Histamine intolerance

Contents

What is histamine intolerance

What is histamine intolerance

Histamine intolerance is the results of a disequilibrium of accumulated histamine and the capacity for histamine degradation ¹⁾. The main enzyme for the breakdown (metabolism) of ingested histamine is diamine oxidase (DAO) ²⁾. An impaired histamine degradation based on a reduced diamine oxidase (DAO) activity and the resulting excess of histamine may cause numerous symptoms mimicking an allergic reaction. Ingestion of histamine-rich food ³⁾, alcohol ⁴⁾, or drugs (e.g., aminoguanidine, dihydralazine, chloroquine, pentamidine, cycloserine, clavulanic acid, dobutamine, pancuronium and others) ⁵⁾ that release histamine or block diamine oxidase (DAO) enzyme may provoke diarrhea, headache ⁶⁾, congestion of the nose, asthmatoid wheezing ⁷⁾, hypotension, arrhythmia, urticaria ⁸⁾, pruritus, flushing, and other conditions in these patients. Approximately 1% of the population has histamine intolerance, and 80% of those patients are middle-aged ⁹⁾. Because of the multifaceted symptoms, the existence of histamine intolerance is frequently underestimated, or its symptoms are misinterpreted.

Histamine intolerance belongs to the group of non-IgE-mediated hypersensitivity-like reactions and is known as a pharmacological food intolerance ¹⁰⁾. 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 ¹¹⁾.

In patients with typical symptoms of histamine intolerance that are triggered by histamine-rich food and alcohol, with intolerance of drugs that liberate histamine or block diamine oxidase (DAO), and with a negative diagnosis of allergy or internal disorders, histamine intolerance should be considered. A histamine-free diet, if necessary, supported by antihistamines or the substitution of diamine oxidase (DAO), leads to an improvement of symptoms. However, further studies investigating histamine intolerance due to double-blind, placebo-controlled provocations are indispensable.

Clinical symptoms and their provocation by certain foods and beverages appear similar in different diseases, such as food allergy and intolerance of sulfites, histamine, or other biogenic amines (e.g, tyramine). Therefore, the differentiation of the causal agent in adverse reactions to food, alcohol, and drugs is a difficult challenge. There is poor evidence of adverse reactions to these agents based on double-blind, placebo-controlled provocations ¹²⁾. However, a better understanding of the pathophysiology, clinical picture, trigger factors, and diagnostic tools may help to clarify the confusing debate surrounding histamine intolerance.

Due to microbial contamination, food and beverages sometimes contain varying amounts of biogenic amines in relevant amounts. Therefore, spoiled or fermented foods can contain high levels of biogenic amines. In particular, food that undergoes microbial ripening, such as cheese, salami, sauerkraut, or red wine, can contain high levels of histamine (see Table 1 below) ¹³⁾.

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 experiments¹⁴⁾. A clinically relevant activity via histamine release or inhibition of DAO has been observed for various drugs ¹⁵⁾. 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
Contrast media
Muscle relaxants	Pancuronium, alcuronium, d-tubocurarine
Narcotics	Thiopental
Analgetics	Morphine, pethidine, nonsteroidal antiinflammatory drugs, acetylsalicylic acid, metamizole
Local anesthetics	Prilocaine
Antihypotonics	Dobutamine
Antihypertensive drugs	Verapamil, alprenolol, dihydralazine
Antiarrhythmics	Propafenone
Diuretics	Amiloride
Drugs influencing gut motility	Metoclopramide
Antibiotics	Cefuroxime, cefotiam, isoniazid, pentamidin, clavulanic acid, choroquine
Mucolytics	Acetylcysteine, ambroxol
Broncholytics	Aminophylline
H2-receptor antagonists	Cimetidine
Cytostatics	Cyclophosphamide
Antidepressants	Amitriptyline

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Histamine function

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 1 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 ¹⁷⁾ and intestinal ischemia ¹⁸⁾.

Figure 1. Histamine effects

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Table 1. Histamine effects according to plasma histamine concentration (ng/mL or nanogram per mililiter)

Histamine	Clinical effect
0–1	Reference
1–2	↑ Gastric acid secretion ↑ Heart rate
3–5	Tachycardia, headache, flush, urticaria, pruritus
6–8	↓ Arterial pressure
7–12	Bronchospasm
≈100	Cardiac arrest

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Histamine metabolism

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 ²¹⁾.

