritus
- flushing
- asthma
Overproduction of inability to break down varies from person to person.
Examples include:
Central nervous system/hormonal:
- Migraines
- Fatigue
- Anxiety/panic attacks/palpitation
- Dizziness
- Blood pressure fluctuati0on with food
- Fibromyalgia
- Difficulty regulating body temperature
- Psychosis and hallucination
- Bipolar/schizophrenia
- Alcoholism
Respiratory:
- Nasal congestion/sneezing
- Difficulty breathing
- Asthma
- Reactive airways
Gut:
- Nausea, vomiting after eating.
- Abdominal pain
- Bloating
- SIBO/SIFO
- Food intolerances
- Constipation/diarrhea
Skin:
- Flushing
- Hives
- Rashes after eating.
Headaches
Histamine-induced headache is a vascular headache caused mainly by nitrate monoxide (Maintz and Novak 2007). Histamine releases endothelial nitrate monoxide upon stimulation of H1R, which is also expressed in the large intracranial arteries. In migraine patients, plasma histamine concentrations have been shown to be elevated both during headache attacks and during symptom-free periods.
An increase in the number of brain mast cells is associated with pathologic conditions such as migraine, cluster headache, and multiple sclerosis (Maintz and Novak 2007). Many migraine patients have histamine intolerance evidenced by reduced DAO activity, triggering of headache by food rich in histamine (eg, long-ripened cheese or wine), and the alleviation of headache (ie, disappearance of symptoms) under a histamine-free diet and therapy with antihistamines(Maintz and Novak 2007)
GI -tract/ digestion
Gastrointestinal ailments including diffuse stomach ache, colic, flatulence, and diarrhea are leading symptoms of histamine intolerance. Elevated histamine concentrations and diminished DAO activities have been shown for various inflammatory and neoplastic diseases such as Crohn disease, ulcerative colitis, allergic enteropathy, food allergy,and colorectal neoplasmas (Maintz and Novak 2007). In the colonic mucosa of patients with food allergy, a concomitant reduced HNMT and an impaired total histamine degradation capacity (THDC) have been found, so that the enzymes cannot compensate each other. Therefore, an impaired histamine metabolism has been suggested to play a role in the pathogenesis of these diseases.
Airways
During or immediately after the ingestion of histamine-rich food or alcohol, rhinorrhea or nasal obstruction may occur in patients with histamine intolerance; in extreme cases, asthma attacks also may occur. Reduced HNMT activity has been shown for patients with food allergy and asthma bronchiale (Maintz and Novak 2007)
Histamine and food
Histamine and other biogenic amines are present to various degrees in many foods, and their presence increases with maturation of the food. These can be problematic for patients with histamine intolerance. The formation of biogenic amines in food requires the availability of free amino acids, the presence of decarboxylase-positive microorganisms, and conditions allowing bacterial growth and decarboxylase activity. Free amino acids either occur as such in foods or may be liberated by proteolysis during processing or storage.
Numerous bacterias and some yeast display high HDC activity and thus have the capacity to form histamine. Histidine is generated from autolytic or bacterial processes. Therefore, high concentrations of histamine are found mainly in products of microbial fermentation, such as aged cheese, sauerkraut, wine, and processed meat or in microbially spoiled food.
Thus, histamine, tyramine, putrescine, and cadaverine serve as indicators of hygienic food quality. Tyramine and putrescine also may lead to intolerance reactions in combination with histamine. Possible explanations may be the inhibition of DAO by other amines or the promotion of histamine liberation from the mucosa by putrescine.
In addition to histamine-rich food, many foods such as citrus foods are considered to have the capacity to release histamine directly from tissue mast cells, even if they themselves contain only small amounts of histamine. In vitro studies of persons with a history of pseudo allergic reactions to food have shown a fragility of duodenal mast cells with massive degranulation in the presence of histamine-releasing substances that is significantly greater than that shown by control subjects.
Alcohol, especially red wine, is rich in histamine and is a potent inhibitor of DAO. The relation between the ingestion of wine, an increase in plasma histamine, and the occurrence of sneezing, flushing, headache, asthma attacks, and other anaphylactoid reactions and a reduction of symptoms by antihistamines has been shown in various studies (Maintz and Novak 2007).
However, among the multitude of substances contained in wine, other biogenic amines such as tyramine and sulfites have been supposed to contribute to symptoms summarized as “wine intolerance” or “red wine asthma”(Maintz and Novak 2007).
