What is histamine
Histamine is a biogenic amine (2-[4-imidazolyl]ethylamine) and is synthesized by the pyridoxal phosphate (vitamin B-6)–containing L-histidine decarboxylase from the amino acid histidine 1). Histamine is synthesized by mast cells, basophils, platelets, histaminergic neurons, and enterochromaffine cells, where it is stored intracellularly in vesicles and released on stimulation 2). Histamine is a potent mediator of numerous biologic reactions. Besides the well-known triggering of degranulation of mast cells by crosslinking of the FcεRI receptor by specific allergens, several other nonimmunologic stimuli, such as neuropeptides, complement factors (i.e, C3a and C5a), cytokines, hyperosmolarity, lipoproteins, adenosine, superoxidases 3), hypoxia, chemical and physical factors (e.g, extreme temperatures, traumas) 4), or alcohol and certain food and drugs, may activate mast cells.
Due to microbial contamination, food and beverages sometimes contain varying amounts of histamine in relevant amounts. Therefore, spoiled or fermented foods can contain high levels of histamine. In particular, food that undergoes microbial ripening, such as cheese, salami, sauerkraut, or red wine, can contain high levels of histamine (see Tables 3 and 4 below) 5). Histamine intolerance belongs to the group of non-IgE-mediated hypersensitivity-like reactions, and is known as a pharmacological food intolerance. Currently, no valid in vitro tests can prove histamine intolerance; thus, a double-blind, placebo-controlled food challenge test remains the gold standard for diagnostic workup of non-IgE-mediated food intolerance 6).
Histamine producing cells and stimuli that trigger histamine release
Histamine is synthesized primarily by mast cells, basophils, histaminergic neurons in the basal ganglia of the brain and enterochromaffin-like cells in the stomach 7). These cells produce large amounts of histamine and are thought to be the major histamine-producing cells (Figure 1). They continuously synthesize histamine, which is then linked to the carboxyl group of heparin and stored in intracellular granules until the cells receive the appropriate activating stimulus. Upon external stimulation, these cells degranulate, releasing the stored histamine. Stimuli that trigger histamine release by these major histamine-producing cells have been reviewed extensively 8). Antigen crosslinking of antigen-specific IgE bound to the high-affinity IgE receptor, FcεRI, on the mast cell and basophil surface is the most robust stimulus that triggers histamine release by these cells 9). Substance P and allergy-inducing drugs that bind to G-protein-coupled receptors can also trigger basophils and mast cells to release histamine via different signaling pathway 10). In addition, complement components, such as the C3a and C5a “anaphylatoxins,” have also been shown to induce histamine release by mast cells 11). Many cytokines, including IL-3, IL-18, IL-33, GM-CSF, and SCF, promote histamine synthesis 12). In general, cytokines alone do not induce histamine release although it remains controversial whether IL-33 can have this effect. Some reports describe that IL-33 stimulates histamine release 13), while other reports dispute this 14). It is suggested that IL-33 alone does not induce histamine release by basophils, but enhances histamine release in response to IgE/FcεRI crosslinking 15).
Additional histamine-producing cells have also been identified, including T cells 16), dendritic cells 17), macrophages 18), and epithelial cells 19) (Figure 1). In contrast to mast cells and basophils, these cells produce relative small quantities of histamine and do not store it in their cytoplasm 20). The small amounts of histamine that they produced are released without external stimulation 21). The biological significance of the small amounts of histamine produced by these minor histamine-producing cells remains unclear. Cell type-specific deletion of the Hdc gene, which encodes HDC (histidine decarboxylase), an enzyme essential for histamine synthesis, would shed light on the role of histamine synthesis and secretion by the minor histamine-producing cells.
Figure 1. Histamine-producing cells and stimuli that trigger histamine release
What does histamine do?
Histamine exerts its effects by binding to its 4 receptors [histamine 1 receptor (H1R), H2R, H3R, and and H4R] on target cells in various tissues (see Figure 2 and Table 1). Histamine causes smooth muscle cell contraction, vasodilatation (blood vessels to dilate), increased vascular permeability and mucus secretion, tachycardia (increase heart rate), alterations of blood pressure, and arrhythmias (abnormal heart rates or rhythms), and histamine stimulates gastric acid secretion and nociceptive nerve fibers. In addition, histamine has been known to play various roles in neurotransmission, immunomodulation, hematopoiesis (red blood cell formation), wound healing, day-night rhythm, and the regulation of histamine- and polyamine-induced cell proliferation and angiogenesis in tumor models 23) and intestinal ischemia 24).
