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Abstract and Figures

Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine, is a disorder associated with an impaired ability to metabolize ingested histamine that was described at the beginning of the 21st century. Although interest in histamine intolerance has considerably grown in recent years, more scientific evidence is still required to help define, diagnose and clinically manage this condition. This article will provide an updated review on histamine intolerance, mainly focusing on its etiology and the existing diagnostic and treatment strategies. In this work, a glance on histamine intoxication will also be provided, as well as the analysis of some uncertainties historically associated to histamine intoxication outbreaks that may be better explained by the existence of interindividual susceptibility to ingested histamine.
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biomolecules
Review
Histamine Intolerance: The Current State of the Art
Oriol Comas-Basté1,2,3 , Sònia Sánchez-Pérez 1,2,3, Maria Teresa Veciana-Nogués1,2,3,
Mariluz Latorre-Moratalla 1,2,3 and María del Carmen Vidal-Carou 1,2,3,*
1Departament de Nutrició, Ciències de l’Alimentaciói Gastronomia, Facultat de Farmàcia i Ciències de
l’Alimentació, Campus de l’Alimentacióde Torribera, Universitat de Barcelona, Av. Prat de la Riba 171,
08921 Santa Coloma de Gramenet, Spain; oriolcomas@ub.edu (O.C.-B.); soniasanchezperez@ub.edu (S.S.-P.);
veciana@ub.edu (M.T.V.-N.); mariluzlatorre@ub.edu (M.L.-M.)
2Institut de Recerca en Nutriciói Seguretat Alimentària (INSA·UB), Universitat de Barcelona, Av. Prat de la
Riba 171, 08921 Santa Coloma de Gramenet, Spain
3
Xarxa de Refer
è
ncia en Tecnologia dels Aliments de la Generalitat de Catalunya (XaRTA), C/Baldiri Reixac 4,
08028 Barcelona, Spain
*Correspondence: mcvidal@ub.edu; Tel.: +34-934-031-984
Received: 28 July 2020; Accepted: 11 August 2020; Published: 14 August 2020


Abstract:
Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary
histamine, is a disorder associated with an impaired ability to metabolize ingested histamine that
was described at the beginning of the 21st century. Although interest in histamine intolerance has
considerably grown in recent years, more scientific evidence is still required to help define, diagnose
and clinically manage this condition. This article will provide an updated review on histamine
intolerance, mainly focusing on its etiology and the existing diagnostic and treatment strategies.
In this work, a glance on histamine intoxication will also be provided, as well as the analysis of some
uncertainties historically associated to histamine intoxication outbreaks that may be better explained
by the existence of interindividual susceptibility to ingested histamine.
Keywords:
histamine; food intolerance; histamine intolerance; histaminosis; histamine intoxication;
diamine oxidase (DAO); low-histamine diet; food supplement
1. Introduction
In 2011, the European Food Safety Authority (EFSA) issued a scientific report warning that the
levels of biogenic amines found in foods marketed in European Union countries may still entail a
consumer health risk [
1
]. Among them, histamine has the highest toxic potential, along with tyramine,
and is therefore of great interest in terms of food safety. First described more than 60 years ago,
the deleterious eects of excessive histamine ingestion were initially referred to as scombroid fish
poisoning or scombrotoxicosis, as they were associated with the consumption of fish in this family,
but the condition is now known as histamine intoxication or histamine poisoning. In recent years,
another disorder associated with histamine intake, arising from an enzymatic deficiency, has been
described. The inability of certain individuals to metabolize histamine in the intestine, resulting in
sensitivity to normal or even low histamine levels in food, may help to explain some of the uncertainties
historically associated with histamine intoxication.
During the last decade, histamine intolerance has gained social and scientific recognition, with a
significant increase in the interest of researchers to investigate this disorder. This review aims to
analyze the pathophysiological relevance of dietary histamine, giving special focus to the adverse
eects derived from histamine intake and, in particular, to the state of the art concerning the etiology,
diagnosis and treatment of histamine intolerance.
Biomolecules 2020,10, 1181; doi:10.3390/biom10081181 www.mdpi.com/journal/biomolecules
Biomolecules 2020,10, 1181 2 of 26
2. Histamine
Histamine (2-[4-imidazolyl]ethylamine) is a bioactive amine that is synthesized by decarboxylation
of its precursor amino acid, histidine, in an enzymatic reaction first described by Windaus and Vogt in
1907 involving L-histidine decarboxylase (EC 4.1.1.22) (Figure 1) [
2
]. Due to its chemical structure and
number of functional groups, histamine can be defined as a heterocyclic diamine with an imidazole
ring and ethylamine (i.e., an organic compound that provides a functional group in the form of a
primary amine) [1,3].
Biomolecules 2020, 10, x 2 of 28
2. Histamine
Histamine (2-[4-imidazolyl]ethylamine) is a bioactive amine that is synthesized by
decarboxylation of its precursor amino acid, histidine, in an enzymatic reaction first described by
Windaus and Vogt in 1907 involving L-histidine decarboxylase (EC 4.1.1.22) (Figure 1) [2]. Due to its
chemical structure and number of functional groups, histamine can be defined as a heterocyclic
diamine with an imidazole ring and ethylamine (i.e., an organic compound that provides a functional
group in the form of a primary amine) [1,3].
Figure 1. Synthesis of histamine by decarboxylation of its precursor amino acid.
The physiological and pathophysiological effects of histamine on the body were first described
in 1910 by Dale and Laidlaw, two pioneering researchers who studied the functions of this organic
compound at the Wellcome Physiological Research Laboratories [4–6]. Specifically, histamine is
synthesized and stored in high concentrations in secretory granules, mainly in basophils and mast
cells, and also in gastric enterochromaffin cells, lymph nodes and the thymus [1,7]. Functionally, this
amine is involved in various immune and physiological mechanisms, stimulating gastric acid
secretion, inflammation, smooth muscle cell contraction, vasodilation and cytokine production,
among other processes [8–11]. In addition, histamine functions as a neurotransmitter, being
synthesized by neurons located in the posterior region of the hypothalamus whose axons extend
through the brain [12]. These wide-ranging physiological effects occur by interaction with four G-
protein-coupled receptors with seven transmembrane domains (H1, H2, H3 and H4), which activate
signal transduction pathways upon perceiving their ligand, histamine [7,12].
Two main histamine metabolic pathways are known in humans, involving the enzymes diamine
oxidase (DAO) and histamine-N-methyltransferase (HNMT) (Figure 2) [10,11,13]. DAO (EC 1.4.3.22),
also called histaminase or amiloride-binding protein, is a copper-dependent amino oxidase encoded
by the AOC1 gene located on chromosome 7 (7q34-36) [14–16]. This functional enzyme, a homodimer
with two isoforms, catalyzes the oxidative deamination of the primary amine group of histamine
[14,16,17]. On the other hand, histamine can be metabolized to 1-methylhistamine by the enzyme
HNMT (EC 2.1.1.8), a small monomeric protein encoded by a gene located on chromosome 2q22.1
[18]. HNMT catalyzes the methylation of the secondary amine group of the histamine imidazole
aromatic heterocycle by a reaction requiring the S-adenosyl methionine cosubstrate as a methyl group
donor [11,13,19].
Figure 1. Synthesis of histamine by decarboxylation of its precursor amino acid.
The physiological and pathophysiological eects of histamine on the body were first described
in 1910 by Dale and Laidlaw, two pioneering researchers who studied the functions of this organic
compound at the Wellcome Physiological Research Laboratories [
4
6
]. Specifically, histamine is
synthesized and stored in high concentrations in secretory granules, mainly in basophils and mast
cells, and also in gastric enterochroman cells, lymph nodes and the thymus [
1
,
7
]. Functionally,
this amine is involved in various immune and physiological mechanisms, stimulating gastric acid
secretion, inflammation, smooth muscle cell contraction, vasodilation and cytokine production, among
other processes [
8
11
]. In addition, histamine functions as a neurotransmitter, being synthesized
by neurons located in the posterior region of the hypothalamus whose axons extend through the
brain [
12
]. These wide-ranging physiological eects occur by interaction with four G-protein-coupled
receptors with seven transmembrane domains (H1, H2, H3 and H4), which activate signal transduction
pathways upon perceiving their ligand, histamine [7,12].
Two main histamine metabolic pathways are known in humans, involving the enzymes diamine
oxidase (DAO) and histamine-N-methyltransferase (HNMT) (Figure 2) [
10
,
11
,
13
]. DAO (EC 1.4.3.22),
also called histaminase or amiloride-binding protein, is a copper-dependent amino oxidase encoded by
the AOC1 gene located on chromosome 7 (7q34-36) [
14
16
]. This functional enzyme, a homodimer with
two isoforms, catalyzes the oxidative deamination of the primary amine group of histamine [
14
,
16
,
17
].
On the other hand, histamine can be metabolized to 1-methylhistamine by the enzyme HNMT
(EC 2.1.1.8), a small monomeric protein encoded by a gene located on chromosome 2q22.1 [
18
]. HNMT
catalyzes the methylation of the secondary amine group of the histamine imidazole aromatic heterocycle
by a reaction requiring the S-adenosyl methionine cosubstrate as a methyl group donor [11,13,19].
Thus, depending on its location, the histamine present in the body is deaminated or methylated
by the action of the enzymes DAO and HNMT, respectively [
1
,
10
,
20
]. DAO is a secretory protein
stored in vesicular structures of the plasma membrane and is responsible for the degradation of
extracellular histamine [
1
,
15
]. In mammals, the expression of DAO is restricted to certain tissues,
mainly the small intestine, ascending colon, placenta and kidneys [
14
,
21
]. In the intestine, DAO activity
increases progressively from the duodenum to theileum and is located mainly in the intestinal villi [
22
].
In contrast, the enzyme HNMT is expressed in a wide range of human tissues, above all in the kidneys
and liver, and also the spleen, colon, prostate, ovaries, spinal cord cells and the trachea and respiratory
tract [
10
,
13
]. HNMT is a cytosolic protein responsible for the inactivation of intracellular histamine
and can be synthesized in the cell itself or incorporated from the extracellular space by binding to
a receptor or by membrane transporters [
7
,
18
]. Regarding substrates, HNMT is highly selective for
histamine, whereas DAO can also metabolize other biogenic amines such as putrescine and cadaverine,
Biomolecules 2020,10, 1181 3 of 26
although it shows a preference for histamine [
14
,
16
,
23
]. The anity of DAO and HNMT for histamine
is very similar, although the latter shows a slightly lower Michaelis–Menten enzymatic constant (K
M
:
6–13 µmol/L) than DAO (KM: 20 µmol/L) [10].
Biomolecules 2020, 10, x 3 of 28
Figure 2. Histamine metabolism in humans. DAO: diamine oxidase; HNMT: histamine-N-
methyltransferase; ALDH: aldehyde dehydrogenase; MAO: monoamine oxidase.
