Histamine and histamine intolerance1⫺3

Laura Maintz and Natalija Novak

ABSTRACT of those patients are middle-aged (18). Because of the multifac-

Histamine intolerance results from a disequilibrium of accumulated eted symptoms, the existence of histamine intolerance is fre-
histamine and the capacity for histamine degradation. Histamine is quently underestimated, or its symptoms are misinterpreted.
a biogenic amine that occurs to various degrees in many foods. In Clinical symptoms and their provocation by certain foods and

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healthy persons, dietary histamine can be rapidly detoxified by beverages appear similar in different diseases, such as food al-
amine oxidases, whereas persons with low amine oxidase activity lergy and intolerance of sulfites, histamine, or other biogenic
are at risk of histamine toxicity. Diamine oxidase (DAO) is the main amines (eg, tyramine). Therefore, the differentiation of the causal
enzyme for the metabolism of ingested histamine. It has been pro- agent in adverse reactions to food, alcohol, and drugs is a difficult
posed that DAO, when functioning as a secretory protein, may be challenge. There is poor evidence of adverse reactions to these
responsible for scavenging extracellular histamine after mediator agents based on double-blind, placebo-controlled (DBPC) prov-
release. Conversely, histamine N-methyltransferase, the other im- ocations (19). However, a better understanding of the pathophys-
portant enzyme inactivating histamine, is a cytosolic protein that can iology, clinical picture, trigger factors, and diagnostic tools may
convert histamine only in the intracellular space of cells. An im- help to clarify the confusing debate surrounding histamine intol-
paired histamine degradation based on reduced DAO activity and the erance.
resulting histamine excess may cause numerous symptoms mimick-
ing an allergic reaction. The ingestion of histamine-rich food or of
alcohol or drugs that release histamine or block DAO may provoke HISTAMINE AND HISTAMINE METABOLISM
diarrhea, headache, rhinoconjunctival symptoms, asthma, hypoten- Histamine (2-[4-imidazolyl]ethylamine) was discovered in
sion, arrhythmia, urticaria, pruritus, flushing, and other conditions in 1910 by Dale and Laidlaw (20), and it was identified as a medi-
patients with histamine intolerance. Symptoms can be reduced by a ator of anaphylactic reactions in 1932 (21). Histamine belongs to
histamine-free diet or be eliminated by antihistamines. However, the biogenic amines and is synthesized by the pyridoxal phos-
because of the multifaceted nature of the symptoms, the existence of phate (vitamin B-6)– containing L-histidine decarboxylase
histamine intolerance has been underestimated, and further studies (HDC) from the amino acid histidine. It is synthesized by mast
based on double-blind, placebo-controlled provocations are needed. cells, basophils, platelets, histaminergic neurons, and entero-
In patients in whom the abovementioned symptoms are triggered by chromaffine cells, where it is stored intracellularly in vesicles
the corresponding substances and who have a negative diagnosis of and released on stimulation. Histamine is a potent mediator of
allergy or internal disorders, histamine intolerance should be con- numerous biologic reactions. Besides the well-known triggering
sidered as an underlying pathomechanism. Am J Clin Nutr of degranulation of mast cells by crosslinking of the Fc␧RI re-
2007;85:1185–96. ceptor by specific allergens, several other nonimmunologic stim-
uli, such as neuropeptides, complement factors (ie, C3a and C5a),
KEY WORDS Histamine intolerance, histamine, diamine ox- cytokines, hyperosmolarity, lipoproteins, adenosine, superoxi-
idase, food intolerance, allergy dases (22), hypoxia, chemical and physical factors (eg, extreme
temperatures, traumas) (23), or alcohol and certain food and
drugs, may activate mast cells.
Histamine exerts its effects by binding to its 4 receptors [his-
INTRODUCTION
tamine 1 receptor (H1R), H2R, H3R, and and H4R] on target
Histamine intolerance results from a disequilibrium of accu- cells in various tissues (Figure 1, Table 1). It causes smooth
mulated histamine and the capacity for histamine degradation.
The main enzyme for metabolism of ingested histamine is dia- 1
From the Department of Dermatology, University of Bonn, Bonn,
mine oxidase (DAO) (1–5). An impaired histamine degradation Germany.
2
based on a reduced DAO activity and the resulting excess of Supported by grants no. DFG NO454/1-4 and DFG NO454/2-3 from the
histamine may cause numerous symptoms mimicking an allergic Deutsche Forschungsgemeinschaft (DFG), by a BONFOR grant from the
reaction. Ingestion of histamine-rich food (6), alcohol (7–9), or University of Bonn, and by Heisenberg Fellowship no. DFG NO454/3-1
drugs (10 –13) that release histamine or block DAO may provoke from the Deutsche Forschungsgemeinschaft (to NN).
3
Reprints not available. Address correspondence to N Novak, Department
diarrhea, headache (14), congestion of the nose, asthmatoid
of Dermatology, University of Bonn, Sigmund-Freud-Strasse 25, 53105
wheezing (6, 8, 15), hypotension, arrhythmia, urticaria (16, 17), Bonn, Germany. E-mail: natalija.novak@ukb.uni-bonn.de.
pruritus, flushing, and other conditions in these patients. Approx- Received July 3, 2006.
imately 1% of the population has histamine intolerance, and 80% Accepted for publication November 7, 2006.

