The intake of food may be an initiator of adverse reactions. We are referring to any kind of abnormal reaction related to the intake of foods. Adverse food reactions are nowadays rather accepted in practice but are however less frequently objectively examined [
1]. In addition to specific and well-differentiated disorders, allergic reactions and food aversions, we also class food intolerance among them. Distinguishing food intolerance from an allergic reaction to food is possible on the basis of key pathophysiological differences through the use of relevant diagnostic approaches. Food allergy is an inadequate response of the immune system to an antigen (in the majority of cases of a protein nature) ingested in food, that is accompanied by IgE or non-IgE (cellular) immunological mechanisms. Its cumulative prevalence is 3–6%, appearing much more frequently in children [
2]. Testing for foods IgG or IgA antibodies is not of fundamental clinical importance [
3,
4]. Levels of these antibodies may rather reflect an intestinal permeability disorder regardless of its origin, which is often post-infectious [
5]. One specific form of an adverse food reaction with an immunopathological feature is celiac disease, in which genetic disposition and epigenetic influences lead to adverse immunity reactions to gluten.
Food intolerance is an abnormal non-immunological response of the organism to the ingestion of food or its components in a dosage normally tolerated [
6]. It is at the same time a simplified term for non-allergic food hypersensitivity according to the World Health Organization (WHO) [
7]. Food hypersensitivity belongs among the most frequently occurring undesirable reactions to food. It affects from 15–20% of the population and can be the result of the pharmacological effects of food ingredients, non-celiac gluten sensitivity or malfunction of enzyme(s) or transport [
8].
Despite the fact that food intolerance is spread throughout the world, its diagnosing is difficult and demanding. For example, in patients with suspected histamine intolerance (HIT) it is necessary to carefully consider other possible reasons for the manifestations of symptoms (
Table 1) [
1]. Food intolerance (and especially HIT) requires a comprehensive understanding of the symptoms, especially their diversity, severity and time of onset [
6].
In this review, we provide a critical overview on possible benefits of published diagnostic approaches. We present the current knowledge of the therapeutic options and suggest the management of HIT accordingly. Another strength of this review lies in its comprehensiveness of tables summarizing data of clinical importance.
1.1. Histamine Intolerance (HIT)
HIT is the term for that type of food intolerance which includes a set of undesirable reactions as a result of accumulated or ingested histamine. In the German guideline from 2017, German and Swiss specialists prefer the term “
adverse reactions to ingested histamine” [
1]. In older publications, this type of intolerance is designated by the expressions
pseudoallergy,
enteral histaminosis or
histamine sensitivity. HIT is defined as a condition caused by an imbalance between the histamine released from food and the ability of the organism to degrade such an amount. It is accompanied by decreased activity of the DAO enzyme, leading to an increased concentration of histamine in plasma and the emergence of adverse reactions. In some publications, the state of decreased activity of DAO is referred to as a DAO deficiency. DAO deficiency predisposes a certain subgroup of the population to HIT. It can be of genetic, pathologic or pharmacological origin [
9].
It is necessary to distinguish HIT from histamine intoxication designated as
scrombroid syndrome,
scombroidosis or
histamine poisoning. The term originates from the name of the mackerel fish family (
Scombridae), after the consumption of which the intoxication was most often observed. The
Scombridae family includes tuna, herring and mackerel. Histamine poisoning is considered worldwide as one of the most frequent intoxications caused by the consuming of fish (Dalgaard, 2008 in [
10]). According to Colombo et al., from 103 analysed samples which caused histamine poisoning, 101 showed fish or seafood sources, and only two contained cheese [
10]. Manifestations of histamine intoxication may include rash, abdominal pain, vomiting, diarrhoea and shortness of breath, and the intoxication may also have a fatal outcome [
11].