Figure 2. Histamine effects
Table 1. Histamine effects according to plasma histamine concentration (ng/mL or nanogram per mililiter)
|1–2||↑ Gastric acid secretion ↑ Heart rate|
|3–5||Tachycardia, headache, flush, urticaria, pruritus|
|6–8||↓ Arterial pressure|
Histamine can be metabolized in 2 ways (Figure 2 and Table 2):
- By oxidative deamination by diamine oxidase (DAO) (former name: histaminase) or
- By ring methylation by histamine-N-methyltransferase 27).
Whether histamine is catabolized by diamine oxidase (DAO) or histamine-N-methyltransferase is supposed to depend on the localization of histamine. The diamine oxidase (DAO) protein is stored in plasma membrane–associated vesicular structures in epithelial cells and is secreted into the circulation on stimulation 28). Therefore, it has been proposed that diamine oxidase (DAO) may be responsible for scavenging extracellular histamine (e.g, after ingestion of histamine-rich food) after mediator release. Conversely, histamine-N-methyltransferase, the second most important enzyme inactivating histamine, is a cytosolic protein 29), which can convert histamine only in the intracellular space of cells 30). Thus, the enzymes do not seem to compete for the substrate, although they have a similar affinity for histamine and they are expressed in some overlapping tissues. Histamine-N-methyltransferase has a slightly higher affinity for histamine [Michaelis-Menten constant (kM): 6–13 μmol/L] than does diamine oxidase (DAO) (kM: 20 μmol/L). In mammals, diamine oxidase (DAO) expression is restricted to specific tissues; the highest activities are shown for small bowel and colon 31) and for placenta and kidney 32). Lower diamine oxidase (DAO) activity has been discussed as a potential indicator of intestinal mucosa damage in inflammatory and neoplastic diseases 33) and in persons undergoing chemotherapy 34). Histamine-N-methyltransferase 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 trachea35). Histamine-N-methyltransferase is regarded as the key enzyme for histamine degradation in the bronchial epithelium 36).
Figure 2. Histamine metabolism
Footnotes: Summary of the histamine metabolism. The biogenic amine histamine is synthesized by decarboxylation of the amino acid histidine catalyzed by l-histidine decarboxylase (HDC) (1). Histamine can be metabolized by extracellular oxidative deamination of the primary amino group by diamine oxidase (DAO) (2) or intracellular methylation of the imidazole ring by histamine-N-methyltransferase (HNMT) (3). Therefore, insufficient enzyme activity caused by enzyme deficiency or inhibition may lead to accumulation of histamine. Both enzymes can be inhibited by their respective reaction products in a negative feedbackloop (4). N-Methylhistamine is oxidatively deaminated to N-methyl-imidazole acetaldehyde by monoamine oxidase B (MAO B) (5) or by DAO (6). Because the methylation pathway takes place in the cytosolic compartment of cells, MAO B (5) has been suggested to catalyze this reaction in vivo 37).[Source 38)]
Table 2. Characteristics of the histamine-degrading enzymes diamine oxidase (DAO) and histamine N-methyl-transferase (HNMT)
|Gene map locus||Chromosome 7q35||Chromosome 2q22|
|Gene||10 kbp, 5 exons, 4 introns||35 kbp, 6 exons|
|Associated with SNPs||Inflammatory and neoplastic gastrointestinal diseases such as food allergy, gluten-sensitive enteropathy, Crohn disease, ulcerative colitis, and colon adenoma||Asthma|
|Protein||Soluble homodimeric glycoprotein of MR 200 000 with subunits of 70–125 kDa; 750 amino acid residues||Soluble, cytosolic protein of MR 33 000 with subunits of 29–34 kDa; 292 amino acid residues|
|Group||Copper-containing amine oxidases||Methyltransferases|
|Active form||Homodimer with the active-site cofactor 2,4,5-trihydroxyphenylalanine quinone (Topa quinone)||Monomer with a 2-domain structure|
|Enzyme kinetics (km)||Histamine, 20 μmol/L||Histamine, 6–13 μmol/L|
|Putrescine, 350 μmol/L||S-adenosyl-l-methionine, 6–10 μmmol/L|
|Spermidine, 3 mmol/L|
|Inhibititors||Copper-chelating agents, eg cyanide Carbonylgroup reagents, eg, aminoguanidine, semibarbacide||Reaction products: N-methylhistamine, S-adenosyl-l-homocysteine|
|Sulphydryl groups: p-chloromercuriobenzoate|
|Major expression||Intestine, kidney, placenta||Highest: kidney and liver; considerable: spleen, colon, prostate, ovary, spinal cord cells, trachea, and bronchi; to a smaller amount, nearly ubiquitous expression|