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 ²²⁾. 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 ²³⁾, which can convert histamine only in the intracellular space of cells ²⁴⁾. 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 ²⁵⁾ and for placenta and kidney ²⁶⁾. Lower diamine oxidase (DAO) activity has been discussed as a potential indicator of intestinal mucosa damage in inflammatory and neoplastic diseases ²⁷⁾ and in persons undergoing chemotherapy ²⁸⁾. 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 trachea²⁹⁾. Histamine-N-methyltransferase is regarded as the key enzyme for histamine degradation in the bronchial epithelium ³⁰⁾.

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 ³¹⁾.

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Table 2. Characteristics of the histamine-degrading enzymes diamine oxidase (DAO) and histamine N-methyl-transferase (HNMT)

	DAO	HNMT
Gene
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 M_R 200 000 with subunits of 70–125 kDa; 750 amino acid residues	Soluble, cytosolic protein of M_R 33 000 with subunits of 29–34 kDa; 292 amino acid residues
Enzyme
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 (k_m)	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
Optimum pH	7.2	7.5–9.0
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

Abbreviations:

SNPs = single-nucleotide polymorphisms; kbp = kilobase pair; M_R = molecular weight; kDa = kiloDalton; k_M = Michaelis-Menten constant.

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What causes histamine intolerance?

Different mechanisms have been proposed as causing histamine intolerance ³⁴⁾. Histamine intolerance can develop through both increased availability of histamine and impaired histamine degradation ³⁵⁾. Underlying conditions for increased availability may be an endogenous histamine overproduction caused by allergies, mastocytosis, bacterias, gastrointestinal bleeding, or 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 diamine oxidase (DAO) or histamine N-methyl-transferase (HNMT). Gastrointestinal diseases with altered enterocytes also may cause decreased production of diamine oxidase (DAO) ³⁶⁾. Yet another cause can be competitive inhibition of histamine degradation of diamine oxidase (DAO) by other biogenic amines, alcohol ³⁷⁾, or drugs ³⁸⁾. Acquired histamine intolerance may be transient and therefore reversible after the elimination of causes, such as by discontinuing diamine oxidase (DAO)-blocking drugs. Diamine oxidase (DAO) inhibits the transepithelial permeation of exogenous histamine ³⁹⁾ and impaired diamine oxidase (DAO) activity results in increased enteral histamine uptake with consequent increased plasma histamine concentrations ⁴⁰⁾ and corresponding symptoms. Increased amounts of histamine metabolites may also inhibit histamine N-methyl-transferase (HNMT), the second enzyme metabolizing histamine ⁴¹⁾.

Reduced diamine oxidase (DAO) activity—or, rather, reduced diamine oxidase (DAO) release—after the application of heparin could be shown to be a marker of tissue damage in patients with chronic renal failure ⁴²⁾, viral hepatitis (101), or gut failure and of endotoxemia in patients with liver cirrhosis ⁴³⁾. Reduced diamine oxidase (DAO) activity has also been shown in patients with chronic urticaria as a typical histamine-mediated disease ⁴⁴⁾ combined with a reduced tolerance for infused histamine ⁴⁵⁾ and an improvement of urticaria by maintaining a histamine-free diet ⁴⁶⁾.

The genetic background of histamine intolerance

Recently, a potential genetic background of a reduced histamine metabolism has also been investigated. The human diamine oxidase (DAO) gene spans ≈10 kbp and is located on chromosome 7q35 ⁴⁷⁾. Various single-nucleotide polymorphisms in the DAO gene have been shown to be associated with inflammatory and neoplastic gastrointestinal diseases, such as food allergy ⁴⁸⁾, gluten-sensitive enteropathy, Crohn disease, ulcerative colitis, and colon adenoma ⁴⁹⁾. No significant difference in the distribution of the investigated histamine N-methyl-transferase (HNMT) alleles could be shown between patients with gastrointestinal diseases and control subjects ⁵⁰⁾, but a functional relevant polymorphism of the HNMT gene (chromosome 2q22) has been described for white asthma patients ⁵¹⁾. Conversely, this association could not be observed in Japanese ⁵²⁾, German pediatric ⁵³⁾, and East Indian ⁵⁴⁾ populations. Thus, histamine intolerance seems to be acquired mostly through the impairment of diamine oxidase (DAO) activity caused by gastrointestinal diseases or through the inhibition of diamine oxidase (DAO), but the high interindividual variations in the expression of diamine oxidase (DAO) in the gut and the association of single-nucleotide polymorphisms in the DAO gene with gastrointestinal diseases provide evidence for a genetic predisposition in a subgroup of patients with histamine intolerance ⁵⁵⁾.