The term HIT is used in a similar manner as the concept of lactose intolerance (which occurs due to a lack of the lactase enzyme), since it is presumed that the HIT symptoms are related to a lack or diminished activity of the enzyme DAO. Ingested exogenous histamine is distributed into the blood stream and may trigger symptoms in the susceptible population. It should be stated that with HIT, the amount of histamine taken in is much lower than with histamine poisoning. HIT manifestations also have a milder course in comparison with intoxication [
10].
With intolerances, gender-specific variations generally apply; women are affected with intolerances more frequently than men, although this distinction is not satisfactorily explained [
12]. Increased sensitivity to the intake of histamine was observed in women in the premenstrual phase [
13]. Serum diamine oxidase (DAO) levels in premenopausal women appear to be associated with the menstrual cycle, with higher DAO activity measured during the luteal phase compared to the follicular phase [
14]. Painful menstruation may be associated with increased sensitivity to histamine. Administration of H
1 antihistamines on the first day of menstruation has had a preventive effect on dysmenorrhea. High levels of histamine metabolites in urine during the ovulatory phase could be related to the effect of oestrogens (especially oestradiol) [
15].
Manifestations of HIT
One of the reasons why the adverse reactions caused by the intake of histamine cannot be clearly defined and outlined, as against other sicknesses, is their heterogeneity. Due to the fact that histamine enters into the circulation and that histamine receptors occur ubiquitously in the human body, a typical clinical picture cannot be strictly defined. The adverse manifestations related to the intake of histamine are usually complex and may affect different organ systems. Paradoxically, if the set of manifestations appears in various ways, unexpectedly and randomly, and at the same time following the ingestion of food, the symptoms may have their origin in histamine intake.
As typical signs, we can observe skin manifestations—for example erythema in the facial area (flushing), pruritus, urticarial rash on the body. Gastrointestinal symptoms include diarrhoea (±vomiting) but also constipation and abdominal pain. Manifestations in the cardiovascular system, such as low blood pressure (counter-regulatory hypertension may subsequently occur) and tachycardia are less frequent [
1], as are manifestations in the nervous and respiratory systems (
Figure 1) [
9].
The problem with a “diagnosis” of HIT is precisely the inconstancy and variety of the manifestations in the same individual following similar stimuli. In cross-over placebo-controlled trials in which symptoms were assessed, the subjects reacted randomly to the histamine provocation test. Although the total score of symptoms when histamine was administered was significantly higher as compared to the placebo, with many individuals no relationship between the ingestion of the histamine and the individual symptoms could be established [
16].
New findings have been recorded just recently. A 45-year-old woman who experienced Nissen’s fundoplication for long-lasting laryngopharyngeal reflux developed episodes of throat clearing and coughing. Laryngopharyngeal reflux indicates the return flow of gastric contents to the laryngopharynx and upper aerodigestive space. It is a clinical unit different from the gastroesophageal reflux disease. In this case, consultations with nutrition specialists led to considerations of HIT. A low-histamine diet led to a significant improvement in the patient’s symptoms. For patients who do not respond according to expectations to typical laryngopharyngeal reflux treatment, a potential link to HIT should be taken into consideration [
17], with a 3-month diet treatment prior to a possible operation.
In another study, 30 laryngopharyngeal reflux patients with chronic coughs underwent a histamine provocation test. Using a visual analogue scale, videolaryngostroboscopy findings and voice and throat symptoms were assessed directly before and after the exposure test. Moreover, the correlation between the relative changes in spirometry values in relation to changes in vocal fold oedema was also evaluated, along with redness and changes in the voice and throat symptoms reported by the patients during the histamine provocation test. The relative changes in inspiratory and expiratory air flow and voice and throat symptoms during the histamine challenge test correlated. Histamine induced oedema of the vocal folds, visible by videolaryngostroboscopic imaging, did not significantly influence spirometric air flow values [
18].