Sulfite hypersensitivity has been reported mainly in patients with chronic asthma; the estimated prevalence is 5–10% in all patients. Asthmatic reactions have been attributed to reflex activation of the parasympathetic system by the irritating effect of sulfites, possibly enhanced by a deficiency of sulfite oxidase SUOX, whose cofactor is Molybdenum. Besides this pseudoallergic mechanism, in at least some cases of sulfite hypersensitity, an immunoglobulin E (IgE)–mediated immediate-type allergic reaction must be considered (95).
Sulfites may be contained in wine, but they are also contained in foods that are poor in histamine, such as fruit juice, frozen vegetables, and lettuce. Thus, in patients reporting intolerance to wine, a careful history of reactions to other foods rich in histamine or sulfites should be taken. In patients who are suspected of having sulfite intolerance, skin testing and a DBPC challenge with capsules containing increasing doses of bisulfite or placebo should be performed.
In contrast to an IgE–mediated food allergy, in which the ingestion of even a small amount of the allergen elicits symptoms, in histamine intolerance, the cumulative amount of histamine is crucial. Besides variations in the amount of histamine in food according to storage and maturation, the quantity consumed, the presence of other biogenic amines, and the additional intake of alcohol or DAO-blocking drugs are pivotal factors in the tolerance of the ingested food. Generally, an upper limit of 100 mg histamine/kg in foods and of 2 mg histamine/L in alcoholic beverages has been suggested
Histamine and drugs
he effect of drugs as specific DAO inhibitors and their capacity to induce histamine intolerance have been shown in various studies with human placental DAO and in animal experiments. A clinically relevant activity via histamine release or inhibition of DAO has been observed for various drugs. Therefore, the intake of drugs, especially long-term medication, should be considered in interpretation of histamine intolerance symptoms and DAO concentrations.
Histamine and hormones
In the female genital tract, histamine is mainly produced by mast cells, endothelial cells, and epithelial cells in the uterus and ovaries. Histamine-intolerant women often suffer from headache that is dependent on their menstrual cycle and from dysmenorrhea. Besides the conctractile action of histamine, these symptoms may be explained by the interplay of histamine and hormones. Histamine has been shown to stimulate, in a dose-dependent manner, the synthesis of estradiol via H1R; meanwhile, only a moderate effect on progesterone synthesis was observed (Maintz and Novak 2007). The painful uterine contractions of primary dysmenorrhea are mainly caused by an increased mucosal production of prostaglandine F2α stimulated by estradiol and attenuated by progesterone. Thus, histamine may augment dysmenorrhea by increasing estrogen concentrations.
And, in reverse, estrogen can influence histamine action. A significant increase in weal and flare size in response to histamine has been observed to correspond to ovulation and peak estrogen concentrations. In pregnancy, DAO is produced at very high concentrations by the placenta, and its concentration may become 500 times that when the woman is not pregnant. This increased DAO production in pregnant women may be the reason why, in women with food intolerance, remissions frequently occur during pregnancy (Maintz and Novak 2007).
Treatment recommendations:
In a patient with clinical suspicion of histamine intolerance (ie, ≥2 typical symptoms), improvement of symptoms by histamine-free diet or antihistamines, DAO may be determined in serum or tissue biopsy . In patients with a DAO activity Histamine intolerance is presumably highly likely in patients with DAO activity <3 U/mL, likely (but less likely) in patients with DAO activity <10 U/mL, and improbable in patients with DAO activity ≥10 U/mL.
There are 3 primary interventions that can help with histamine load.
First:
The first line of therapy is to remove all high histamine foods. This can lead to a quick reduction in symptoms by decreasing the load on the body. Supporting with antihistamines can also be helpful as well.
Examples include:
High histamine foods:
- Fermented foods
- Alcohol
- Cured meats
- Dried fruit
- Most citrus fruits
- Nuts
- Smoked or cured fish
- Leftover meat
Foods that inhibit DAO synthesis
- Alcohol
- Energy drinks
- Black tea
- Mate tea
- Green tea
Histamine liberators
- Alcohol
- Bananas
- Strawberries
- Chocolate
- Cow’s milk
- Nuts
- Papaya
- Pineapple
- Shellfish
- Tomatoes
- Wheat germ
- Artificial preservatives
- Artificial dyes
Low histamine foods
- Fresh meat and poultry (fresh or frozen)
- Freshly caught fish.