Am J Clin Nutr 2007;85:1185–96. Printed in USA. © 2007 American Society for Nutrition 1185
1186 MAINTZ AND NOVAK

Contribution to the
Vertigo Headache Nausea, Vomitus Circadian rhythm, arousal
regulation of
body temperature,
food intake,
Hypotonia, locomotion,
Hypertension Central learning, memory
nervous system
Bone marrow
Ana- Mast cell secretion
phylaxia
Neurotransmitter Regulation of
release hematopoiesis
?
Cardiovascular Vasodilatation cGMP
H3 Leukocytes
system H4

Tachycardia, H1/2 cAMP

Arrhythmia Arrhythmias

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H2
HISTAMINE
Stimulation of H2
H1 Gastric acid
nociceptive
Pruritus nerve fibres
H1 secretion Diarrhea
H1
H1/2
H1
Skin Endothelial Smooth muscle
Gastrointestinum
permeability constriction

Mucus Estrogen
Flush
secretion

Stomach ache,
cramps
Urticaria Respiratory Uterus
tract

Meteorism
Congestion of the nose,
Bronchoconstriction, dyspnea Dysmenorrhea
rhinorrhea, sneezing
FIGURE 1. Summary of histamine-mediated symptoms. Adapted with permission from Maintz L et al. Dtsch Artzebl 2006;103:A3477-83.

muscle cell contraction, vasodilatation, increased vascular per- secreted into the circulation on stimulation (28, 29). Therefore, it
meability and mucus secretion, tachycardia, alterations of blood has been proposed that DAO may be responsible for scavenging
pressure, and arrhythmias, and it stimulates gastric acid secretion extracellular histamine (eg, after ingestion of histamine-rich
and nociceptive nerve fibers. In addition, histamine has been food) after mediator release. Conversely, HNMT, the second
known to play various roles in neurotransmission, immuno- most important enzyme inactivating histamine, is a cytosolic
modulation, hematopoiesis, wound healing, day-night rhythm, protein (30), which can convert histamine only in the intracellu-
and the regulation of histamine- and polyamine-induced cell lar space of cells (31, 32). Thus, the enzymes do not seem to
proliferation and angiogenesis in tumor models (24, 25) and compete for the substrate, although they have a similar affinity
intestinal ischemia (26). Histamine can be metabolized in 2 for histamine and they are expressed in some overlapping tissues.
ways: by oxidative deamination by DAO (former name: histam- HNMT has a slightly higher affinity for histamine [Michaelis-
inase) or by ring methylation by histamine-N-methyltransferase Menten constant (kM): 6 –13 ␮mol/L] than does DAO (kM:
(HNMT) (27) (Figure 2, Table 2). Whether histamine is catab- 20 ␮mol/L). In mammals, DAO expression is restricted to spe-
olized by DAO or HNMT is supposed to depend on the local- cific tissues; the highest activities are shown for small bowel and
ization of histamine. The DAO protein is stored in plasma mem- colon ascendens (4, 5, 33) and for placenta and kidney (28, 31).
brane–associated vesicular structures in epithelial cells and is Lower DAO activity has been discussed as a potential indicator
of intestinal mucosa damage in inflammatory and neoplastic
TABLE 1 diseases (17, 24, 34) and in persons undergoing chemotherapy
Histamine effects according to plasma histamine concentration (ng/mL) (35). HNMT is widely expressed in human tissues; the greatest
expression is in kidney and liver, followed by spleen, colon,
Histamine Clinical effect
prostate, ovary, spinal cord cells, bronchi, and trachea (36).
0–1 Reference HNMT is regarded as the key enzyme for histamine degradation
1–2 1 Gastric acid secretion in the bronchial epithelium (37).
1 Heart rate
3–5 Tachycardia, headache, flush, urticaria, pruritus
6–8 2 Arterial pressure ETIOPATHOGENESIS OF HISTAMINE INTOLERANCE
7–12 Bronchospasm Different mechanisms have been proposed as causing hista-
앒100 Cardiac arrest
mine intolerance (38). Histamine intolerance can develop
 HISTAMINE AND HISTAMINE INTOLERANCE 1187
COO-