Thus, depending on its location, the histamine present in the body is deaminated or methylated
by the action of the enzymes DAO and HNMT, respectively [1,10,20]. DAO is a secretory protein
stored in vesicular structures of the plasma membrane and is responsible for the degradation of
extracellular histamine [1,15]. In mammals, the expression of DAO is restricted to certain tissues,
mainly the small intestine, ascending colon, placenta and kidneys [14,21]. In the intestine, DAO
activity increases progressively from the duodenum to the ileum and is located mainly in the
intestinal villi [22]. In contrast, the enzyme HNMT is expressed in a wide range of human tissues,
above all in the kidneys and liver, and also the spleen, colon, prostate, ovaries, spinal cord cells and
the trachea and respiratory tract [10,13]. HNMT is a cytosolic protein responsible for the inactivation
of intracellular histamine and can be synthesized in the cell itself or incorporated from the
extracellular space by binding to a receptor or by membrane transporters [7,18]. Regarding substrates,
HNMT is highly selective for histamine, whereas DAO can also metabolize other biogenic amines
such as putrescine and cadaverine, although it shows a preference for histamine [14,16,23]. The
affinity of DAO and HNMT for histamine is very similar, although the latter shows a slightly lower
Michaelis–Menten enzymatic constant (K
M
: 6–13 μmol/L) than DAO (K
M
: 20 μmol/L) [10].
The gateway for dietary histamine in the body is the intestinal epithelium. Therefore, although
HNMT is also present in the gastrointestinal tract, the more highly expressed DAO plays the major
role in protecting the body against exogenous histamine, whether originating from ingested food or
generated by the intestinal microbiota [24–26]. The protective effect of DAO has been demonstrated
in animal experimentation models that were administered aminoguanidine for irreversible and
selective DAO inhibition, followed by a dose of histamine [24,27,28]. The development of anaphylaxis
symptoms in DAO-inhibited pigs and sheep compared to control groups indicates that the enzyme
exerts a significant barrier effect against the absorption of exogenous histamine into the systemic
circulation [1,13,19,24,29]. The HNMT enzyme ranks second to DAO in protecting against the
Figure 2.
Histamine metabolism in humans. DAO: diamine oxidase; HNMT: histamine-N-
methyltransferase; ALDH: aldehyde dehydrogenase; MAO: monoamine oxidase.
The gateway for dietary histamine in the body is the intestinal epithelium. Therefore, although
HNMT is also present in the gastrointestinal tract, the more highly expressed DAO plays the major role in
protecting the body against exogenous histamine, whether originating from ingested food or generated
by the intestinal microbiota [
24
26
]. The protective eect of DAO has been demonstrated in animal
experimentation models that were administered aminoguanidine for irreversible and selective DAO
inhibition, followed by a dose of histamine [
24
,
27
,
28
]. The development of anaphylaxis symptoms in
DAO-inhibited pigs and sheep compared to control groups indicates that the enzyme exerts a significant
barrier eect against the absorption of exogenous histamine into the systemic circulation [
1
,
13
,
19
,
24
,
29
].
The HNMT enzyme ranks second to DAO in protecting against the absorption of dietary histamine
from the intestinal lumen, but appears to be more eective against intravenously or intradermally
supplied histamine [13,30].
3. Histamine in Foods
Histamine is present in a wide range of foods in highly variable concentrations, which are the
main exogenous source of this compound [
31
]. The main route for histamine formation in food is the
decarboxylation of histidine through the action of L-histidine decarboxylase, an enzyme of bacterial
origin [
32
,
33
]. Apart from histamine, food can also contain other biogenic amines, mainly tyramine
(4-hydroxy-phenethylamine), putrescine (1,4-diaminobutane) and cadaverine (1,5-diaminopentane),
Biomolecules 2020,10, 1181 4 of 26
which are formed through enzymatic deamination of the amino acids tyrosine, ornithine (and/or
agmatine) and lysine, respectively [
31
,
34
]. The accumulation of these compounds in food is the result
of the transformation of amino acids by microorganisms and depends on various factors, such as the
availability of the precursor amino acids and environmental conditions favorable for growth and/or
the bacterial decarboxylase activity [31,34,35].
These decarboxylation reactions have been described as a survival strategy for microorganisms in
acidic environments, as well as an alternative source of metabolic energy in situations of suboptimal
substrate availability [
1
,
9
]. This enzymatic activity in bacteria is a species- and strain-dependent
property [
32
]. Several Gram-positive and Gram-negative bacteria responsible for microbial spoilage or
fermentative processes in food are able to produce histamine [
1
,
36
]. Specifically, the Enterobacteriaceae
species Hafnai aluei,Morganella morganii and Klebsiella pneumonia have been identified as some of the
most prolific histamine-forming bacteria in fish [
9
,
37
]. On the other hand, in cheeses, fermented meat,
vegetable derivatives and fermented beverages, various lactic acid bacteria have also been described
as histamine-producing microorganisms (e.g., Lactobacillus hilgardii,Lactobacillus buchnerii,Lactobacillus
curvatus and Oenococcus oeni) as well as certain strains of Enterobacteriaceae [1,38,39].
Foods that potentially contain high levels of histamine are: a) those microbiologically altered,
such as fish and meat, or derived products that may have been preserved or processed in unsuitably
hygienic conditions; and b) fermented products, in which the bacteria responsible for the fermentation
process may also have aminogenic capacity [
3
,
40
]. Table 1shows histamine content in the dierent
food categories from the Spanish market [31].
Table 1. Histamine content in dierent food categories. Adapted from [31].
Food Histamine Content (mg/kg)
n Mean (SD) Median Minimum Maximum
Fruits, vegetables and plant-based products
Fruits 136 0.07 (0.20) ND ND 2.51
Nuts 41 0.45 (1.23) ND ND 11.86
Vegetables 98 2.82 (7.43) ND ND 69.72
Legumes 11 ND ND ND ND
Cereals 28 0.12 (0.33) ND ND 0.89
Chocolate 25 0.58 (0.44) 0.17 0.16 0.56
Spices 12 ND ND ND ND
Alcoholic beverages
Beer 176 1.23 (2.47) 0.70 ND 21.60
White wine 83 1.24 (1.69) 0.45 0.10 13.00
Red wine 260 3.81 (3.51) 1.90 0.09 55.00
Fish and seafood products
Fresh fish 136 0.79 (0.71) ND ND 36.55
Canned fish 96
14.42 (16.03)
5.93 ND 657.05
Semipreserved fish 49 3.48 (3.37) 2.18 ND 34.90
Fresh meat 6 ND ND ND ND
Cooked meat 48 0.30 (0.26) ND ND 4.80
Cured meat 23
12.98 (37.64)
0.80 ND 150.00
Dry-fermented sausages 209
32.15 (14.22)
8.03 ND 357.70
Biomolecules 2020,10, 1181 5 of 26
Table 1. Cont.
Food Histamine Content (mg/kg)
n Mean (SD) Median Minimum Maximum
Meat and meat products
Dairy products
Unripened cheese 20 ND ND ND ND
Raw milk cheese 20 59.37
(106.74) 18.38 ND 389.86
Pasteurized milk cheese 20
18.05 (38.23)
4.59 ND 162.03
ND: not detected.
4. Uncertainties Associated with Histamine Poisoning: A Paradigm Shift Towards
Histamine Intolerance
Although histamine has important physiological functions in the body, it can pose a health risk
when ingested in high levels [
41
]. The proper functioning of histamine degradation systems is key in
preventing its accumulation. Histamine intoxication, a kind of food poisoning, may occur after the
consumption of foods with an unusually high histamine content that overpowers the degradation
mechanisms (generally higher than 500 mg/kg) [1,3,42].
Historically, histamine intoxication has also been termed scombroid fish poisoning or the
mahi-mahi flush because of its repeated association with the consumption of fish in the Scombridae
and Scomberesocidae families (e.g., tuna, herring and mackerel) [
43
]. Histamine was first identified
in 1946 as the causative agent of the toxic eects of consuming poorly transported tuna, and for a
long time histamine poisoning was associated almost exclusively with the consumption of spoiled
fish [
44
,
45
]. Over the years, the World Health Organization (WHO) has recommended the use of the
term histamine intoxication to better designate this pathology, as it can be caused by marine species
from other families (e.g., Clupeidae, Engraulidae, Coriphaenidae and Pomatomidae) and even other
foods, such as cheese [
43
]. A meta-analysis carried out in 2018 of the dierent scientific reports of
histamine intoxication between 1959 and 2013 established that the causative food in 98% of cases
was fish, the remaining percentage being attributed to cheese [
46
]. Currently, international health
administrations consider histamine intoxication to be one of the main problems of global food security,
both for its eects on human health and its impact on trade [47,48].
Histamine intoxication is characterized by occurring in outbreaks and having a short incubation
period (i.e., 20–30 min post-ingestion), with symptoms that are generally of low/moderate severity
and remit in a few hours [
3
]. The symptoms are closely linked to the various physiological
functions of histamine in the body, aecting the skin (e.g., redness, rash, urticaria, pruritus, edema
and local inflammation), the gastrointestinal tract (e.g., nausea, vomiting and diarrhea) and the
hemodynamic (hypotension) and neurological (e.g., headache, palpitations and tingling) bodily
functions [
1
,
41
]. The symptomatic similarity of histamine intoxication with allergy means it is likely
to be underdiagnosed [
43
,
48
,
49
]. The diagnosis of histamine intoxication is based primarily on the
determination of elevated plasma histamine levels and/or the identification of an ingested food with an
unusually high histamine content [
13
]. In general, an outbreak of histamine poisoning tends to involve
more than one individual, lasts a short period of time and a particular causative food is identified [
38
].
In terms of incidence, the data available for the European Union shows an increase in histamine
intoxication outbreaks in the last ten years, unlike other types of food poisoning, and with an almost
hegemonic predominance of fish as the causative agent (over 90% of cases) [
42
,
50
]. The most recent
data from the EFSA and European Center for Disease Prevention and Control (ECDC) show that in
2017, there was a 22% increase in outbreaks compared to the previous year [
50
]. Specifically, in 2017,
there were a total of 117 outbreaks of histamine intoxication involving 572 people, 9% of whom required
hospitalization. Fortunately, no deaths have been attributed to histamine poisoning over the past
Biomolecules 2020,10, 1181 6 of 26
decade [
42
]. The same trend is observed in the information provided by the European Union Food and
Feed Warning System (RASFF), with a progressive rise in the number of cases of histamine poisoning
linked to tuna consumption in 2014–2017 and a particularly high increase in 2017 [3].
Although histamine intoxication has been extensively studied in recent decades, unresolved
questions remain, concerning, for example, the variable histamine concentrations in the foods triggering
outbreaks, or the heterogeneity in the degree and type of adverse eects [
46
]. Furthermore, the fact that
oral administration of histamine in doses equivalent to those normally found in foods causing illness
does not produce the same range and/or severity of symptoms is a paradox that has led to multiple
hypotheses [30].
Several authors have proposed that alcohol and certain food components, such as other biogenic
amines, may have a potentiating eect on histamine toxicity [
13
,
48
]. Amines such as putrescine and
cadaverine, which are usually found in foods along with histamine, can also act as DAO substrates.
It has therefore been suggested that these amines could weaken the protective barrier against dietary
histamine by competitively interacting with degradation enzymes in the intestine [
3
,
49
]. Other possible
potentiators are alcohol and its metabolite acetaldehyde, as they compete with histamine for the
enzyme aldehyde dehydrogenase (ALDH), which is simultaneously involved in histamine and alcohol
metabolism [
1
,
32
]. The potentiation eect of these components could help explain the dierences
in absorption of the same dose of histamine when ingested in isolation or in a food matrix [
48
,
49
].
The FAO and WHO have acknowledged that the involvement of potentiators can alter the threshold
dose for toxicity, and they recommend that future studies focus on clarifying the ambiguities in the
pathogenesis of histamine intoxication [30].