- Eggs
- Gluten free grains
- Fresh fruits such as pear, watermelon, apple, cantaloupe, grapes
- Fresh vegetables except tomatoes, spinach, avocados and eggplant
- Dairy substitutes
- Cooking oils
- Leafy herbs
- Herbal teas
Antihistamines therapy
Over the counter
- Cetirizine 10mg daily
- Fexofenadine 60mg twice daily or 180mg once daily
- Ranitidine 75-150mg twice daily
- Loratadine 10mg daily
- Diphenhydramine 12.5-50mg up to 4 times daily
Prescription
- Hydroxyzine dosing: 10- 100mg up to 4 times daily
- Ketotifen doing: 1mg twice daily
- Cromolyn sodium dosing is 200mg orally 4 x daily
- Montelukast dosing is 10mg daily
- Xolair dosing 75-375mg SQ every 3-4 weeks
- LDN 1.5-4.5 mg at bedtime
Nutraceutical to stabilize mast cells (you can do 1-2 supplements from each group)
Group A
- Quercetin 2000mg in divided doses
- Green tea or EGC/L theanine- 2 to 3 cups daily or 500mg twice daily (175mg ECGC)
- Curcumin- 1-4g daily in divided doses
- Chamomile tea 1-2c before bed
- Resveratrol 20mg twice a day
- DAO- 2 caps with each meal
- Vitamin C (use with caution due to oxalate production)- 250-1000mg a day
Group B
- Luteolin- 100mg 2x a day
- Ginko biloba- 500mg a day
- Silymarin 500-1000mg a day, divided doses
- Shea oil- 3 caps a day
- Ellagic acid- 500mg a day
- Pycnogenol- 500-1000mg day
- Magnolia or honokiol- 200-250mg 2x a day
- Feverfew- 200-500mg 2x a day
Group C
- Fiestin 100mg 2x a day
- Rutin 200mg a day
- Mngostin 500-1000mg a day
- Xanthium- 6-9 caps
- Isastis 6-9 caps
Second:
Secondly, attend to the histamine pathways biochemically in the body. These 3 pathways include:
Acetylation that runs through N-acetyl-transferase- that is regulated by vitamin B5. This has been used for decades to help with histamine issues.
DAO (explained earlier)- and the cofactors are B6, B1, copper, magnesium, vitamin C
HMNT pathway (explained earlier)- cofactors SAMe, also B12, B9 and minerals molybdenum, Copper, selenium and zinc, Vitamin A and Vitamin D
Starting with acetylation and DAO can take some of the pressure off.
The HMNT is a little tricky.
The first step of HMNT uses a methyl donor- and often people will feel worse when they take methyl donors like methyl folate. This is because methylated histamine can bind harder than regular histamine- and this intermediate can actually cause more problems. Once methylated, it goes to MAO- which takes methyl histamine and converts it to an aldehyde of histamine that can also be very disturbing to the body. The symptoms are a little different and can make you feel “toxic”.
This is where nutrient therapy can be very helpful.
You need methyl donors, MAO support, and aldehyde support as well. But sometimes this must be done in a step wise fashion.
One important nutrient that can help remove aldehyde is B3 in the form of niacinamide. NAD is a cofactor for this step but also for many other things in the body- which I can do another blog on in the future. B3 can also support getting the toxic aldehydes out of the body as well.
Third:
And lastly, understanding why histamine could be a problem for you. There are a lot of upstream triggers such as mold, dysbiosis, poor digestion, overall toxicity, chronic infections, mast cell activation and even your own genetic susceptibilities. That is why doing the proper tests and identifying your genetic predispositions.
References
Anderson, P. (2023, August 20). How to Reduce Histamine Inflammation in 12 Weeks. [Video] Youtube. https://youtu.be/PDUIllUCQpM?si=mCkiqFNBxRYxn2Mi
Clayton, G. (2023, August 23). The Mold Detox Diet with Gail Clayton. [Vide] Youtube. https://youtu.be/AXxAEV83R8w?si=CGeZ7meS7WSXrGHL
Comas-Basté, O., et al. (2020). “Histamine Intolerance: The Current State of the Art.” Biomolecules 10(8).
Maintz, L. and N. Novak (2007). “Histamine and histamine intolerance.” Am J Clin Nutr 85(5): 1185-1196.
Moriguchi, T. and J. Takai (2020). “Histamine and histidine decarboxylase: Immunomodulatory functions and regulatory mechanisms.” Genes Cells 25(7): 443-449.