Histidine HC
NH3+

CH2

HN N

H+
1 L-Histidine decarboxylase
CO2 (HDC)
NH2

2 HN N S-adenosyl-methionine 3

DAO HISTAMINE HNMT

S-adenosylhomocysteine

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4 4

Imidazole N-methyl- N-methylhistamine

acetaldehyde imidazole
DAO MAO-B 5
Aldehyde acetaldehyde
dehydrogenase 6 Aldehyde dehydrogenase

NH2
OH

N N
O
HN N H5C
O

Imidazole acetate N-methylimidazole acetate

FIGURE 2. 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 (35).

through both increased availability of histamine and impaired gene spans 앒10 kbp and is located on chromosome 7q35 (27)
histamine degradation. Underlying conditions for increased Various single-nucleotide polymorphisms (SNPs) in the DAO
availability may be an endogenous histamine overproduction gene have been shown to be associated with inflammatory and
caused by allergies, mastocytosis, bacterias, gastrointestinal neoplastic gastrointestinal diseases, such as food allergy (44),
bleeding, or increased exogenous ingestion of histidine or hista- gluten-sensitive enteropathy, Crohn disease, ulcerative colitis,
mine by food or alcohol. Other biogenic amines, such as pu- and colon adenoma (45– 47). No significant difference in the
trescine, may also be involved in displacing histamine from its distribution of the investigated HNMT alleles could be shown
mucosal mucine linkage, which results in an increase of free between patients with gastrointestinal diseases and control sub-
absorbable histamine in circulation. However, the main cause of jects (45, 47), but a functional relevant polymorphism of the
histamine intolerance is an impaired enzymatic histamine deg- HNMT gene (chromosome 2q22) has been described for white
radation caused by genetic or acquired impairment of the enzy- asthma patients (48). Conversely, this association could not be
matic function of DAO or HNMT. Gastrointestinal diseases with observed in Japanese (49), German pediatric (50), and East In-
altered enterocytes also may cause decreased production of DAO dian (51) populations. Thus, histamine intolerance seems to be
(17, 33, 39). Yet another cause can be competitive inhibition of acquired mostly through the impairment of DAO activity caused
histamine degradation of DAO by other biogenic amines, alcohol by gastrointestinal diseases or through the inhibition of DAO, but
(7–9), or drugs (10, 12, 40). Acquired histamine intolerance may the high interindividual variations in the expression of DAO in
be transient and therefore reversible after the elimination of the gut and the association of SNPs in the DAO gene with gas-
causes, such as by discontinuing DAO-blocking drugs. DAO trointestinal diseases provide evidence for a genetic predisposi-
inhibits the transepithelial permeation of exogenous histamine tion in a subgroup of patients with histamine intolerance (27).
(41, 42), and impaired DAO activity results in increased enteral
histamine uptake with consequent increased plasma histamine
concentrations (10, 41) and corresponding symptoms. Increased CLINICAL PICTURE
amounts of histamine metabolites may also inhibit HNMT, the Basal plasma histamine concentrations of 0.3 to 1.0 ng/mL are
second enzyme metabolizing histamine (6, 43). considered normal (52). Exceeding the individual histamine
tolerance gives rise to concentration-dependent histamine-
THE GENETIC BACKGROUND OF HISTAMINE mediated symptoms (15, 53, 54) (Table 1). Even healthy persons
INTOLERANCE may develop severe headache or flushing due to ingestion
Recently, a potential genetic background of a reduced hista- of massive amounts of histamine as is known from studies of
mine metabolism has also been investigated. The human DAO scromboid poisoning (55). It has been shown that inhibition of
1188 MAINTZ AND NOVAK