Finally, several authors have reported considerable interindividual variability in histamine
tolerance, which has been demonstrated in intervention studies [
1
,
3
,
10
,
13
]. After the oral administration
of the same histamine dosage, not all participants showed symptoms, and those who did varied in
symptom type and severity and even had dierent blood histamine levels [
48
,
51
,
52
]. These results
indicate the existence of population subgroups with greater sensitivity and clinical responses to
histamine, likely linked to a diminished histamine degradation capacity, which could explain some of
the historical uncertainties associated with histamine intoxication outbreaks [
1
]. Without disputing the
clinical entity of histamine intoxication, the paradigm shift lies precisely in moving the focus from food
to the human body, maintaining histamine as the causative agent, but focusing on how each person is
able to respond to the intake of variable levels of histamine from food. Thus, histamine intolerance
is the clinical condition that describes the inability of certain individuals to degrade histamine and
results in the onset of symptoms caused by its accumulation in the blood (Figure 3).
Figure 3.
Intestinal degradation of histamine by the DAO enzyme in three dierent situations: in a
healthy individual, with histamine intoxication and with histamine intolerance. Adapted from [13].
Biomolecules 2020,10, 1181 7 of 26
5. Histamine Intolerance
According to the 2003 review of allergy nomenclature by the World Allergy Organization,
adverse reactions to food without an immunological basis should be referred to as nonallergic food
hypersensitivity, in order to clearly dierentiate them from food allergies initiated by a specific immune
mechanism [
53
]. Nonallergic food hypersensitivity is commonly known as food intolerance, a response
triggered by a food or any of its components at a dose normally tolerated by the healthy population [
54
].
While the prevalence of food allergies is estimated at 1–2% in adults, currently almost 20% of the
Westernized world’s population suers from some type of food intolerance, with lactose intolerance
being the most common [54].
Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine,
can be defined as a disorder arising from reduced histamine degradation capacity in the intestine
due to impaired DAO activity, leading to its accumulation in plasma and the appearance of adverse
eects [11,41,55].
The DAO enzyme was first identified back in 1929 by Charles H. Best in autolyzing lung tissue,
which he called histaminase because of its ability to degrade histamine [
56
]. Years later, given its
ability to also degrade other diamines, as described above, the more accurate designation of DAO
was proposed [
57
,
58
]. Beyond its role in the intestinal degradation of histamine in humans, DAO is
also present in microorganisms, plants and animals, where it also catalyzes the oxidative deamination
of the primary amino group of histamine into its corresponding aldehyde, concomitantly producing
stoichiometric amounts of ammonia and hydrogen peroxide (Figure 4) [14,59,60].
Biomolecules 2020, 10, x 7 of 28
5. Histamine Intolerance
According to the 2003 review of allergy nomenclature by the World Allergy Organization,
adverse reactions to food without an immunological basis should be referred to as nonallergic food
hypersensitivity, in order to clearly differentiate them from food allergies initiated by a specific
immune mechanism [53]. Nonallergic food hypersensitivity is commonly known as food intolerance,
a response triggered by a food or any of its components at a dose normally tolerated by the healthy
population [54]. While the prevalence of food allergies is estimated at 1–2% in adults, currently almost
20% of the Westernized world’s population suffers from some type of food intolerance, with lactose
intolerance being the most common [54].
Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine,
can be defined as a disorder arising from reduced histamine degradation capacity in the intestine due
to impaired DAO activity, leading to its accumulation in plasma and the appearance of adverse
effects [11,41,55].
The DAO enzyme was first identified back in 1929 by Charles H. Best in autolyzing lung tissue,
which he called histaminase because of its ability to degrade histamine [56]. Years later, given its
ability to also degrade other diamines, as described above, the more accurate designation of DAO
was proposed [57,58]. Beyond its role in the intestinal degradation of histamine in humans, DAO is
also present in microorganisms, plants and animals, where it also catalyzes the oxidative deamination
of the primary amino group of histamine into its corresponding aldehyde, concomitantly producing
stoichiometric amounts of ammonia and hydrogen peroxide (Figure 4) [14,59,60].
Figure 4. Oxidative deamination of histamine by the DAO enzyme.
Although the first scientific references to histamine intolerance date from more than 20 years
ago, it is significant that almost 80% are from the last decade, reflecting the growing interest of
researchers in this disorder (Figure 5). In 2011, EFSA already considered histamine intolerance as one
of the risks associated with histamine intake, clinically differentiating it from histamine intoxication
[1]. In a subsequent joint report, the WHO and FAO emphasized that the no observed adverse effect
level (NOAEL) established for histamine was only valid for healthy people, and not for members of
susceptible populations, such as those with histamine intolerance [30]. EFSA concluded that only
foods with histamine levels below the detection limits are safe for individuals with histamine
intolerance [1].
Figure 5. Count of scientific publications containing the keywords histamine intolerance or
histaminosis, according to a search performed through the PubMed search engine at the MEDLINE
bibliographic database (search performed in July 2020).
Figure 4. Oxidative deamination of histamine by the DAO enzyme.
Although the first scientific references to histamine intolerance date from more than 20 years ago,
it is significant that almost 80% are from the last decade, reflecting the growing interest of researchers
in this disorder (Figure 5). In 2011, EFSA already considered histamine intolerance as one of the
risks associated with histamine intake, clinically dierentiating it from histamine intoxication [
1
].
In a subsequent joint report, the WHO and FAO emphasized that the no observed adverse eect
level (NOAEL) established for histamine was only valid for healthy people, and not for members of
susceptible populations, such as those with histamine intolerance [
30
]. EFSA concluded that only foods
with histamine levels below the detection limits are safe for individuals with histamine intolerance [
1
].
Biomolecules 2020, 10, x 7 of 28
5. Histamine Intolerance
According to the 2003 review of allergy nomenclature by the World Allergy Organization,
adverse reactions to food without an immunological basis should be referred to as nonallergic food
hypersensitivity, in order to clearly differentiate them from food allergies initiated by a specific
immune mechanism [53]. Nonallergic food hypersensitivity is commonly known as food intolerance,
a response triggered by a food or any of its components at a dose normally tolerated by the healthy
population [54]. While the prevalence of food allergies is estimated at 1–2% in adults, currently almost
20% of the Westernized world’s population suffers from some type of food intolerance, with lactose
intolerance being the most common [54].
Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine,
can be defined as a disorder arising from reduced histamine degradation capacity in the intestine due
to impaired DAO activity, leading to its accumulation in plasma and the appearance of adverse
effects [11,41,55].
The DAO enzyme was first identified back in 1929 by Charles H. Best in autolyzing lung tissue,
which he called histaminase because of its ability to degrade histamine [56]. Years later, given its
ability to also degrade other diamines, as described above, the more accurate designation of DAO
was proposed [57,58]. Beyond its role in the intestinal degradation of histamine in humans, DAO is
also present in microorganisms, plants and animals, where it also catalyzes the oxidative deamination
of the primary amino group of histamine into its corresponding aldehyde, concomitantly producing
stoichiometric amounts of ammonia and hydrogen peroxide (Figure 4) [14,59,60].
Figure 4. Oxidative deamination of histamine by the DAO enzyme.
Although the first scientific references to histamine intolerance date from more than 20 years
ago, it is significant that almost 80% are from the last decade, reflecting the growing interest of
researchers in this disorder (Figure 5). In 2011, EFSA already considered histamine intolerance as one
of the risks associated with histamine intake, clinically differentiating it from histamine intoxication
[1]. In a subsequent joint report, the WHO and FAO emphasized that the no observed adverse effect
level (NOAEL) established for histamine was only valid for healthy people, and not for members of
susceptible populations, such as those with histamine intolerance [30]. EFSA concluded that only
foods with histamine levels below the detection limits are safe for individuals with histamine
intolerance [1].
Figure 5. Count of scientific publications containing the keywords histamine intolerance or
histaminosis, according to a search performed through the PubMed search engine at the MEDLINE
bibliographic database (search performed in July 2020).
Figure 5.
Count of scientific publications containing the keywords histamine intolerance or histaminosis,
according to a search performed through the PubMed search engine at the MEDLINE bibliographic
database (search performed in July 2020).
Biomolecules 2020,10, 1181 8 of 26
Clinical manifestations of histamine intolerance consist of a wide range of nonspecific
gastrointestinal and extraintestinal symptoms, due to the ubiquitous distribution of the four histamine
receptors in dierent organs and tissues of the body (Figure 6) [
10
,
13
,
54
,
61
]. In a very recently
published study, a team of Austrian researchers comprehensively analyzed the symptoms experienced
by 133 patients diagnosed with histamine intolerance [
62
]. The most frequent and severe manifestations
were gastrointestinal, with abdominal distension observed in 92% of patients and postprandial fullness,
diarrhea, abdominal pain and constipation in 55–73%. Impairments of the nervous and cardiovascular
systems, such as dizziness, headaches and palpitations, were recorded in second place, followed
by respiratory and dermatological symptoms. Highlighting the complexity of the clinical picture
of histamine intolerance, combinations of three or more symptoms involving dierent organs were
recorded in 97% of cases, with an average of 11 symptoms per patient. The low specificity and complex
variability of symptoms undoubtedly contribute to the current diculty in achieving consensus on
the diagnostic criteria for histamine intolerance, as will be discussed in detail below [
13
]. A lack of
data also makes it dicult to determine the current incidence of this condition, although some authors
have estimated that it aects 1–3% of the population, a percentage that will possibly increase as more
knowledge and diagnostic tools for histamine intolerance become available [10,13,63].
Biomolecules 2020, 10, x 8 of 28
Clinical manifestations of histamine intolerance consist of a wide range of nonspecific
gastrointestinal and extraintestinal symptoms, due to the ubiquitous distribution of the four
histamine receptors in different organs and tissues of the body (Figure 6) [10,13,54,61]. In a very
recently published study, a team of Austrian researchers comprehensively analyzed the symptoms
experienced by 133 patients diagnosed with histamine intolerance [62]. The most frequent and severe
manifestations were gastrointestinal, with abdominal distension observed in 92% of patients and
postprandial fullness, diarrhea, abdominal pain and constipation in 55–73%. Impairments of the
nervous and cardiovascular systems, such as dizziness, headaches and palpitations, were recorded
in second place, followed by respiratory and dermatological symptoms. Highlighting the complexity
of the clinical picture of histamine intolerance, combinations of three or more symptoms involving
different organs were recorded in 97% of cases, with an average of 11 symptoms per patient. The low
specificity and complex variability of symptoms undoubtedly contribute to the current difficulty in
achieving consensus on the diagnostic criteria for histamine intolerance, as will be discussed in detail
below [13]. A lack of data also makes it difficult to determine the current incidence of this condition,
although some authors have estimated that it affects 1–3% of the population, a percentage that will
possibly increase as more knowledge and diagnostic tools for histamine intolerance become available
[10,13,63].
Figure 6. Main symptoms of histamine intolerance and possibly corresponding histamine receptors
[10,64].
5.1. The Etiology of Histamine Intolerance
As mentioned in previous sections, the main barrier against exogenous histamine in the
intestines is the DAO enzyme, which prevents its passage into the systemic circulation [10,13,65].
Numerous clinical studies have provided data on the prevalence of low plasma DAO levels in
individuals showing symptoms of histamine intolerance, mainly headaches and gastrointestinal or
dermatological disorders [66]. Although certain studies have limitations, either in the design or
number of participants, the majority point to an association between symptoms and DAO deficiency,
Figure 6.