|Storage||Plasma membrane–associated vesicular structures in epithelial cells, secretion into the circulation upon stimulation||Cytosolic compartment of the cells|
|Function||Extracellular scavenger of histamine and other diamines by oxidative deamination of the primary amino group of histamine||Intracellular histamine inactivation by methylation of the imidazole ring|
SNPs = single-nucleotide polymorphisms; kbp = kilobase pair; MR = molecular weight; kDa = kiloDalton; kM = Michaelis-Menten constant.[Source 39)]
Histamine and atopic eczema
Higher basal plasma histamine concentrations 40) and increased spontaneous histamine release toward different stimuli 41) and after food challenges 42) have been shown in patients with severe atopic eczema than in control subjects. In addition, reduced diamine oxidase (DAO) activities have been shown in a subgroup of atopic eczema patients 43). Thus, these patients have a significantly greater occurrence of chronic headache, dysmenorrhea, flushing, gastrointestinal symptoms, and intolerance to alcohol and food than do control subjects. Reduction of both the symptoms of histamine intolerance and the severity score of atopic dermatitis has been shown in a subgroup of patients with atopic eczema and low diamine oxidase (DAO) serum activity who were following a histamine-free diet for 2 week 44). Orally ingested histamine has been shown to aggravate eczema in atopic eczema patients in a double-blind, placebo-controlled provocation 45). A feedback inhibition of diamine oxidase (DAO) through its degradation product imidazole acetic acid 46) or substrate inhibition 47) caused by the elevated histamine concentrations in atopic eczema may be a pathomechanism of a reduced histamine degradation capacity in a subgroup of patients with atopic eczema.
Histamine and sexual steroids
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 (histamine 1 receptor); meanwhile, only a moderate effect on progesterone synthesis was observed 48). The painful uterine contractions of primary dysmenorrhea are mainly caused by an increased mucosal production of prostaglandin 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 49). In pregnancy, diamine oxidase (DAO) is produced at very high concentrations by the placenta 50), and its concentration may become 500 times that when the woman is not pregnant 51). This increased diamine oxidase (DAO) production in pregnant women may be the reason why, in women with food intolerance, remissions frequently occur during pregnancy 52).
Histamine and drugs
The effect of drugs as specific diamine oxidase (DAO) inhibitors and their capacity to induce histamine intolerance have been shown in various studies with human placental diamine oxidase (DAO) and in animal experiments53). A clinically relevant activity via histamine release or inhibition of DAO has been observed for various drugs 54). Therefore, the intake of drugs, especially long-term medication, should be considered in interpretation of histamine intolerance symptoms and diamine oxidase (DAO) concentrations.
Drugs releasing histamine or inhibiting diamine oxidase (DAO)
|Substance class||Agent interfering with the histamine metabolism|
|Muscle relaxants||Pancuronium, alcuronium, d-tubocurarine|
|Analgetics||Morphine, pethidine, nonsteroidal antiinflammatory drugs, acetylsalicylic acid, metamizole|
|Antihypertensive drugs||Verapamil, alprenolol, dihydralazine|
|Drugs influencing gut motility||Metoclopramide|
|Antibiotics||Cefuroxime, cefotiam, isoniazid, pentamidin, clavulanic acid, choroquine|
Histamine and other biogenic amines are present to various degrees in many foods, and their presence increases with maturation 56). 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 57). Numerous bacteria and some yeasts display high L-histidine decarboxylase activity and thus have the capacity to form histamine. Histidine is generated from autolytic or bacterial processes 58). Therefore, high concentrations of histamine are found mainly in products of microbial fermentation, such as aged cheese 59), sauerkraut, wine 60), and processed meat 61) (see Tables 3 and 4 below) or in microbially spoiled food. Thus, histamine, tyramine, putrescine, and cadaverine serve as indicators of hygienic food quality 62). Tyramine and putrescine also may lead to intolerance reactions in combination with histamine. Possible explanations may be the inhibition of diamine oxidase (DAO) by other amines 63) or the promotion of histamine liberation from the mucosa by putrescine 64).