TABLE 2
Characteristics of the histamine-degrading enzymes diamine oxidase (DAO) and histamine N-methyl-transferase (HNMT)1

DAO HNMT

Gene
Gene map locus Chromosome 7q35 Chromosome 2q22
Gene 10 kbp, 5 exons, 4 introns 35 kbp, 6 exons
Associated with Inflammatory and neoplastic gastrointestinal diseases such as Asthma
SNPs food allergy, gluten-sensitive enteropathy, Crohn disease,
ulcerative colitis, and colon adenoma
Protein Soluble homodimeric glycoprotein of MR 200 000 with subunits Soluble, cytosolic protein of MR 33 000 with
of 70–125 kDa; 750 amino acid residues 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- Monomer with a 2-domain structure
trihydroxyphenylalanine quinone (Topa quinone)

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Enzyme kinetics (km) Histamine, 20 ␮mol/L Histamine, 6–13 ␮mol/L
Putrescine, 350 ␮mol/L S-adenosyl-L-methionine, 6–10 ␮mmol/L
Spermidine, 3 mmol/L
Optimum pH 7.2 7.5–9.0
Inhibititors Copper-chelating agents, eg cyanide Reaction products: N-methylhistamine, S-adenosyl-
Carbonylgroup reagents, eg, aminoguanidine, semibarbacide 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 Cytosolic compartment of the cells
cells, secretion into the circulation upon stimulation
Function Extracellular scavenger of histamine and other diamines by Intracellular histamine inactivation by methylation
oxidative deamination of the primary amino group of of the imidazole ring
histamine
1
SNPs, single-nucleotide polymorphisms; kbp, kilobase pair; MR, molecular weight; kDa, kiloDalton; kM, Michaelis-Menten constant.

DAO followed by oral histamine administration may induce histamine intolerance evidenced by reduced DAO activity, trig-
severe and even life-threatening reactions, such as hypotension, gering of headache by food rich in histamine (eg, long-ripened
bronchospasm, or shock (10, 43). Recurrent anaphylactic reac- cheese or wine), and the alleviation of headache (ie, disappear-
tions have been reported in patients with hyperhistaminemia ance of symptoms) under a histamine-free diet (57, 65) and
(56). In histamine-sensitive patients with reduced DAO activity, therapy with antihistamines (66).
symptoms occur even after the ingestion of the small amounts of
histamine that are well tolerated by healthy persons. Symptoms Histamine and gastrointestinum
can be manifest via the abovementioned actions of histamine in
multiple organs, such as the gastrointestinum, lung, skin, cardio- Besides headache, gastrointestinal ailments including diffuse
vascular system, and brain, according to the expression of his- stomach ache, colic, flatulence, and diarrhea are leading symp-
tamine receptors. Typical symptoms of histamine intolerance toms of histamine intolerance. Elevated histamine concentra-
include gastrointestinal disorders, sneezing, rhinorrhea and con- tions and diminished DAO activities have been shown for vari-
gestion of the nose, headache (14, 57), dysmenorrhea, hypoto- ous inflammatory and neoplastic diseases such as Crohn disease
nia, arrhythmias (58, 59), urticaria (16, 60), pruritus, flushing, (17), ulcerative colitis (67), allergic enteropathy (39), food al-
and asthma (7, 8). lergy (33, 68, 69), and colorectal neoplasmas (24). In the colonic
mucosa of patients with food allergy, a concomitant reduced
Histamine and headache HNMT (70) and an impaired total histamine degradation capac-
ity (THDC) (69) have been found (33), so that the enzymes
Headache can be induced dose-dependently by histamine in cannot compensate each other. Therefore, an impaired histamine
healthy persons as well as in patients with migraine (53, 61). metabolism has been suggested to play a role in the pathogenesis
Histamine-induced headache is a vascular headache caused of these diseases.
mainly by nitrate monoxide (62). Histamine releases endothelial
nitrate monoxide upon stimulation of H1R, which is also ex-
pressed in the large intracranial arteries (63). In migraine pa- Histamine and airways
tients, plasma histamine concentrations have been shown to be During or immediately after the ingestion of histamine-rich
elevated both during headache attacks and during symptom-free food or alcohol, rhinorrea or nasal obstruction may occur in
periods. An increase in the number of brain mast cells is associ- patients with histamine intolerance; in extreme cases, asthma
ated with pathologic conditions such as migraine, cluster head- attacks also may occur. Reduced HNMT activity has been shown
ache, and multiple sclerosis (64). Many migraine patients have for patients with food allergy (70) and asthma bronchiale (71).
 HISTAMINE AND HISTAMINE INTOLERANCE 1189
TABLE 3
Foods rich in histamine1