Histamine intolerance symptoms

Typical symptoms of histamine intolerance include gastrointestinal disorders, sneezing, rhinorrhea and congestion of the nose, headache ⁵⁶⁾, dysmenorrhea, hypotonia, arrhythmias ⁵⁷⁾, urticaria ⁵⁸⁾, pruritus, flushing, and asthma ⁵⁹⁾.

Diarrhea,
Headache ⁶⁰⁾,
Congestion of the nose,
Asthmatoid wheezing ⁶¹⁾,
Hypotension (low blood pressure),
Arrhythmia (abnormal heart rate or rhythm),
Urticaria ⁶²⁾,
Pruritus,
Flushing.

Histamine and headache

Headache can be induced dose-dependently by histamine in healthy persons as well as in patients with migraine ⁶³⁾. Histamine-induced headache is a vascular headache caused mainly by nitrate monoxide ⁶⁴⁾. Histamine releases endothelial nitrate monoxide upon stimulation of H1R (histamine 1 receptor), which is also expressed in the large intracranial arteries ⁶⁵⁾. 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 ⁶⁶⁾. Many migraine patients have histamine intolerance evidenced by reduced diamine oxidase (DAO) activity, triggering of headache by food rich in histamine (e.g, long-ripened cheese or wine), and the alleviation of headache (i.e, disappearance of symptoms) under a histamine-free diet ⁶⁷⁾ and therapy with antihistamines ⁶⁸⁾.

Histamine and gastrointestinal tract

Besides headache, gastrointestinal ailments including diffuse stomach ache, colic, flatulence, and diarrhea are leading symptoms of histamine intolerance. Elevated histamine concentrations and diminished diamine oxidase (DAO) activities have been shown for various inflammatory and neoplastic diseases such as Crohn disease ⁶⁹⁾, ulcerative colitis ⁷⁰⁾, allergic enteropathy ⁷¹⁾, food allergy ⁷²⁾, and colorectal cancers ⁷³⁾. In the colonic mucosa of patients with food allergy, a concomitant reduced histamine N-methyl-transferase (HNMT) ⁷⁴⁾ and an impaired total histamine degradation capacity ⁷⁵⁾ have been found ⁷⁶⁾, 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 ⁷⁷⁾.

Histamine and 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 histamine N-methyl-transferase (HNMT) activity has been shown for patients with food allergy ⁷⁸⁾ and bronchial asthma ⁷⁹⁾.

Histamine intolerance diagnosis

Diagnosis of histamine intolerance has been based on low serum diamine oxidase (DAO) values, functional gastrointestinal disorders and improvement of symptoms with a histamine-reduced diet.

Basal plasma histamine concentrations of 0.3 to 1.0 ng/mL are considered normal ⁸⁰⁾. Exceeding the individual histamine tolerance gives rise to concentration-dependent histamine-mediated symptoms ⁸¹⁾ (see Table 1). Even healthy persons may develop severe headache or flushing due to ingestion of massive amounts of histamine as is known from studies of scromboid poisoning ⁸²⁾. It has been shown that inhibition of diamine oxidase (DAO) followed by oral histamine administration may induce severe and even life-threatening reactions, such as hypotension, bronchospasm, or shock ⁸³⁾. Recurrent anaphylactic reactions have been reported in patients with hyperhistaminemia ⁸⁴⁾. In histamine-sensitive patients with reduced diamine oxidase (DAO) activity, symptoms occur even after the ingestion of the small amounts of histamine that are well tolerated by healthy persons. Symptoms can be manifest via the above mentioned actions of histamine in multiple organs, such as the gastrointestinal tract, lung, skin, cardiovascular system, and brain, according to the expression of histamine receptors.