Main symptoms of histamine intolerance and possibly corresponding histamine receptors [
10
,
64
].
5.1. The Etiology of Histamine Intolerance
As mentioned in previous sections, the main barrier against exogenous histamine in the intestines
is the DAO enzyme, which prevents its passage into the systemic circulation [
10
,
13
,
65
]. Numerous
clinical studies have provided data on the prevalence of low plasma DAO levels in individuals
showing symptoms of histamine intolerance, mainly headaches and gastrointestinal or dermatological
disorders [
66
]. Although certain studies have limitations, either in the design or number of participants,
the majority point to an association between symptoms and DAO deficiency, establishing a general
Biomolecules 2020,10, 1181 9 of 26
trend that supports the key role of DAO in the etiology of these disorders. A DAO deficiency that
predisposes a population subgroup to histamine intolerance may have a genetic, pathological or
pharmacological origin [1,41].
Regarding the genetic background of histamine intolerance, several studies have analyzed in
depth the polymorphisms in genes encoding the enzymes L-histidine decarboxylase, DAO and
HNMT, as well as the dierent histamine receptors. More than 50 nonsynonymous single-nucleotide
polymorphisms (SNPs) in the DAO-encoding gene have been identified, some of which can produce
a protein with altered activity and lead to symptoms of histamine intolerance [
67
72
]. Specifically,
the most relevant SNPs aecting DAO enzyme functionality in Caucasian individuals are rs10156191,
rs1049742, rs2268999 and especially rs1049793 [
69
,
71
]. On the other hand, an SNP in the promoter region
of the gene has also been identified that causes a lower transcriptional activity of the DAO-encoding
gene (rs2052129), as well as several genetic variations responsible for enzyme deficiency in people of
Asian or African origin (rs45558339 and rs35070995, respectively) [
67
,
72
]. In most cases, the eect of
these genetic variations on DAO functionality is through changes in enzyme kinetics, the resulting
increase in K
M
causing a reduction in the rate of histamine degradation [
69
]. In parallel, three SNPs
have been identified as being responsible for enhanced DAO enzyme activity (rs2071514, rs1049748
and rs2071517) [
72
]. There is also evidence of DAO mutations in patients with certain cardiovascular,
gastrointestinal and nervous system pathologies, although with contradictory results regarding
positive/negative eects [68].
DAO deficiency can also be an acquired condition, caused by certain pathologies or interaction
with drugs. Several inflammatory bowel pathologies aecting mucosal integrity are known to result
in impaired DAO activity, the degree of which can be correlated with the severity of mucosal
damage [
73
75
]. Thus, DAO activity has been proposed as a marker of integrity of the intestinal
mucosa. Miyoshi et al. demonstrated that DAO activity can be a useful predictor of intestinal mucosal
damage in patients receiving chemotherapy [
76
]. Additionally, DAO deficiency has also been linked
to certain functional gastrointestinal disorders, such as carbohydrate malabsorption and nonceliac
gluten sensitivity (NCGS) [
63
,
73
,
77
79
]. Enko et al. found that a concomitant reduction in DAO and
lactase enzyme activities could be a consequence of mucosal damage in the small intestine due to
gastrointestinal disorders (e.g., gastroenteritis, irritable bowel syndrome, short bowel syndrome and
gastrointestinal surgery) [
73
]. Moreover, patients with lactose intolerance and plasma DAO deficit
showed higher end-expiratory H
2
levels and the appearance of more symptoms during the H
2
breath
test in comparison with lactose-intolerant individuals with normal DAO activity [
79
]. More recently,
two works have suggested a potential relationship between a reduced DAO activity and the presence
of NCGS. Schnedl et al. based this relationship on the broad parallelism between the symptomatology
of NCGS and histamine intolerance, while the pilot study conducted by Griauzdaite et al. reported a
strong association between reduced DAO activity and the presence of NCGS, although with a reduced
number of patients [
77
,
78
]. In fact, Griauzdaite et al. found out that nine of 10 patients with NCGS had
decreased serum DAO activity levels [
78
]. This recently indicated relationship between both disorders,
NCGS and histamine intolerance, should be further explored as it may be of interest for the correct
clinical management of aected patients.
Finally, DAO deficiency can be a temporary and reversible condition, caused by the inhibitory
eect of substances such as biogenic amines and alcohol, as discussed above, as well as several widely
used drugs (Table 2) [
1
,
10
]. It has been estimated that approximately 20% of the European population
regularly take DAO-inhibiting drugs, which significantly increases the number of people susceptible
to the adverse eects of dietary histamine [
28
].
In vitro
experimental results show a potent inhibitory
eect (greater than 90%) of chloroquine, a historical antimalarial active ingredient, and clavulanic acid,
a
β
-lactam antibiotic widely used in combination with amoxicillin [
80
]. A significant inhibition of the
enzymatic activity has also been observed with the antihypertensive drug verapamil and the histamine
H2 receptor antagonist cimetidine, although the clinical use of the latter is currently anecdotal [
23
,
80
].
Other substances have also shown an inhibitory eect, albeit to a lesser extent (Table 2) [
23
,
80
,
81
].
Biomolecules 2020,10, 1181 10 of 26
In most cases, the structural similarity of the cited drugs with histamine could explain their potential to
bind to the active site of DAO and reduce its enzymatic activity [
23
]. Along the same lines, substances
with an inhibitory eect on other enzymes involved in any of the metabolic pathways of histamine in
the body (i.e., HNMT, ALDH and MAO) may act as a trigger of histamine hypersensitivity [82].
Table 2.
Active ingredients with an experimentally demonstrated inhibitory eect on the DAO
enzyme [23,28,80,81].
Active Ingredient Indication
Chloroquine Antimalarial
Clavulanic acid Antibiotic
Colistimethate Antibiotic
Cefuroxime Antibiotic
Verapamil Antihypertensive
Clonidine Antihypertensive
Dihydralazine Antihypertensive
Pentamidine Antiprotozoal
Isoniazid Antituberculous
Metamizole Analgesic
Diclofenac Analgesic and anti-inflammatory
Acetylcysteine Mucoactive
Amitriptyline Antidepressant
Metoclopramide Antiemetic
Suxamethonium Muscle relaxant
Cimetidine Antihistamine (H2 antagonist)
Prometazina Antihistamine (H1 antagonist)
Ascorbic acid Vitamin C
Thiamine Vitamin B1
5.2. Prevalence of DAO Deficit in Persons with Symptoms Related to Histamine Intolerance
Several studies have evaluated the prevalence of DAO deficit in plasma of individuals with
symptoms of histamine intolerance and/or diagnosis with certain chronic disorders.
Mušiˇc et al. found DAO deficiency in 80% of 316 adult patients showing various symptoms
associated with histamine intolerance (e.g., urticaria, pruritus, diarrhea, abdominal pain, vomiting,
constipation, cough, rhinitis and headache), as well as significantly lower plasma DAO activity
compared to the control group [
83
]. Similarly, in a retrospective study, Manzotti et al. evaluated
DAO activity in 14 patients with a confirmed diagnosis of histamine intolerance who showed mainly
gastrointestinal and dermatological symptoms, but also headaches [
84
]. In this case, patients showed
a high prevalence of DAO deficit (71%) and a significantly lower mean DAO activity compared to
healthy volunteers. A lower percentage of DAO deficiency in histamine-intolerant patients (24%) was
reported by Pinzer et al. [
63
]. Those patients featured elevated histamine levels and constantly reduced
DAO activities throughout the day.
In a study focused only on headache symptoms, Steinbrecher and Jarisch reported DAO deficiency
in 23 of 27 patients (85%) [
85
]. In parallel, the authors described a significant increase in DAO activity
after patients followed a low-histamine diet for four weeks, along with a remission or reduction in
frequency of headaches in almost 90% of individuals. More recently, Izquierdo et al. studied the
prevalence of DAO deficit in 137 patients diagnosed with a confirmed migraine diagnosis and in a
control group of 61 nonmigraine individuals [
66
]. In this study, a high prevalence of DAO deficiency
was observed in the migraine group (87%) and with a mean DAO activity significantly lower in
comparison with that obtained from control volunteers. However, the prevalence of DAO deficiency in
the control population amounted up to 44%, which was attributed to the fact that certain individuals
could present other symptoms associated with histamine intolerance or DAO deficiency other than
Biomolecules 2020,10, 1181 11 of 26
migraines. Another study with 44 migraine patients reported a 60% prevalence of DAO deficiency and
a significant copresence of certain gastrointestinal disorders, such as celiac disease and NCGS [78].
In the field of dermatological symptomatology, several studies have monitored plasma DAO
activity in patients with eczema, chronic idiopathic urticaria and atopic dermatitis. Overall, the reported
prevalence of DAO deficiency ranges from 19 to 57%, with the exception of the study by Worm et al.,
who did not detect statistically significant dierences in plasma DAO activity between control patients
and those with atopic dermatitis [8689].
Finally, regarding gastrointestinal symptoms, Honzawa et al. assessed the clinical significance
of plasma DAO activity levels in 98 patients suering inflammatory bowel disease [
90
]. This study
showed that DAO activity in blood was significantly lower in patients with Crohn’s disease and
ulcerative colitis compared to the control population, suggesting its potential importance as a marker of
intestinal permeability. In a pediatric population under 15 years of age, Rosell-Camps et al. determined
DAO deficiency in 88% of patients with abdominal pain, diarrhea and vomiting [
91
]. In contrast, in a
more recent study by a group of Austrian researchers, DAO deficiency was found in only 8% of 394
children with chronic abdominal pain [92].
To date, little data is available on the prevalence of this enzymatic deficiency related to gender, and
it is inconclusive. Klockler et al. found no dierences in plasma DAO activity between men and women,
although the number of individuals considered was scarce (n =28) [
93
]. Likewise, the study performed
by Izquierdo et al. reported similar percentages of DAO deficiency in migraine-suering women
(83%) and men (90%) [
66
]. On the contrary, Garc
í
a-Mart
í
n et al. did describe dierences in plasma
DAO activity by gender, with the prevalence of this enzyme deficiency being higher in women [
94
].
Significant fluctuations in DAO activity values have also been reported in women associated with
dierent stages of the menstrual cycle [94,95].
One factor that could explain the discordance among the prevalence data of DAO deficit in
patients with disorders associated with histamine intolerance is that the parameter considered in all
of them was serum DAO activity, which, a priori, would not reflect an enzymatic deficiency derived
from certain intestinal pathologies. Overall, in spite of the varying percentages in DAO deficiency,
the currently available studies seem to indicate an etiological relationship between DAO deficiency
and certain symptoms or disorders related to histamine intolerance. Nevertheless, more studies are
needed to assess the clinical significance of the determination of plasma DAO activity, as well as to
develop new diagnostic methods aimed at identifying individuals with histamine intolerance due to
DAO deficiency.
5.3. Diagnosis of Histamine Intolerance
Despite significant advances in the understanding of histamine intolerance, reaching a consensus
on a diagnostic algorithm remains a pending challenge. The nonspecificity of symptoms and lack
of validated diagnostic tools prompts many aected individuals to go “doctor shopping”; that is,
to consult several medical specialists in search of an explanation and solution for their varied
symptomatology [
13
,
63
]. In the absence of a consensual and clinically validated diagnosis, Figure 7
shows a schematic summary of the diagnostic algorithm for histamine intolerance based on the
available scientific evidence reviewed below.