Recommended upper limit

Food categories Histamine 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

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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
1
ND, not detected. Data taken from references 13, 73, 75, 78, and 86.

Histamine and food in otherwise unmedicated subjects. Conversely, in patients tak-

Histamine and other biogenic amines are present to various ing MAO-inhibiting drugs, the pressor sensitivity was 7- to 56-
degrees in many foods, and their presence increases with matu- fold that in patients not taking MAO-inhibiting drugs (79). Eight
ration (1, 72). The formation of biogenic amines in food requires DBPC studies have investigated the effect of tyramine on mi-
the availability of free amino acids, the presence of decar- graine. Two studies showed positive results in migraine patients
boxylase-positive microorganisms, and conditions allowing bac- who were sensitive to foods that are high in tyramine (n ҃ 45)
terial growth and decarboxylase activity. Free amino acids either (19) or who had wine-provoked migraine (n ҃ 19) (80); 6 studies
occur as such in foods or may be liberated by proteolysis during showed negative results with 97 (81), 80 (82), 25 (83), and 65
processing or storage (73). Numerous bacterias and some yeast (84) patients. The 2 positive studies and 2 of the negative studies
display high HDC activity and thus have the capacity to form were regarded as inconclusive (19) because of a lack of random-
histamine. Histidine is generated from autolytic or bacterial pro- ization (79), questionable blinding (80), or inappropriate
cesses (74). Therefore, high concentrations of histamine are selection of migraine patients without a history of suspected
found mainly in products of microbial fermentation, such as aged
tyramine intolerance (81, 82). Conversely, in 2 conclusive stud-
cheese (75), sauerkraut, wine (76), and processed meat (77, 78)
ies of migraine patients with a positive or negative dietary his-
(Table 3) or in microbially spoiled food. Thus, histamine, tyra-
tory, 125 mg oral tyramine did not precipitate more headaches
mine, putrescine, and cadaverine serve as indicators of hygienic
food quality (73). Tyramine and putrescine also may lead to than did placebo.
intolerance reactions in combination with histamine. Possible In addition to histamine-rich food, many foods such as citrus
explanations may be the inhibition of DAO by other amines (43) foods are considered to have the capacity to release histamine
or the promotion of histamine liberation from the mucosa by directly from tissue mast cells, even if they themselves contain
putrescine (34). only small amounts of histamine (Table 4). In vitro studies of
Intolerance of tyramine that has vasoconstrictive properties persons with a history of pseudoallergic reactions to food have
that lead to hypertensive crisis and headache has been known shown a fragility of duodenal mast cells with massive degranu-
mostly in patients taking monoamine oxidase (MAO)–inhibiting lation in the presence of histamine-releasing substances that is
drugs. Orally administered tyramine in doses of 200 to 800 mg significantly greater than that shown by control subjects (85).
has been shown to increase systolic blood pressure by 30 mm Hg However, clinical studies using oral challenge tests to support the
1190 MAINTZ AND NOVAK