Intolerance of tyramine that has vasoconstrictive properties that lead to hypertensive crisis and headache has been known mostly in patients taking monoamine oxidase (MAO)–inhibiting drugs. Orally administered tyramine in doses of 200 to 800 mg has been shown to increase systolic blood pressure by 30 mm Hg in otherwise unmedicated subjects. Conversely, in patients taking MAO-inhibiting drugs, the pressor sensitivity was 7- to 56-fold that in patients not taking MAO-inhibiting drugs 65). Eight double-blind, placebo-controlled studies have investigated the effect of tyramine on migraine. Two studies showed positive results in migraine patients who were sensitive to foods that are high in tyramine (n = 45) (19) or who had wine-provoked migraine (n = 19) 66); 6 studies showed negative results with 97 67) patients. The 2 positive studies and 2 of the negative studies were regarded as inconclusive 68) because of a lack of randomization 69), questionable blinding 70), or inappropriate selection of migraine patients without a history of suspected tyramine intolerance 71). Conversely, in 2 conclusive studies of migraine patients with a positive or negative dietary history, 125 mg oral tyramine did not precipitate more headaches than did placebo.
Alcohol, especially red wine, is rich in histamine and is a potent inhibitor of diamine oxidase (DAO) 72). 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 73). However, among the multitude of substances contained in wine, other biogenic amines such as tyramine 74) and sulfites 75) have been supposed to contribute to symptoms summarized as “wine intolerance” or “red wine asthma” 76). In double-blind, placebo-controlled wine tests with healthy persons 77) and in patients with chronic urticaria and wine intolerance 78), the histamine content did not influence wine tolerance. In the latter group, an increase in plasma histamine could be shown, paradoxically, after ingestion of the histamine-poor wine. In these patients, the ethanol metabolite acetaldehyde has been discussed as a histamine-releasing substance 79). However, the high percentage of responses to the placebo (87%) could be responsible for the absence of an effect in this study 80). Another randomized double-blind, placebo-controlled oral wine challenge in patients with a history of red wine–provoked asthma (n = 18) found no relation between wine tolerance and the wine’s content of histamine or other amines but did find a greater bronchoconstrictive response to wine with a high sulfite content 81). Sulfiting agents are widely used as antioxidants and preservatives in foods, beverages, and pharmaceuticals. Adverse reactions with a presumed relation to sulfites include anaphylactic shock, bronchospasm, urticaria, angioedema, nausea, abdominal pain, diarrhea, stroke, and death 82). Sulfite hypersensitivity has been reported mainly in patients with chronic asthma; the estimated prevalence is 5–10% in all patients 83). 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. Besides this pseudoallergic mechanism, in at least some cases of sulfite hypersensitity, an immunoglobulin E (IgE)–mediated immediate-type allergic reaction must be considered 84). 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 double-blind, placebo-controlled 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 diamine oxidase (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 85). This threshold may be too high, considering the occurrence of histamine-mediated symptoms after oral ingestion of 75 mg histamine in 5 of 10 females without a history of histamine intolerance 86).
However, most of the positive studies for intolerant reactions to sulfite, histamine, and other biogenic amines do not fulfill the current scientific criteria for providing substantiated evidence of the clinical effect of these foods. Nevertheless, patients who have a conclusive history of adverse reactions to food, alcohol, drugs containing histamine, other biogenic amines, and sulfite but without proof of IgE exist. In such patients, a double-blind, placebo-controlled provocation of the suspected causal agents under close supervision by experienced specialists should be performed after exclusion of other causal diseases and informed consent of the patients—if the provocation is not unreasonably hazardous, considering the grade of the anaphylactoid reaction. Because of the great effort, time, and costs or because of patients’ fear of a repeated reaction, double-blind, placebo-controlled provocations often are not performed in clinical practice, even when they are indicated.
Table 3. High histamine foods
|Food categories||Histamine||Recommended upper limit for histamine||Tyramine|
|Fish (frozen/smoked or salted/canned)||200||ND|
|Red wine vinegar||4|
Abbreviation: ND = not detected[Source 87)]
Table 4. Histamine food list
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 (Table 5). In vitro studies of persons with a history of pseudoallergic 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 89). However, clinical studies using oral challenge tests to support the hypothesis for the histamine-releasing capacity of foods are required 90).
Table 5. Foods with suggested histamine-releasing capacities
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