Because of the multifaceted symptoms in multiple organs, a detailed history of the basal histamine-mediated symptoms, any triggering of symptoms after the intake of histamine-rich food or drugs interfering with the histamine metabolism, and concomitant gastrointestinal diseases or allergies is indispensable for diagnosis of histamine intolerance (Figure 3). Clinically, histamine-induced symptoms cannot always be assigned to the underlying pathomechanism. A massive intake of histamine from decomposed fish may result in the same symptoms as are seen in a person with an IgE-mediated fish allergy. Histamine actions may be possible causes of endogenous cell activation, increased exogenous uptake, decreased histamine degradation, or a combination of these mechanisms. An occult systemic mastocytosis should be excluded by measurement of the serum tryptase. Diagnosis of histamine intolerance is set by presentation of ≥2 typical symptoms of histamine intolerance ⁸⁵⁾ and improvement by histamine-free diet and antihistamines. The diagnosis of allergy using using the skin-prick test for food allergens or determination of specific IgE should be carried out to exclude food allergy. The diagnosis of allergy usually proves to be negative because histamine intolerance is a pseudoallergy. Keeping of a diet diary has proven useful in tracking significant improvement of symptoms with a histamine-free diet and relapses in histamine intolerance after dietary errors.

Figure 3. Diagnostic pathway for histamine intolerance

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Histamine intolerance test

In a patient with clinical suspicion of histamine intolerance (i.e, ≥2 typical symptoms), improvement of symptoms by histamine-free diet or antihistamines, diamine oxidase (DAO) may be determined in serum ⁸⁷⁾ or tissue biopsy ⁸⁸⁾. Several radioextraction assays have been developed for the determination of the enzymatic activity of diamine oxidase (DAO) by using [3H]- or [¹⁴C]-labeled putrescinedihydrochloride as a substrate ⁸⁹⁾. Determination of the HNMT activity is based on transmethylation of histamine by S-adenosyl-l [methyl-¹⁴C] methionine ⁹⁰⁾. Furthermore, the total histamine degradation capacity can be measured ⁹¹⁾. Plasma activity of DAO, which generally is relatively low, may be increased by the liberation of tissue-bound DAO through an injection of heparin ⁹²⁾, which was the main method used before the development of more sensitive assays. Serum diamine oxidase (DAO) concentrations showed no significant daily variations and no significant sex differences ⁹³⁾. In patients with a diamine oxidase (DAO) activity Histamine intolerance is presumably highly likely in patients with DAO activity <3 U/mL, likely (but less likely) in patients with diamine oxidase (DAO) activity <10 U/mL, and improbable in patients with diamine oxidase (DAO) activity ≥10 U/mL ⁹⁴⁾.

Conversely, in some patients with a clear clinical picture of histamine intolerance, normal diamine oxidase (DAO) activities have been observed, so that an additional determination of histamine concentrations and interpretation of laboratory data in view of the clinic seem advisable. Histamine can be measured in plasma or in urine, as can its degradation product N-methylhistamine ⁹⁵⁾. Deficiency of the DAO cofactors vitamin B-6, copper, and vitamin C, which are thought to supplement histamine degradation ⁹⁶⁾, has been discussed as being controversial ⁹⁷⁾. Elevated histamine concentrations, reduced diamine oxidase (DAO) activities, or both are classically found in histamine intolerance. A double-blind, placebo-controlled histamine provocation after a 4-week histamine-free diet is considered the gold standard in diagnosis. Because the amount of histamine in natural food varies tremendously according to storage and maturation, the provocation can be performed with alternate administration of capsules containing increasing doses of histamine-di-hydrochloride (0.75 and 1.5 mg/kg body weight, respectively) and placebo capsules ⁹⁸⁾. Blood pressure and heart rate should be continuously controlled, and positive reactions (e.g, hypotonia, tachycardia, urticaria, or other symptoms of an anaphylactoid reaction) should be immediately treated by a physician. Afterward, symptoms should be evaluated by using a standardized symptom-scoring system.