TABLE 4 In contrast to an IgE–mediated food allergy, in which the

Foods with suggested histamine-releasing capacities1 ingestion of even a small amount of the allergen elicits symp-
Plant-derived Animal-derived Other toms, in histamine intolerance, the cumulative amount of hista-
mine is crucial. Besides variations in the amount of histamine in
Citrus fruit Fish Additives food according to storage and maturation, the quantity con-
Papaya Crustaceans Liquorice
sumed, the presence of other biogenic amines, and the additional
Strawberries Pork Spices
intake of alcohol or DAO-blocking drugs are pivotal factors in
Pineapple Egg white
Nuts the tolerance of the ingested food. Generally, an upper limit of
Peanuts 100 mg histamine/kg in foods and of 2 mg histamine/L in alco-
Tomatoes holic beverages has been suggested (96). This threshold may be
Spinach too high, considering the occurrence of histamine-mediated
Chocolate symptoms after oral ingestion of 75 mg histamine in 5 of 10
1
Data were taken from reference 21. females without a history of histamine intolerance (15).
However, most of the positive studies for intolerant reactions
to sulfite, histamine, and other biogenic amines do not fulfill the

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hypothesis for the histamine-releasing capacity of foods are re- current scientific criteria for providing substantiated evidence of
quired (22). the clinical effect of these foods. Nevertheless, patients who have
Alcohol, especially red wine, is rich in histamine and is a a conclusive history of adverse reactions to food, alcohol, drugs
potent inhibitor of DAO (9, 86). The relation between the inges- containing histamine, other biogenic amines, and sulfite but
tion of wine, an increase in plasma histamine, and the occurrence without proof of IgE exist. In such patients, a DBPC provocation
of sneezing, flushing, headache, asthma attacks, and other ana- of the suspected causal agents under close supervision by expe-
phylactoid reactions and a reduction of symptoms by antihista- rienced specialists should be performed after exclusion of other
mines has been shown in various studies (7, 8, 14, 65, 87, 88). causal diseases and informed consent of the patients—if the
However, among the multitude of substances contained in wine, provocation is not unreasonably hazardous, considering the
other biogenic amines such as tyramine (80) and sulfites (89) grade of the anaphylactoid reaction. Because of the great effort,
have been supposed to contribute to symptoms summarized as time, and costs or because of patients’ fear of a repeated reaction,
“wine intolerance” or “red wine asthma” (19, 89, 90). In DBPC DBPC provocations often are not performed in clinical practice,
wine tests with healthy persons (91) and in patients with chronic even when they are indicated.
urticaria and wine intolerance (92), the histamine content did not
influence wine tolerance. In the latter group, an increase in Histamine and drugs
plasma histamine could be shown, paradoxically, after ingestion The effect of drugs as specific DAO inhibitors and their ca-
of the histamine-poor wine. In these patients, the ethanol metab- pacity to induce histamine intolerance have been shown in var-
olite acetaldehyde has been discussed as a histamine-releasing ious studies with human placental DAO and in animal experi-
substance (92). However, the high percentage of responses to the ments (10, 40, 97, 98). A clinically relevant activity via histamine
placebo (87%) could be responsible for the absence of an effect release or inhibition of DAO has been observed for various drugs
in this study (19). Another randomized DBPC oral wine chal- (10, 40, 97, 98) (Table 5). Therefore, the intake of drugs,
lenge in patients with a history of red wine–provoked asthma especially long-term medication, should be considered in inter-