The combination of diagnostic criteria currently in use includes the appearance of typical clinical
manifestations and the exclusion of other related disorders [
10
,
13
,
54
]. All the authors who have
proposed a diagnostic algorithm for histamine intolerance emphasize the need to initially rule out
other potential causes of symptoms associated with an increase in plasma histamine [
10
,
13
,
54
]. For this
purpose, it is advisable to carry out an intradermal skin allergy test (i.e., skin prick test) to discard
IgE sensitization caused by food allergy, and to measure plasma tryptase to exclude an underlying
systemic mastocytosis [
10
]. It is also important to know whether the patient is taking any medication
with a possible inhibitory eect on DAO activity [
55
]. If these conditions are negative, the appearance
of two or more typical symptoms of histamine intolerance and their improvement or remission
Biomolecules 2020,10, 1181 12 of 26
after the following of a low-histamine diet (i.e., a diet excluding foods that, a priori, contain high
histamine levels) will confirm the diagnosis of histamine intolerance [
10
,
54
,
96
,
97
]. In the diet follow-up,
a thorough 24-h record of all the foods consumed and symptoms experienced is recommended in order
to establish a relationship, if any, between a food and the onset of symptoms [
10
,
13
]. The duration of
the low-histamine diet to confirm the diagnosis is not clearly stipulated, although some studies suggest
a period of 4 to 8 weeks [
54
,
97
]. In addition to the diet, testing the eect of antihistamine treatment
on symptoms has also been proposed, although its usefulness once dietary histamine is removed is
unclear [10,54].
Presenting 2 symptoms of histamine
intolerance
Dismiss food allergies (skin prick test) and
systemic mastocytosis (tryptase)
Dismiss other concomitant gastrointestinal
pathologies
Dismiss DAO-inhibitor drugs
Follow-up of a low-histamine diet (4-8 weeks)
Thorough 24-hour record of food
consumption and symptomatology
Remission or improvement of symptoms
Determination of DAO enzymatic activity in
plasma or intestinal biopsy
Histamine challenge/provocation test
Histamine 50-skin-prick
Identification of genetic polymorphisms (SNPs)
Determination of biomarkers of histamine
metabolism in urine or stool samples
ANAMNESIS
HISTAMINE EXCLUSION
COMPLEMENTARY TESTS
Figure 7.
Summary of the described approaches to the diagnosis of histamine intolerance. SNPs:
single-nucleotide polymorphisms.
Once it has been established that dietary histamine is responsible for the intolerance-associated
symptoms, the diagnosis of this disorder is virtually confirmed. A range of nonvalidated complementary
tests have also been proposed by several authors with the aim of obtaining a marker to confirm the
diagnosis [
97
]. However, it has to be taken into account that not all of the tests consider the dierent
origins of DAO deficiency (i.e., genetic, pathological or pharmacological). Thus, a genetic origin would
lead to a reduction of the DAO enzymatic activity in the whole organism. Likewise, the pharmacological
blockade of DAO would take place in all tissues where the drug is distributed after entering the systemic
circulation, although in a punctual manner upon the substance’s introduction. Lastly, the scope of a
DAO deficit due to intestinal pathologies would be limited to the local intestinal environment.
Due to the genetic background of DAO deficiency, one of the strategies for the diagnosis could be
the determination of genetic polymorphisms (SNPs) that characterize the population as genetically
susceptible to histamine [
54
]. Currently, there is already the possibility of performing a noninvasive
genetic analysis capable of identifying three of the SNPs associated with reduced DAO activity
(i.e., rs10156191, rs1049742 and rs1049793) from a sample of the oral mucosa, although evidence-based
studies on the diagnosis potential of this test are still needed. It is important to note that this test will
only reflect the existence of a genetic DAO deficiency.
The most studied, and possibly also the most controversial, is the determination of plasma DAO
activity. This analytical test consists of measuring the amount of histamine degraded in a blood sample
in a given time interval. Two types of commercial testing kits are currently available on the market,
one consisting of an ELISA-type immunoassay, and the other a radioimmunoassay using radioactively
Biomolecules 2020,10, 1181 13 of 26
labeled putrescine [
83
,
84
]. The evidence for the validity of blood DAO activity measurements for the
diagnosis of histamine intolerance is neither abundant nor conclusive. Some studies have proposed
that determining blood DAO activity may be helpful in identifying subjects with symptoms associated
with histamine intolerance [
63
,
83
,
84
]. In contrast, three studies did not find a significant relationship
between the clinical history of patients with typical symptoms of histamine intolerance and blood
DAO activity values, concluding that this technique cannot be recommended as a diagnostic tool in
routine clinical practice until studies have validated its eectiveness [
98
100
]. Moreover, the work
performed by Schnoor et al. also reported a high interassay variation in DAO activity values that
made the proper classification of histamine-intolerant subjects impossible [
100
]. This controversy is
described in a joint article published in 2017 by the German and Swiss allergology societies, which
emphasizes the need for more research before giving plasma DAO activity a definitive diagnostic value
for histamine intolerance [97].
A variant of the intradermal skin allergy test called the histamine 50-skin-prick test was also
proposed by Kofler et al. to diagnose histamine intolerance [
101
]. In this technique, the results were
read after 50 min (as opposed to the usual 20 min) and showed that, although the size of the wheal
did not dier between the histamine intolerant and control groups, the time course was significantly
dierent. Patients with symptoms of intolerance showed a delayed remission of the wheal induced by
cutaneous administration of histamine, signaling a reduced degradation ability. The same results were
obtained in a study recently published by Wagner et al., who re-evaluated this skin test as a diagnostic
tool of histamine intolerance, also observing a correlation between the delay in wheal disappearance
and a lower plasma DAO activity [102].
Both the determination of plasma DAO activity and the histamine 50-skin-prick test could be
suitable tests to identify a DAO deficiency from genetic or pharmacological origin, but they would not
be useful to determine a deficit secondary to certain intestinal diseases.
On the contrary, there are certain alternatives, such as the intestinal biopsy, the histamine
provocation test or the histamine metabolomics in urine, that could make it possible to diagnose
histamine intolerance due to DAO deficiency without excluding any of the possible etiological causes.
The measurement of intestinal DAO activity by a colon biopsy during endoscopic procedures
has been studied as a possible diagnostic marker. The few available studies have shown a reduced
intestinal DAO catabolic activity in patients with recurrent urticaria, food allergy and colon adenoma,
accompanied by an increase in histamine levels [
103
106
]. Although this test has interesting diagnostic
potential, more studies are needed to validate its clinical significance and its relationship with the
symptoms of histamine intolerance [
97
]. If proven, this diagnostic test would be very adequate since this
disorder originates from a reduced ability of the intestinal DAO enzyme to cope with dietary histamine.
Histamine challenge/provocation test has also been proposed by some authors as a diagnostic
tool for intolerance, which would, at the same time, establish the individual tolerance threshold.
This double-blind, placebo-controlled test involves oral administration of histamine and requires patient
medical supervision and hospitalization. In the study by Wöhrl et al., half of the healthy volunteers
developed symptoms after the administration of a solution containing 75 mg of histamine [
107
].
In contrast, the results of a multicenter study by Komericki et al. using the same oral dose of histamine
indicated the challenge test was unreliable for diagnosing histamine intolerance due to a lack of
intraindividual reproducibility of symptoms after two dierent provocation tests [
108
]. The application
of this procedure is still limited because of the risk of serious adverse side eects and the absence of a
standardized dose of histamine and properly established protocol [97].
Finally, in recent years, eorts have been made to identify a noninvasive marker to establish a
solid and clinically irrefutable diagnostic criterion for histamine intolerance due to DAO deficiency.
Currently, the application of metabolomics as a tool for the identification of biomarkers of histamine
metabolism in urine is also being challenged as a possible new diagnostic strategy [
11
]. The hypothesis
is that individuals with histamine intolerance could have a dierent excretion profile of histamine and
its metabolites in urine than normal individuals. For this purpose, Comas-Bast
é
et al. have recently
Biomolecules 2020,10, 1181 14 of 26
proposed a chromatographic approach that allows for determining in a fast and unequivocal manner
the urinary levels of histamine and its methylated metabolite, methylhistamine [
11
]. It is still necessary
to validate the potential diagnostic utility of this approach in patients with histamine intolerance,
as well as complementing the excretion profile with other histamine metabolites to obtain a more
accurate image of the possible alterations produced in this intolerance.
5.4. Treatment Approaches to Histamine Intolerance
Currently, the main strategy to avoid the symptoms of histamine intolerance is to follow
a low-histamine diet. Supplementation with exogenous DAO has recently been postulated as a
complementary treatment to enhance dietary histamine degradation in intolerant individuals who
have a deficiency of this enzyme in the intestine [109,110].
5.4.1. Low-Histamine Diet
A low-histamine or histamine-free diet has been proposed as the main strategy for the preventive
treatment of histamine intolerance [
10
,
54
,
82
,
111
]. Conceptually, these diets exclude a number of foods
that patients associate with the onset of symptoms, primarily those that may contain high levels of
histamine [
82
]. However, there is no a single dietary recommendation of a low-histamine diet. As it
may be seen in Table 3, there is no coincidence in all the foods excluded in the dierent low-histamine
diets found in the literature [10,87,91,112118].
Table 3.
Foods excluded in the dierent low-histamine diets found in the literature [
10
,
87
,
91
,
112
118
].
Foods Excluded by Low-Histamine Diets
<20% * 20–60% * >60% *
Milk Shellfish Cured and semicured cheese
Lentils Eggs Grated cheese
Chickpeas Fermented soy derivatives Oily fish
Soybeans Eggplant Canned and semipreserved oily fish
derivatives
Mushrooms Avocado Dry-fermented meat products
Banana Spinach
Kiwi Tomatoes
Pineapple Fermented cabbage
Plum Citrus
Nuts Strawberries
Chocolate Wine
Beer
* Percentage of low-histamine diets from the literature that exclude each foodstu.
Histamine is widely distributed in different food categories and in highly variable concentrations, as its
accumulation is influenced by multiple factors [
3
,
119
]. In fresh foods such as fish and meat, and in some
derived products, the presence of histamine is due to a lack of freshness or an inadequately hygienic quality
of raw materials and/or production processes [
31
]. For this reason, meat and fish can be consumed in the
framework of a low-histamine diet, as long as their freshness is ensured. In contrast, fermented products are
systematically excluded, due to a high probability of containing histamine [
31
]. Other foods such as spinach,
eggplant and tomatoes should also be avoided for the same reason. In general, all these abovementioned
foods are unanimously eliminated in most published low-histamine diets (Table 3).
On the other hand, there are certain foods that a priori do not contain histamine, but that patients
associate with the appearance of symptoms. For these foods, there is much more variability when it
comes to their exclusion from low-histamine diets (Table 3). The exclusion of foods could be based on
their content of other biogenic amines, such as putrescine and cadaverine, which act as competitive
substrates for DAO and may therefore inhibit intestinal degradation of histamine if present in significant
Biomolecules 2020,10, 1181 15 of 26
quantities [
1
,
82
]. Thus, the onset of symptoms after the consumption of citrus fruits, mushrooms,
soybeans, bananas and nuts may be due to high levels of other amines, specially putrescine [
82
].