Histamine intolerance treatment

Histamine intolerance treatment is based on histamine-free diet. Alcohol and long-ripened or fermented (and therefore histamine-rich) food, such as aged cheese, cured meat, and yeast products; histamine-rich food, such as spinach or tomatoes; or histamine liberators, such as citrus fruit, should be avoided ⁹⁹⁾; the histamine-free diet can be complemented with adjuvant administration of H1 and H2 antagonists. Most antihistamines have no influence on diamine oxidase (DAO) activity, although inhibition of DAO by cimetidine and dihydralazine and increased activity by diphenhydramine have been observed ¹⁰⁰⁾. In patients consuming a strictly histamine-free diet, no additional benefit due to an intake of antihistamines could be observed ¹⁰¹⁾. An increase in DAO activity with the histamine-free diet was shown in migraine patients ¹⁰²⁾. In addition, histamine degradation can be supported by the administration of vitamin C ¹⁰³⁾ and vitamin B-6, which leads to an increase in diamine oxidase (DAO) activity ¹⁰⁴⁾. Positive effects have been reported for mast cell stabilizers and pancreatic enzymes ¹⁰⁵⁾, especially with respect to gastrointestinal symptoms. Because of the frequent intolerant reactions toward drugs that interfere with the histamine metabolism, their intake should be avoided. Recently, capsules containing diamine oxidase (DAO) isolated from pig kidneys have been generated to supplement the lack of endogenous human diamine oxidase (DAO) in patients with histamine intolerance. These capsules contain only stabilizers—i.e, cellulose, sucrose, solanum tuberosum, polyacrylic acid, cellulose gum, triethyl citrate, and potato starch. Patients who are suspected of having histamine intolerance should be given a certificate noting that condition and stating that the administration of contrast and other drugs that release histamine should be avoided. If the administration of theses drugs is unavoidable, prior medication with antihistamines is recommended ¹⁰⁶⁾.

Histamine intolerance diet

Histamine and other biogenic amines are present to various degrees in many foods, and their presence increases with maturation ¹⁰⁷⁾. 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 ¹⁰⁸⁾. 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 ¹⁰⁹⁾. Therefore, high concentrations of histamine are found mainly in products of microbial fermentation, such as aged cheese ¹¹⁰⁾, sauerkraut, wine ¹¹¹⁾, and processed meat ¹¹²⁾ (see Table 3) or in microbially spoiled food. Thus, histamine, tyramine, putrescine, and cadaverine serve as indicators of hygienic food quality ¹¹³⁾. 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 ¹¹⁴⁾ or the promotion of histamine liberation from the mucosa by putrescine ¹¹⁵⁾.

Histamine foods

Alcohol, especially red wine, is rich in histamine and is a potent inhibitor of diamine oxidase (DAO) ¹¹⁶⁾. 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 ¹¹⁷⁾. However, among the multitude of substances contained in wine, other biogenic amines such as tyramine ¹¹⁸⁾ and sulfites ¹¹⁹⁾ have been supposed to contribute to symptoms summarized as “wine intolerance” or “red wine asthma” ¹²⁰⁾. In double-blind, placebo-controlled wine tests with healthy persons ¹²¹⁾ and in patients with chronic urticaria and wine intolerance ¹²²⁾, 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 ¹²³⁾. However, the high percentage of responses to the placebo (87%) could be responsible for the absence of an effect in this study ¹²⁴⁾. 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 ¹²⁵⁾. 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 ¹²⁶⁾. Sulfite hypersensitivity has been reported mainly in patients with chronic asthma; the estimated prevalence is 5–10% in all patients ¹²⁷⁾. 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 ¹²⁸⁾. 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 ¹²⁹⁾. 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 ¹³⁰⁾.

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
	mg/kg	mg/L	mg/kg	mg/L	mg/kg	mg/L
Fish (frozen/smoked or salted/canned)			200		ND
Mackerel	1–20/1–1788/ND–210
Herring	1–4/5–121/1–479
Sardine	ND/14–150/3–2000
Tuna	ND/ND/1–402
Cheese			No recommendation
Gouda	10–900				10–900
Camembert	0–1000				0–4000
Cheddar	0–2100				0–1500
Emmental	5–2500				0–700
Swiss	4–2500				0–700
Parmesan	10–581				0–840
Meat			No recommendation
Fermented sausage	ND–650				ND–1237
Salami	1–654				–
Fermented ham	38–271				123–618
Vegetables
Sauerkraut	0–229		10		2–951
Spinach	30–60
Eggplant	26
Tomato ketchup	22
Red wine vinegar	4
Alcohol
White wine		ND–10		2		1–8
Red wine		ND–30		2		ND–25
Top-fermented beer		ND–14				1.1–36.4
Bottom-fermented beer		ND–17				0.5–46.8
Champagne		670

Abbreviation: ND = not detected

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Table 4. Histamine food list

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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 ¹³³⁾. However, clinical studies using oral challenge tests to support the hypothesis for the histamine-releasing capacity of foods are required ¹³⁴⁾.

Table 5. Foods with suggested histamine-releasing capacities

Plant-derived	Animal-derived	Other
Citrus fruit	Fish	Additives
Papaya	Crustaceans	Liquorice
Strawberries	Pork	Spices
Pineapple	Egg white
Nuts
Peanuts
Tomatoes
Spinach
Chocolate

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References [ + ]

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