(n ҃ 18) found no relation between wine tolerance and the wine’s pretation of histamine intolerance symptoms and DAO concen-
content of histamine or other amines but did find a greater bron- trations.
choconstrictive response to wine with a high sulfite content (89).
Sulfiting agents are widely used as antioxidants and preserva- Other associated diseases
tives in foods, beverages, and pharmaceuticals. Adverse reac-
tions with a presumed relation to sulfites include anaphylactic Reduced DAO activity— or, rather, reduced DAO release—
shock, bronchospasm, urticaria, angioedema, nausea, abdominal after the application of heparin could be shown to be a marker of
pain, diarrhea, stroke, and death (93). Sulfite hypersensitivity has tissue damage in patients with chronic renal failure (99, 100),
been reported mainly in patients with chronic asthma; the esti- viral hepatitis (101), or gut failure and of endotoxemia in patients
mated prevalence is 5–10% in all patients (94). Asthmatic reac- with liver cirrhosis (102). Reduced DAO activity has also been
tions have been attributed to reflex activation of the parasympa- shown in patients with chronic urticaria as a typical histamine-
thetic system by the irritating effect of sulfites, possibly mediated disease (60) combined with a reduced tolerance for
enhanced by a deficiency of sulfite oxidase. Besides this infused histamine (16) and an improvement of urticaria by main-
pseudoallergic mechanism, in at least some cases of sulfite hy- taining a histamine-free diet (103).
persensitity, an immunoglobulin E (IgE)–mediated immediate-
type allergic reaction must be considered (95). Sulfites may be Histamine and atopic eczema
contained in wine, but they are also contained in foods that are Higher basal plasma histamine concentrations (104, 105) and
poor in histamine, such as fruit juice, frozen vegetables, and increased spontaneous histamine release toward different stimuli
lettuce. Thus, in patients reporting intolerance to wine, a careful (106 –108) and after food challenges (109) have been shown in
history of reactions to other foods rich in histamine or sulfites patients with severe atopic eczema (AE) than in control subjects.
should be taken. In patients who are suspected of having sulfite In addition, reduced DAO activities have been shown in a sub-
intolerance, skin testing and a DBPC challenge with capsules group of AE patients (104, 110, 111). Thus, these patients have
containing increasing doses of bisulfite or placebo should be a significantly greater occurrence of chronic headache, dysmen-
performed. orrhea, flushing, gastrointestinal symptoms, and intolerance to
 HISTAMINE AND HISTAMINE INTOLERANCE 1191
TABLE 5 be the reason why, in women with food intolerance, remissions
Drugs releasing histamine or inhibiting diamine oxidase frequently occur during pregnancy (14).
Agent interfering with the
Substance class histamine metabolism
PRACTICAL CONSEQUENCES
Contrast media
Because of the multifaceted symptoms in multiple organs, a
Muscle relaxants Pancuronium, alcuronium,
D-tubocurarine
detailed history of the basal histamine-mediated symptoms, any
Narcotics Thiopental triggering of symptoms after the intake of histamine-rich food or
Analgetics Morphine, pethidine, nonsteroidal drugs interfering with the histamine metabolism, and concomi-
antiinflammatory drugs, tant gastrointestinal diseases or allergies is indispensable for
acetylsalicylic acid, metamizole diagnosis of histamine intolerance (Figure 3). Clinically,
Local anesthetics Prilocaine histamine-induced symptoms cannot always be assigned to the
Antihypotonics Dobutamine underlying pathomechanism. A massive intake of histamine
Antihypertensive drugs Verapamil, alprenolol, dihydralazine from decomposed fish may result in the same symptoms as are
Antiarrhythmics Propafenone seen in a person with an IgE-mediated fish allergy. Histamine