These diets may also exclude certain foods free of histamine and with low enough concentrations of
other amines to justify their exclusion. This is the case, for example, for papayas, kiwis, strawberries,
pineapples and plums, which have been reported to trigger the release of endogenous histamine,
although the mechanism responsible has not yet been elucidated [8,13].
The eectiveness of a low-histamine diet has been demonstrated in clinical studies, which report
favorable results in terms of improvement or total remission of symptoms frequently associated with
histamine intolerance and DAO deficiency (Table 4). As shown in Table 4, over the past three decades,
various clinical studies have assessed the eect of a low-histamine diet on the evolution of various
symptoms, mainly dermatological, gastrointestinal and neurological, including cases with more than
one type. Although most studies have involved only a small group of patients (a mean of 38 per study,
with a minimum of 10 and maximum of 157), they report an ecacy rate for the diet ranging from
33% to 100%. Specifically, 10 of the 13 studies reviewed found an improvement in symptoms in more
than 50% of patients who followed the diet; two studies show success rates of less than 50% (33%
and 46%), and only one did not observe any beneficial eects (Table 4). Most of the studies involved
patients with dermatological symptoms, primarily chronic idiopathic urticaria, atopic dermatitis and
eczema. In this field, a recent systematic literature review included a total of 1668 patients with
chronic urticaria undergoing dierent exclusion diets, including low-histamine, pseudoallergen-free
(i.e., without preservatives and artificial colors present in processed foods or aromatic compounds
from certain natural products) and fish exclusion diets [
120
]. Overall, following any of the exclusion
diets resulted in the total or partial remission of symptoms in 4.9% and 37.5% of patients, respectively.
A low-histamine diet for an average of 3 weeks resulted in one of the highest remission rates. Despite
the promising results of a low-histamine diet for the treatment of dermatological conditions, scientific
societies of dermatology still consider this exclusion diet of unproven utility pending randomized,
double-blind, placebo-controlled clinical trials to confirm its eectiveness [121].
In general, the duration of the dietary treatment considered in the dierent clinical studies ranges
from 3 to 4 weeks, and no positive relationship could be established between a longer duration and
the success rate in symptom remission (Table 4). As may also be seen in this table, some studies have
also assessed the eect of diet on other variables, such as plasma histamine levels or plasma DAO
activity [
83
,
85
87
,
112
,
122
,
123
]. Regarding DAO activity, the studies published by Steinbrecher et al.,
Maintz et al., Mušiˇc et al. and Lackner et al. all point out an increase in plasma enzymatic activity in
more than 50% of patients after the dietary intervention, although no explanatory hypothesis has been
yet suggested [
83
,
85
,
86
,
123
]. In contrast, Guida et al., Wagner et al. and Son et al. reported no changes
in serum DAO activity [
87
,
112
,
122
]. The inconsistency of these data highlights the need to develop
more research in this specific field before conclusions can be drawn.
Table 4.
Clinical studies on the ecacy of a low-histamine diet for the treatment of symptoms of
histamine intolerance.
Design and Outcomes
of the Study
Number of Patients and
Symptoms Duration
Percentage of Patients with
Improvement in the Study
Outcomes
Reference
Prospective study with
evaluation of the
evolution of the
symptomatology
28 patients with chronic
headache and 17 with
other dermatological and
respiratory symptoms
4 weeks
68% reduction in chronic
headache and 82% reduction
in other symptoms
[124]
Prospective study with
evaluation of the
evolution of symptoms,
plasma histamine levels
and DAO activity
10 patients with chronic
idiopathic urticaria and 19
control individuals
3 weeks
100% reduction in
symptoms, 100% reduction
in plasma histamine and no
changes in DAO activity
[122]
Biomolecules 2020,10, 1181 16 of 26
Table 4. Cont.
Prospective study with
evaluation of the
evolution of symptoms,
plasma histamine levels
and DAO activity
35 patients with headache
and other symptoms
(urticaria, arrhythmia,
diarrhea and asthma)
4 weeks
77% reduction in symptoms,
73% increase in DAO
activity and no changes in
plasma histamine levels
[85]
Prospective study with
evaluation of the
evolution of symptoms
and DAO activity (in five
of the patients)
17 patients with DAO
deficiency, atopic eczema
and other symptoms
(headache, flushing and
gastrointestinal
symptoms)
2 weeks
100% reduction in symptoms
and 60% (three out of five)
increase in DAO activity
[86]
Prospective study with
evaluation of the
evolution of symptoms
and the use of
antihistamine drugs
13 patients with chronic
idiopathic urticaria and 35
control patients (without
diet)
4 weeks
Lack of improvement in
symptoms and no changes
in the use of antihistamines
[125]
Prospective study with
evaluation of the
evolution of the
symptomatology
36 patients with atopic
dermatitis and 19 control
individuals
2 weeks 33% reduction in symptoms [88]
Prospective study with
evaluation of the
evolution of the
symptomatology and
DAO activity
20 patients with DAO
deficiency and
dermatological,
gastrointestinal and
respiratory symptoms
6–12 months
100% reduction in
symptoms and 100%
increase in DAO activity
[83]
Retrospective study with
evaluation of the
evolution of the
symptomatology
16 pediatric patients with
diuse abdominal pain,
diarrhea, headache,
vomiting and rash
4 weeks
100% reduction of symptoms
[91]
Prospective study with
evaluation of the
evolution of the
symptomatology
16 pediatric patients with
chronic abdominal pain
and DAO deficiency
4 weeks 88% reduction of symptoms [92]
Retrospective study with
evaluation of the
evolution of the
symptomatology
157 patients with chronic
idiopathic urticaria 4 weeks 46% reduction of symptoms [126]
Prospective study with
evaluation of the
evolution of the
symptomatology and
DAO activity
56 patients with chronic
idiopathic urticaria and
gastrointestinal symptoms
3 weeks
75% reduction in symptoms
and no changes in DAO
activity
[87]
Prospective study with
evaluation of the
evolution of symptoms,
plasma histamine levels
and DAO activity
22 patients with chronic
idiopathic urticaria 4 weeks
100% reduction in
symptoms, 100% reduction
in plasma histamine levels
and no changes in DAO
activity
[112]
Retrospective study with
evaluation of the
evolution of the
symptomatology and
DAO activity
63 patients with
gastrointestinal symptoms 7–18 months
79% reduction in symptoms
and 52% increase in DAO
activity
[123]
5.4.2. Exogenous DAO Supplementation
Similar to the current treatment for lactose intolerance, the possibility of oral supplementation with
exogenous DAO has been proposed by several authors to facilitate dietary histamine degradation [
13
,
127
].
Improving intestinal DAO activity would allow a less restrictive diet, which could include foods with
a tolerable dose of histamine [
10
,
61
]. In this context, in the update of the ocial list of novel foods in
2017, the European Commission gave the green light to the marketing of a DAO supplement as food
supplement or as food for special medical purposes [
128
]. Specifically, European regulations authorize
Biomolecules 2020,10, 1181 17 of 26
the formulation of porcine kidney protein extract with an enteric coating to ensure its integrity during
its passage through the gastric environment [
128
]. In this specific regulation, the minimum DAO
enzymatic capacity required for the supplement is determined through a radio extraction assay (REA).
This technique, based on the radioactive labeling of putrescine and the scintillation counting of its
consumption, is advantageous in terms of rapidity and sensitivity, but it was mainly conceived to
be applicable to serum samples. Comas-Bast
é
et al. have recently developed a rapid and reliable
methodology through ultra-high performance liquid chromatography and fluorimetric detection
(UHPLC-FL) for the
in vitro
determination of DAO activity specifically for the analysis of unpurified
complex matrixes, such as porcine kidney extract and DAO supplements [
129
]. This methodological
approach is based in the direct determination of histamine degradation and overcomes certain
drawbacks in terms of matrix interferences and handling of radioactive materials.
Porcine kidneys are the main source of DAO enzyme, according to the literature. Several studies
have demonstrated the capacity of this product to degrade histamine and other biogenic amines
in vitro
[
57
,
129
133
]. A wide variability of the DAO capacity of porcine kidney extracts has been
reported (with values ranging from 0.1 to more than 100 mU/mg), depending on the purification grade
applied to the matrix and/or the amine compound used as the reaction substrate [
57
,
129
133
]. In fact,
many of these works sought the selective purification of the DAO enzyme to design biosensors for the
biorecognition of biogenic amines as indicators of freshness in foods [
134
]. More recently, two studies
have been published specifically focused in investigating the in vitro DAO activity of porcine kidney
protein extract expressly used as active ingredient to formulate food supplements for the preventive
treatment of histamine intolerance [
129
,
130
]. Comas-Bast
é
et al. studied the
in vitro
enzymatic activity
of 13 dierent production batches of porcine kidney protein extract used in the elaboration of food
supplements, reporting a low influence of the raw material (porcine kidney) on the DAO activity of the
extract, with a mean value of 0.23
±
0.01 mU/mg [
129
]. Later, Kettner et al. obtained a porcine kidney
crude extract with an
in vitro
DAO activity of 0.5
±
0.06 mU/mg, and described a 10-fold increase of
this enzymatic activity through the application of several consecutive purification steps [130].
Regarding the food supplement, divergent results have also been reported, since while certain
authors discard its enzymatic capacity, DAO activity values ranging from 0.04 to 0.20 mU/mg have
also been described for dierent commercial products available in the market [
129
,
130
]. Overall, these
works coincide in the need to identify alternative sources to porcine kidney DAO for exogenous
supplementation in histamine-intolerant individuals.
A higher catalytic capacity of DAO enzymes of plant origin in degrading certain amino substrates
has been described by some authors in comparison with those of animal origin [
129
,
135
137
].
Specifically, the germinated sprouts of certain edible legumes have been pointed out as interesting
sources of DAO enzyme. Germination is a physiological process that has been described as capable
of increasing the DAO enzymatic capacity of sprouts by up to 250 times compared to ungerminated
seeds [
61
,
138
]. The increased presence of DAO enzyme in legume sprouts could be associated with the
importance of hydrogen peroxide, a byproduct of the deamination reaction, in the cell wall structuring,
lignification and mobilization of seed reserves during germination [
139
142
]. In fact, it has been
demonstrated that the germination of legume seeds for a period of 6–8 days in darkness provides the
optimal environment to maximize the DAO activity of this plant-origin matrix [
61
,
138
,
143
]. From a
commercial point of view, having a plant source of this enzyme would expand the target of this
novel food for the vegetarian/vegan population, as well as those with religious restrictions on the
consumption of pork products. In addition, obtaining DAO enzyme from legumes would be a practice
in accordance with the current call for action of the Sustainable Development Goals.
Nowadays, only five published intervention studies (four from the last five years) have tested
the clinical ecacy of exogenous DAO supplementation in patients with symptoms of histamine
intolerance (Table 5). Although there is some variability, the available research points to the eectiveness
of DAO supplements in reducing the appearance and intensity of symptoms. However, it is dicult to
compare the dierent studies, since they dier in the design, the enzyme dosage, the intervention time
Biomolecules 2020,10, 1181 18 of 26
and the measurement of ecacy outcomes. Komericki et al., Manzotti et al. and Schnedl et al. assayed
the ecacy of DAO supplementation in patients with diverse symptoms associated with histamine
intolerance (gastrointestinal, cardiovascular, respiratory and dermatological and/or neurological
complaints) [
84
,
108
,
109
]. All three studies reported an important improvement in the intensity or
frequency of symptoms, although they involved a small study population (14, 28 and 39 patients)
and/or a reduced intervention time (from two to four weeks). Moreover, Schnedl et al. also evaluated
the changes in plasmatic DAO activity, reporting a slight increase in 61% of patients during the
intervention, which the authors linked to a possible improvement in the integrity of the intestinal
mucosa due to the supplementation [109].
