Histamine isa tissue amine and chemical molecule that gets biosynthesized by the decarboxylation of the amino acid, histidine. The biosynthesis of histamine is catalyzed by the presence of L-histidine decarboxylase and the co-factor pyridoxal 5’-phosphate or the active form of B6 (the chemical reaction is presented in figure 1 below). Of all biogenic amines observed in foods, the excessive levels of histamine and tyramine are considered highly toxic and produce unwantedeffects in the human body. 

In 1910,The pioneer researchers in the biogenic amines, Dale and Laidlaw, clarified the physiological and pathophysiological functions of histamine in our bodies. Biosynthesized histamine is stored in basophils, mast cells, gastric enterochromaffin cells, lymph nodes and thymus.

Histamine is involved in several physiological functions such as stimulation of gastric acid secretion and nociceptive nerve fibers, alteration of blood pressure, inflammation, increased vascular permeability, cytokine production, smooth muscle contraction and vasodilatation. Histamine is also synthesized in the brain, specifically in the neurons present in the posterior region of the hypothalamus.As a neurotransmitter, it maintains wakefulnessand carries impulses like pain and itching sensations. Of all G-protein-coupled receptors, H1, H2, H3 and H4 interact with histamine and activate the signal transduction pathways, thereby initiating the biological mechanisms.

Also, histamine actively participates in local immune response, immunomodulation, hematopoiesis, day-night rhythm, wound healing effects and regulation of histamine- and polyamine-induced cell proliferation and angiogenesis in various tumor models and intestinal blood supply. As per the concentration of histamine present in the plasma, different activities are exhibited as mentioned in the below table 1 (Adapted from Mainz et al., Am. J. Clin. Nutr. 2007).

There are two important pathways in the histamine metabolism, namely diamine oxidase (DAO)-dependent and histamine N-methyl transferase (HNMT)-mediated metabolic pathways. DAO facilitates the oxidative deamination of the primary amine group of histamine. Conversely, in the second pathway, the enzyme HNMT converts histamine into 1-methylhistamine through methylation of the secondary amine “N” ofthe imidazole heterocyclic ring. 

In a nutshell, based on the need for physiological processes in the human body, the deamination and methylation reactions are catalyzed by the enzymes, DAO and HNMT respectively. DAO converts histamine into imidazole 2-acetaldehyde, followed by imidazole acetic acid and finally, imidazole acetic acid riboside is formed. Conversely, Histamine is metabolized in the presence of HNMT to obtain methylimidazole acetic acid through the production of intermediate methylimidazole acetaldehyde.It is worth noting that the conversion of histamine into different by-products is the protective role of DAO and HNMT against excess histamine, either from ingested foods or produced by the intestinal microbiota. Therefore, both enzymes DAO and HNMThelp balance and maintain optimum levels of histaminein the human body.

The deficiency and single-nucleotide polymorphisms (SNPs) of enzymes including L-histidine decarboxylase, DAO and HNMT may be suggested an influential role in histamine intolerance. Research studies have revealed that more than 50 SNPs in the DAO-encoding gene have been detected to date. Some of key SNPs (namely rs10156191, rs1049742, rs2268999 and rs1049793) discovered in Caucasian people could produce a protein with impaired activity. Individuals of Asian and African decent may be more affected by SNPs rs45558339 and rs35070995 which have also been reported to show DAO enzyme deficiency. On the another hand, the main SNP related to HNMT (rs11558538) has been associated with reduced HNMT activity. Overall, these SNPs lead to reduced or deficient enzyme activity, which increases the levels of histamine in the plasma and is then typically followed by a histamine intolerance reaction (particularly in these individuals with DAO and HNMT SNPs – or genetic mutations).

Also Read: How does histamine affect anxiety?

Histamine and other biogenic amines such as tyramine, putrescine and cadaverineare present in varying concentrations in different foods, which increases as theyage. The following determines the formation of biogenic amines in food:

1. availability of free amino acids
2. presence of decarboxylase-positive microorganisms 
3. ideal conditions for bacterial growth and
4. decarboxylase activity

IEither food that we consume or proteolysis reactions during food processing and storage may yield free amino acids.Plenty of bacterias and a few yeast types demonstrate high L-histidine decarboxylase activity (assisting the conversion of histidine into histamine) as a result, this increases histamine production. It’s worth noting that high levels of histamine and other biogenic amines are typicallyfound in products of microbial fermentation which include processed meats, aged cheeses, sauerkraut and wine, also in microbially spoiled food. So, the presence of histamine, tyramine, putrescine and cadaverineare allconsidered as indicators of food quality.Other biogenic amines can combine with histamine and cause intolerance or adverse effects. Besides histamine-rich food, several foods such as citrus fruits, a few types of fish and licoriceactually contain less histamine; however, they canstimulate a histamine release from mast cells.The mechanism behind this stimulation of endogenous histamine from these particular foods has not yet been discovered.The concentration of histamine in various food categories is presented in Table 2. 

Although histamine is involved in a copious number of physiological mechanisms in our bodies, the ingestion of foods containing high levels of histamine causes damaging effects on the body. The balance of histamine is reliant on the body’s histamine degradation systems functioning properly;this is required for the body to appropriatelyregulate theexcess levels of histamine.

Histamine intoxication is also a type of food poisoning thatcan happes after the consumption of foods with high histamine levels (higher than 500 mg/kg) which actually subjugates the degradation mechanisms.In 2018, a meta-analysis was performed to identify the foods, which typically cause histamine intoxication. The study covers research data between 1959 and 2013 that focus on several studies of histamine intoxication and revealed that the causative food in 98% of the cases accounted for was fish and the remainingcases were due to cheese.

Histamine intoxication is essentially characterized by a short incubation period with low to moderate severity and subsiding in a few hours. The symptoms of histamine intoxication affect the skin, gastrointestinal tract, hemodynamic and neurological functions. 

The adverse effects of histamine intoxication are listed below.

• Skin - local inflammation, edema, redness, rash, urticaria and pruritus
• Gastrointestinal tract –diarrhea, nausea and vomiting
• Hemodynamic function – hypotension
•  Nervous system – headache, tingling and palpitations

Cardiovascular system 

• Palpitations
• Tachycardia
• Collapse

Gastrointestinal tract 

• Constipation
• Diarrhea
• Emesis
• Bloating
• Flatulence
• Abdominal pain
• Nausea
• Postprandial fullness

Nervous system 

• Headache
• Dizziness

Respiratory system 

• Dyspnea
• Nasal congestion
• Rhinitis
• Rhinorrhea

Skin

• Eczema
• Flush
• Inflammation
• Pruritus
• Urticaria

• antihistamines (histamine receptor antagonists)
• avoiding drugs/substancesthat inhibit DAO and HNMT enzyme activity (i.e. chloroquine, clonidine, isoniazid, diclofenac, cimetidine, verapamil, vitamin B1 and vitamin C)
• supplementing with a DAO enzyme to increase its activity in the body (which in turn decreases histamine levels)