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Diuretics Amiloride
actions may be possible causes of endogenous cell activation,
Drugs influencing gut motility Metoclopramide
Antibiotics Cefuroxime, cefotiam, isoniazid,
increased exogenous uptake, decreased histamine degradation,
pentamidin, clavulanic acid, or a combination of these mechanisms. An occult systemic mas-
choroquine tocytosis should be excluded by measurement of the serum
Mucolytics Acetylcysteine, ambroxol tryptase. Diagnosis of histamine intolerance is set by presenta-
Broncholytics Aminophylline tion of 욷2 typical symptoms of histamine intolerance (122) and
H2-receptor antagonists Cimetidine improvement by histamine-free diet and antihistamines. The di-
Cytostatics Cyclophosphamide agnosis of allergy using using the skin-prick test for food aller-
Antidepressants Amitriptyline gens 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.
alcohol and food than do control subjects. Reduction of both Keeping of a diet diary has proven useful in tracking significant
the symptoms of histamine intolerance and the severity score improvement of symptoms with a histamine-free diet and re-
of atopic dermatitis (SCORAD) has been shown in a subgroup lapses in histamine intolerance after dietary errors.
of patients with AE and low DAO serum activity who were In a patient with clinical suspicion of histamine intolerance (ie,
following a histamine-free diet for 2 wk (111). Orally ingested 욷2 typical symptoms), improvement of symptoms by histamine-
histamine has been shown to aggravate eczema in AE patients free diet or antihistamines, DAO may be determined in serum
in a DBPC provocation (112). A feedback inhibition of DAO (123) or tissue biopsy (32). Several radioextraction assays (REA)
through its degradation product imidazole acetic acid (113, have been developed for the determination of the enzymatic
114) or substrate inhibition (115, 116) caused by the elevated activity of DAO by using [3H]- or [14C]-labeled putrescinedihy-
histamine concentrations in AE may be a pathomechanism of drochloride as a substrate (124, 125). Determination of the
a reduced histamine degradation capacity in a subgroup of HNMT activity is based on transmethylation of histamine by
patients with AE. S-adenosyl-L [methyl-14C] methionine (126). Furthermore, the
total histamine degradation capacity can be measured (69).
Histamine and sexual steroids Plasma activity of DAO, which generally is relatively low, may
In the female genital tract, histamine is mainly produced by be increased by the liberation of tissue-bound DAO through an
mast cells, endothelial cells, and epithelial cells in the uterus and injection of heparin (127–132), which was the main method used
ovaries. Histamine-intolerant women often suffer from headache before the development of more sensitive assays. Serum DAO
that is dependent on their menstrual cycle and from dysmenor- concentrations showed no significant daily variations and no
rhea. Besides the conctractile action of histamine, these symp- significant sex differences (97). In patients with a DAO activity
toms may be explained by the interplay of histamine and Histamine intolerance is presumably highly likely in patients
hormones. Histamine has been shown to stimulate, in a dose- with DAO activity 쏝3 U/mL, likely (but less likely) in patients
dependent manner, the synthesis of estradiol via H1R; mean- with DAO activity 쏝10 U/mL, and improbable in patients with
while, only a moderate effect on progesterone synthesis was DAO activity 욷10 U/mL (18, 131).
observed (117). The painful uterine contractions of primary dys- Conversely, in some patients with a clear clinical picture of
menorrhea are mainly caused by an increased mucosal histamine intolerance, normal DAO activities have been ob-
production of prostaglandine F2␣ stimulated by estradiol and served, so that an additional determination of histamine concen-
attenuated by progesterone. Thus, histamine may augment dys- trations and interpretation of laboratory data in view of the clinic
menorrhea by increasing estrogen concentrations. And, in re- seem advisable. Histamine can be measured in plasma or in urine,
verse, estrogen can influence histamine action. A significant as can its degradation product N-methylhistamine (53, 132). De-
increase in weal and flare size in response to histamine has been ficiency of the DAO cofactors vitamin B-6, copper, and vitamin
observed to correspond to ovulation and peak estrogen concen- C, which are thought to supplement histamine degradation (133),
trations (118). In pregnancy, DAO is produced at very high has been discussed as being controversial (14). Elevated hista-
concentrations by the placenta (119, 120), and its concentration mine concentrations, reduced DAO activities, or both are clas-
may become 500 times that when the woman is not pregnant sically found in histamine intolerance. A DBPC histamine prov-
(120). This increased DAO production in pregnant women may ocation after a 4-wk histamine-free diet is considered the gold
1192 MAINTZ AND NOVAK

Anamnesis
Symptoms of histamine intolerance?
Symptoms triggered by
histamine-rich food?
Drugs liberating histamine or
inhibiting DAO?
Allergies?

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Concomitant diseases?
Mastocytosis?
Tryptase
Diet diary
Improvement by histamine-free diet,
antihistamines, mast cell stabilizers,
substitution of DAO?

Food allergies? Exclusion of other underlying

diseases, eg, endoscopy for
Skin-prick test, RAST,
gastrointestinal symptoms
provocation
≥ 2 Symptoms of
histamine intolerance
+
improvement by histamine-free diet

Measurement of Double-blind, placebo-

controlled histamine
DAO+ histamine
provocation

Histamine-free diet, antihistamines,

mast cell stabilizers, DAO substitution
Certification of medication before
exposure to drugs liberating histamine
or inhibiting DAO
FIGURE 3. Diagnostic pathway for histamine intolerance. Adapted with permission from Maintz L et al. Dtsch Artzebl 2006;103:A3477-83.
 HISTAMINE AND HISTAMINE INTOLERANCE 1193
standard in diagnosis. Because the amount of histamine in natural 2. Bieganski T, Kusche J, Feussner KD, Hesterberg R, Richter H, Lorenz
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