Table 5.
Studies on the ecacy of DAO enzyme supplementation for the treatment of symptoms of
histamine intolerance.
Design Number of Patients and
Symptoms
Duration of DAO
Supplementation Ecacy Outcomes Reference
Randomized, double-blind,
placebo-controlled,
crossover provocation study
using histamine-containing
and histamine-free tea in
combination with DAO
capsules or placebo
39 patients with
histamine intolerance
(headache and
gastrointestinal and skin
complaints)
-
Statistically significant
reduction of
histamine-associated
symptoms compared to
placebo
[108]
Retrospective study with
evaluation of the clinical
response to DAO
supplementation
14 patients with
diagnosis of histamine
intolerance (headache
and gastrointestinal,
cardiovascular,
respiratory and skin
complaints)
2 weeks
Reduction of at least one of
the reported symptoms in
93% of patients
[84]
Double-blind,
placebo-controlled,
crossover study
20 patients with chronic
spontaneous urticaria 1 month
Significant reduction of
7-Day Urticaria Activity
Score (UAS-7) and slight
significant reduction of
daily antihistamine dose
[144]
Randomized, double-blind,
placebo-controlled clinical
trial
100 patients with
episodic migraine and
serum DAO deficit
1 month
Significant decrease in the
duration of migraine
attacks and decrease in
triptans intake
[110]
Open-label interventional
pilot study
28 patients with
histamine intolerance
(gastrointestinal,
cardiovascular,
respiratory and skin
complaints) and reduced
serum DAO values
1 month of
intervention and 1
month of follow-up
Significant improvement
in frequency and intensity
of all symptoms.
61% of patients showed
slightly increase in serum
DAO values.
During the follow-up
period (without DAO
supplementation), the
symptoms sum scores
increased and DAO levels
decreased.
[109]
The clinical trials developed by Yacoub et al. and Izquierdo-Casas et al. were focused on
a single disorder related to histamine intolerance (chronic spontaneous urticaria and migraine,
respectively) [
110
,
144
]. Yacoub et al. considered 20 patients with chronic spontaneous urticaria who
showed a significant reduction in the severity of the complaint according to the Urticaria Activity
Score (UAS-7) [
144
]. Regarding migraines, the randomized double-blind clinical trial conducted by
Izquierdo et al. considered a larger number of patients (100 patients) and obtained a statistically
significant decrease in the duration of pain attacks with no recorded adverse side eects [
110
]. However,
Biomolecules 2020,10, 1181 19 of 26
the authors did not find statistical dierences when considering other research outputs, such as the
frequency and intensity of pain.
Overall, despite the promising results, more ambitious clinical studies with a rigorous experimental
design, longer treatment periods and properly sized samples are essential to establish the clinical
ecacy of this treatment.
6. Conclusions and Perspectives
Histamine intolerance is currently a clinical entity of increasing interest, which can appear due
to the intake of histamine from foods, mainly caused by a deficiency of the DAO enzyme at the
intestinal level. Novel knowledge and studies of histamine intolerance have helped clarify many of
the uncertainties that were classically associated with histamine intoxication. Etiologically, various
SNPs have been identified in the gene encoding the DAO enzyme related to lower enzyme activity.
Moreover, certain inflammatory bowel diseases that limit enzyme secretion or some DAO-inhibiting
drugs have also been identified as possible causes of DAO deficiency. This intolerance manifests
through a plethora of nonspecific gastrointestinal and extraintestinal symptoms.
The diagnosis of histamine intolerance is usually performed after ruling out allergic symptoms
and by the presence of at least two clinical manifestations and their improvement or remission
after following a low-histamine diet. Various complementary tests are currently being proposed to
improve the diagnosis of this intolerance based, among others, on determining the DAO activity
in blood or intestinal biopsy samples or on identifying genetic or metabolic urinary markers by
noninvasive techniques.
The clinical management is carried out mainly through the follow-up of a low-histamine diet,
although there is no consensus on the list of foods to be excluded. Even so, there are dierent clinical
studies that show the ecacy of this dietary intervention in improving the quality of life of patients
with symptoms of histamine intolerance. Oral supplementation with exogenous DAO enzyme from
porcine kidney is also being used to enhance the intestinal capacity to degrade dietary histamine.
Although few works have assayed the clinical ecacy of this preventive treatment, promising results
have been obtained so far. Research is currently also being made to identify new sources of DAO
enzyme, especially of plant origin, due to its higher catalytic capacity and other potential productive
and commercial advantages.
In this context, it is necessary to keep promoting the multidisciplinary study of this disorder,
both from basic (i.e., analytical chemistry, food science, physiology and biochemistry) and clinically
applied research, meant to increase the scientific base and the currently available diagnostic and
treatment strategies for histamine intolerance.
Funding: This research received no external funding.
Acknowledgments:
S
ò
nia S
á
nchez-P
é
rez is a recipient of a doctoral fellowship from the University of Barcelona
(APIF2018).
Conflicts of Interest: The authors declare no conflict of interest.
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... Histamine intolerance (HIT) has become an extremely important medical problem in regard to the practice of physicians in numerous specialties. Interest in the problem has increased significantly in recent years, as reflected by the numerous scientific publications on the matter; however, physicians continue to face challenges related to the absence of standardized diagnostic protocols, as well as therapeutic and management strategies, for use in patients with the suspicion or diagnosis of this condition [1]. ...
... In 1947, Legroux et al. described the onset of symptoms of mass poisoning following the consumption of tuna meat, which was linked to significantly elevated histamine concentrations in the flesh of these fishes [5]. Histamine poisoning is associated with acute ingestion of an excessive dose of histamine (>500 mg) that is greater than a healthy individual's ability to break it down, although cases of poisoning symptoms presenting after the ingestion of 100 mg and severe poisoning after the ingestion of 1000 mg have also been reported [1][2][3]. Histamine poisoning most often occurs after the consumption of improperly stored fish from the mackerel family (Scombridae), such as mackerel or tuna. The meat from this species of fish is naturally rich in free L-histidine [6]. ...
... Since histamine poisoning can also be caused by other foods that are high in histamine, including cheeses, the World Health Organization (WHO) has recommended the use of the more precise term, histamine intoxication [7]. In the 1980s, the first cases of adverse reactions following the ingestion of even small amounts of histamine, considered harmless to healthy people, were observed and the phenomenon was referred to as histamine hypersensitivity (intolerance) [1,8]. ...
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Background/Objectives: Histamine intolerance is becoming a critical medical problem across numerous clinical specialties, due to the absence of a standardized diagnostic and therapeutic strategy to manage patients with a suspicion of or diagnosis of this condition. Histamine intolerance is a type of non-immune food hypersensitivity, characterized by heterogenous etiologies and a very broad range of symptoms. The condition is the result of an imbalance between the amount of histamine accumulated within the body and the body’s systemic ability to degrade it. In regard to the diagnostics of histamine intolerance, the need to preliminarily exclude other potential conditions associated with increased histamine levels in the blood has been highlighted. The co-occurrence of allergies and histamine intolerance is not uncommon, and the similarity of the clinical manifestations can lead to diagnostic, as well as therapeutic, difficulties. This paper details the diagnostic and clinical workflow for a patient with histamine intolerance and polyvalent allergy comorbidity, with the aim being to help outline a protocol that may be helpful to clinicians managing patients with histamine intolerance. Case Presentation: This article presents the case of a 30-year-old patient with a polyvalent allergy and multimorbidity (allergic rhinitis, asthma, a food allergy, and eosinophilic esophagitis), with comorbid histamine intolerance. Due to the violent and severe symptoms, including facial erythema, urticaria, pruritus, abdominal pain, and tachycardia, experienced after meals, the patient received intramuscular epinephrine injections three times a week. The diagnostic protocol and the course of therapeutic management are presented. Conclusions: The diagnosis of histamine intolerance is difficult due to the high variability and heterogeneity of clinical symptoms in individual patients. Many studies on the issue recommend ruling out an allergic background in terms of the complaint. However, the possibility of the symptoms of an IgE-dependent allergy overlapping with those of histamine intolerance should be taken into account in every case. This is particularly important in patients presenting with an atypical and severe course of allergic diseases. The clinical case presented herein may be helpful for the daily practice of allergologists and physicians with other specialties, as an example of multimorbidity with both allergic and non-allergic backgrounds.
... It is worth noting that various biogenic amines, combined with nitrogen, can produce carcinogens such as nitrite and enhance the poisonousness of tyramine and histamine [30]. For fish and other aquatic products, such as tuna, sardines, mackerel, salmon, etc., bacteria-rich muscle histidine in fish can multiply under appropriate temperatures, and the muscle histidine can be converted into histamine [31]. ...
... Histamine poisoning, also known as scombroid fish poisoning, has the strongest toxic effect [31]. The main symptoms of poisoning include facial, neck, and upper arm flushing, urticaria, gastrointestinal symptoms, headache, and difficulty swallowing [32]. ...
Article
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Aquatic products contain a large amount of protein, which can promote the production of a variety of biogenic amines through the function of microorganisms. Biogenic amines are a broad category of organic substances that contain nitrogen and have a low molecular weight. The presence of biogenic amines can cause the deterioration and excessive accumulation of aquatic products, which can cause damage to human health. Therefore, it is essential to discover a fast, convenient, and easy to operate method for the determination of biogenic amines in aquatic products. In this paper, the function and research significance of biogenic amines are analyzed from the aspects of their formation, toxicological properties, harm to the human body, and control methods. Several common direct detection techniques and indirect techniques for biogenic amines are briefly introduced especially sensors. This review provides references for efficient detection in the future.
... Histamine intolerance or enteral histaminosis or sensitivity to dietary histamine is a disorder that occurs due to reduced histamine degradation capacity in the intestine caused by impaired Diamine Oxidase (DAO) activity; the consequent histamine accumulation in plasma seems to be related to many adverse effects, included IBS-like gastrointestinal ones. The influencing factors in histamine intolerance are summarized in Figure 3 [41]. ...
... Histamine intolerance or enteral histaminosis or sensitivity to dietary histamine is a disorder that occurs due to reduced histamine degradation capacity in the intestine caused by impaired Diamine Oxidase (DAO) activity; the consequent histamine accumulation in plasma seems to be related to many adverse effects, included IBS-like gastrointestinal ones. The influencing factors in histamine intolerance are summarized in Figure 3 [41]. Although there are still no certain data, histamine intolerance's estimated prevalence is 1-3%, a percentage that may even increase with the spread of knowledge and diagnostic methods. ...
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Nowadays, the gluten-free diet (GFD) has become much more than the dietary treatment for celiac disease. Due to its presumed beneficial effects even in non-celiac subjects, it has become a new fashion statement and it is promoted by some healthcare professionals, social media and marketing strategists. On the other hand, regardless of a proper medical indication, a GFD may present side effects, such as poor palatability, high costs and socio-psychological adversities. Moreover, it can be an obstacle to correct clinical practice and may induce nutritional deficiency due to a low-quality diet. In addition, a GFD can trigger or exacerbate many irritable bowel syndrome (IBS)-like disorders in predisposed subjects: reactivity to dietary nickel, the increased consumption of FODMAP-rich foods and histamine intolerance seem to frequently play a relevant role. The possible intersections between high-risk foods in these categories of patients, as well as the possible overlaps among IBS-like disorders during GFD, are described. In conclusion, it is advisable to undergo a careful clinical evaluation by a gastroenterologist and a nutritionist (in some cases, also a psychotherapist) before starting and during a GFD, because both benefits and risks are possible. It is also important to take into account IBS-like disorders that can be exacerbated by a GFD and that are still underestimated today.
... DAO inhibits the transepithelial permeation of exogeneous histamine from ingested foods, and impaired DAO activity results in an increase in histamine uptake with the corresponding elevation of histamine plasma concentrations [4,5]. Histamine excess may cause a wide range of nonspecific gastrointestinal and extraintestinal symptoms due to the global distribution of histamine receptors in many tissues and organs [5][6][7]. Moreover, DAO enzyme deficiency seems to be the main underlying mechanism of histamine intolerance, which is clinically manifested by a complex combination of digestive, neurological, dermatological, respiratory, and cardiovascular complaints [5,8]. ...
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Background/Objectives: The prevalence of the diamine oxidase (DAO) enzyme deficiency of a genetic origin has not been previously assessed. A prospective population-based study was conducted in a sample of 200 healthy newborns aimed to determine the prevalence of DAO enzyme deficiency caused by single nucleotide polymorphism (SNP) variants of the AOC1 gene. Methods: Genotyping was performed in oral mucosa samples collected around 2 days after birth. The four more frequent SNPs, c.47C>T (rs10156191), c.995C>T (rs1049742), c.1990C>G (rs10449793), and c.691G>T (rs2052129), were analyzed. Results: DAO deficiency was present in 132 newborns, with a prevalence of 66% (95% confidence interval [CI] 59–73%). The rs10449793 variant showed a prevalence of 46%, followed by rs10156191 with a prevalence of 42.5%, and rs2052129 with a prevalence of 39.5%. The variant rs1049742 showed the lowest prevalence (9.5%). The frequency of one, two, three, or four SNPs was 23%, 23.5%, 10.5%, and 9%, respectively. In all fours SNP variants, heterozygous carriers were more frequent than homozygous carriers (19% homozygosity). Differences in the prevalence of DAO deficiency between males (68%, 66/96) and females (63.4%, 66/104) were not found (p = 0.885). The prevalence in Caucasian newborns was 66.5% (123/185), as compared with 60% (9/15) in Latin Americans (p = 0.821). Conclusions: This study carried out in healthy newborns indicates that there is a high prevalence (66%) of DAO deficiency of a genetic origin in the general population.
... Furthermore, the exclusion of non-low-histamine foods in some HIT diets is unclear but may be due to overlap with MCAS. Additionally, the signs of HIT vary depending on the specific food matrix consumed [27,28]. ...
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Background/Objectives: Limited research has explored histamine intolerance from the perspective of primary caregivers. Our objective was to develop a practical symptom profile from the standpoint of general practice. We also aimed to gather data on the frequency and timing of disease progression and to establish a staging system. Methods: This study utilized a nonrandomized, quasi-experimental design. An in-depth interview was conducted with 217 patients involving 120 questions. To evaluate associations between food intake and symptoms, we recommended either an exclusion diet or a low-histamine diet. A follow-up questionnaire was subsequently administered. We also analyzed 3831 doctor–patient meetings involving upper respiratory symptoms. Results: Symptoms in 77 patients were associated with histamine-rich meals. The most characteristic symptoms included respiratory symptoms (95%), bloating (94%), headache (91%), fatigue (83%), postprandial drowsiness (81%), skin symptoms (81%), diarrhea/loose stool (77%), psychological symptoms (77%), dyspepsia (69%), and muscle/eyelid twitching (61%). Patients with suspected histamine intolerance visited primary care three times more often with upper respiratory symptoms than those without suspected histamine intolerance. The symptom spectrum of histamine intolerance involves multiple organ systems and occurs in distinct, repeating patterns. Symptoms can be described by their duration, sequence, and severity level, which is the key focus of this research, including visual representations. In its most severe stages, histamine intolerance may potentially involve mast cell activation. A personalized diet is associated with a gradual reduction in both the intensity and frequency of symptoms. Conclusions: The spectrum of histamine intolerance can be characterized by specific symptom patterns with defined frequencies, timelines, and symptom stages.
... In addition to following a low-histamine diet, current strategies to prevent histaminerelated symptoms include enhancing intestinal histamine degradation through dietary supplementation with gastrointestinal tablets containing exogenous DAO [7]. These commercial DAO supplements are mainly formulated using porcine kidney protein extract, a DAO-containing active ingredient approved both as a food supplement and as food for special medical purposes by the European Commission in 2017 [8,9]. ...
Article
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Edible legume sprouts have been proposed as a promising plant-based source of the enzyme diamine oxidase (DAO), which plays a key role in degrading histamine at an intestinal level and preventing the development of histamine intolerance symptoms. However, the temperature and humidity conditions required for seed germination can also favor the rapid growth of yeast and mold, potentially compromising sprout yield and quality. The aim of this study was to evaluate the influence of different seed disinfection treatments on both the germination rate and DAO enzymatic activity in sprouts of four Leguminosae species. Seed disinfection with 70% ethanol for either 5 or 15 min slightly increased the germination rates of chickpea and soybean sprouts without affecting DAO activity, regardless of treatment duration. However, in lentil and green pea sprouts, ethanol disinfection caused a statistically significant reduction in histamine-degrading capacity. In contrast, treating seeds with sodium hypochlorite for 15 min increased germination rates by up to 14% and preserved DAO activity in all legume sprouts tested. These results indicate that incorporating a seed disinfection step during legume sprouting may affect both the DAO enzymatic activity and germination rate.
... Besides being a source of significant sensory alterations, these amines, such as cadaverine and putrescine, which cause rot-like odours and unpleasant flavours (Leroi & Joffraud, 2011), are also cytotoxic compounds (del Rio et al., 2019). Similarly, high concentrations of the biogenic amine histidine (also known as scombrotoxin) can cause serious allergic reactions and food poisoning (Comas-Basté et al., 2020). Therefore, by inhibiting the growth of strains of the order Enterobacterales, the red wine vinegar solution and immersion treatment tested appear to provide a product with a potentially longer shelf life and improved safety for the consumer. ...
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Seafood is an essential component of a balanced and healthy diet, which increases its demand. However, its biological composition and high moisture content make these products extremely perishable. To prevent spoilage, and the consequent food waste and financial expenses throughout the seafood supply chain, new technologies have been successfully developed to inhibit bacterial growth, the main cause of seafood spoilage. This work aimed to test a shelf life extension technique for seafood skewers whilst maintaining an all-natural label using a financially feasible red wine vinegar treatment applied by immersion or pulverisation. Bacterial growth was monitored by classical methods and by 16S rRNA gene amplicon sequencing during the 5 days of storage. Immersion of samples in a vinegar-based solution effectively reduced Pseudomonas and Enterobacterales counts (by 2 log cfu/g), immediately after application and throughout storage. The overall structure and diversity of the bacterial community were analysed, and a strong reduction in bacterial diversity and impact on bacterial composition was observed immediately after immersion in the red wine vinegar solution. In untreated samples, Pseudomonadota (especially the Gammaproteobacteria class) was the principal phylum, whereas the microbiota of the treated samples was dominated by Bacillota (mainly the Bacilli class). Sensory analysis revealed a mild vinegar or vinaigrette flavour in treated samples; however, these characteristics were not unpleasant. Although applying a vinegar-based solution by immersion promoted a significant reduction in the growth of spoilage bacteria during the first days of storage, further tests are required to confirm the shelf life extension.
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Biogenic amines (BAs) are low-molecular-mass organic bases that occur in plant- and animal-derived products. BAs in food can occur by free amino acid enzymatic decarboxylation and other metabolic processes. Usually, in the human body, amines contained in foods are quickly detoxified by enzymes such as amine oxidases or by conjugation; however, in allergic individuals or if monoamine oxidase inhibitors are applied, the detoxification process is disturbed and BAs accumulate in the body. Knowing the concentration of BAs is essential because they can affect human health and also because they can be used as freshness indicators to estimate the degree of food spoilage.
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Histamine exists in a multitude of foods and displays an emerging role within food intolerances. Our aim was to identify the activity of porcine diamine oxidase (DAO) required for the in vitro degradation of histamine amounts that are found in typical meals containing histamine (75 mg, equaled 150 mg/L). Furthermore, we investigated an actual dietary supplement that is commercially available for histamine intolerant individuals for its histamine reduction capability. Kinetic investigations of porcine DAO showed a substrate inhibition by histamine concentrations greater than 56 mg/L (0.5 mM). The stability of free porcine DAO was tested in a fed state simulated intestinal fluid and exhibited a half‐life period of around 19 min. A total of 50 nanokatal (nkat) free porcine DAO, which equaled the amount of enzyme isolated from around 100 g pig kidney, were necessary for the in vitro reduction of around 90% of the histamine. The dietary supplement that contains a pig kidney extract did not show DAO activity. Instead, the used histamine (0.75 mg) was apparently reduced due to the adsorption of histamine onto a capsule component by 18.9 ± 2.3% within 5 hr. Although the capsule preparation retained its overall structure and shape for at least 90 min in simulated gastric fluid, the apparent histamine reduction was significantly reduced to 12.1 ± 2.3% (P ≤ 0.05). In conclusion, an alternative to the pig kidney DAO or an improved capsule preparation is needed to ensure an adequate supplementation for histamine‐intolerant humans. Practical Application Histamine intolerance is an emerging issue in our society and the intolerance‐related physiological symptoms are currently not reliably treatable due to a lack of scientific investigation. A commercially available dietary supplement for histamine intolerance does not fulfil the requirements for a satisfactory histamine reduction in intolerant humans. The activity of the histamine degrading enzyme diamine oxidase, required for a satisfactory histamine degradation, is by far higher than the theoretical amount apparently given in the dietary supplement. With this knowledge, it is obvious that improved food supplements must be developed to help histamine intolerant humans.
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Food intolerances are estimated to affect up to 20% of the population but complete understanding of diagnosis and management is complicated, given presentation and non-immunological mechanisms associated vary greatly. This review aims to provide a scientific update on common food intolerances resulting in gastrointestinal and/or extra-intestinal symptoms. FODMAP sensitivity has strong evidence supporting its mechanisms of increased osmotic activity and fermentation with the resulting distention leading to symptoms in those with visceral hypersensitivity. For many of the other food intolerances reviewed including non-coeliac gluten/wheat sensitivity, food additives and bioactive food chemicals, the findings show that there is a shortage of reproducible well-designed double-blind, placebo-controlled studies, making understanding of the mechanisms, diagnosis and management difficult. Enzyme deficiencies have been proposed to result in other food sensitivities including low amine oxidase activity resulting in histamine intolerance and sucrase-isomaltase deficiency resulting in reduced tolerance to sugars and starch. Lack of reliable diagnostic biomarkers for all food intolerances result in an inability to target specific foods in the individual. As such, a trial-and-error approach is used, whereby suspected food constituents are reduced for a short-period and then re-challenged to assess response. Future studies should aim to identify biomarkers to predict response to dietary therapies.