1.2. Histamine
Histamine is a neuro-immuno-endocrine system mediator. In the human organism it influences the whole spectrum of physiologic functions of various tissues and cells, including immunity. From a chemical perspective, it is a ubiquitously occurring biogenic amine. In the organism, its synthesis is ensured by decarboxylation of the amino acid L-histidine by the L-histidine decarboxylase enzyme. In the human organism, histamine is primarily stored in the mast cells and basophils, but its presence has also been found in the enterochromaffin cells [
19] and in the histaminergic neurons [
20]. Histamine acts in the organism as an agonist of histamine H
1, H
2, H
3 and H
4 receptors. H
1 and H
2 receptors appear ubiquitously, with H
2 mostly present in the digestive tract (stomach, duodenum, small intestine). The H
3 receptors are abundant in the nervous system. The H
4 receptors are present in certain tissues (skin, tonsils), but in a small amount [
21]. Among other processes, histamine mediates inflammatory responses, vasodilation, gastric acid production in enterochromaffin cells, congestion and bronchospasm, and secretion in the respiratory system. Its pleiotropic effect was found in the nervous system, where it acts as a neuromediator and a neurohormone, influencing e.g., thermoregulation, alertness, appetite and cognitive and behavioural functions [
22]. The microbiome can also be a source of histamine in the macroorganism [
9]. Its production has been described in some species (see the Microbiome and HIT section). Food is the main exogenous source of histamine [
23].
Metabolism of Histamine
The quantity of endogenous histamine is controlled on a genetic level. In genes encoding the enzymes responsible for the synthesis and degradation of histamine, similarly as in histamine receptor-encoding genes, genetic polymorphisms have been identified [
21]. Genetic polymorphisms for histamine receptors and for DAO are most likely associated with several specific symptoms and their combinations [
24]. In certain polymorphisms of the gene encoding DAO (and similarly, the H
3 receptor), diminished activity of this enzyme has been reported, which increases the risk of migraines. Reduced DAO activity however has also been recorded in healthy individuals. In addition to genetic predisposition, several factors (e.g., variability of histamine content in food etc.) appear to be responsible for the manifestation of symptoms; hence the functional and clinical significance of genetic polymorphisms remains elusive [
21,
24].
The half-life of histamine in plasma is relatively short, a few minutes [
25]. Histamine is metabolized in several pathways in the organism. As clinically most significant is considered enzymatic degradation mediated by the DAO enzyme, with a second pathway represented by the histamine-N-methyl transferase enzyme (HNMT) [
1].
The DAO enzyme is also identified in the literature according to the gene that encodes it, AOC1 Amine Oxidase Copper Containing 1 [
26], formerly known as histaminase. The DAO molecule contains copper and is the essential enzyme responsible for the degradation of histamine from the extracellular space [
27]. The product of oxidative deamination of histamine is imidazole-4-acetaldehyde (
Figure 2).
DAO is found in the epithelial cells of the (small) intestine, the placenta, the kidneys, the thymus and seminal plasma [
28]. The physiological function of the DAO enzyme includes regulation of the inflammation processes, proliferation, allergic response and ischemia [
29]. During digestion, the DAO enzyme is continuously synthesized in the mucosa of the small intestine. It is stored in vesicular structures on the basolateral membrane of the enterocytes and acts as a metabolic barrier against exogenous diamines, including histamine [
30]. The accumulation of ingested histamine and its subsequent penetration into the circulation as a result of reduced or slowed catabolism by the DAO enzyme at the level of the small intestinal epithelium is considered as a possible reason for the HIT syndrome [
6]. The activity and plasmatic level of the DAO may be dependent on the genetic variability of the relevant genes (AOC1 on the 7th chromosome) [
21], or on the physiological state of the organism [
13]. During pregnancy, greatly increased concentrations (up to 150-fold) of serum and plasma DAO were measured [
27]—the placenta is a producer of this enzyme. This is regarded as the reason why during pregnancy, in women suffering from HIT manifestations, a lessening or complete regression of HIT symptoms is observed. DAO activity or histamine release may be influenced by a number of commonly used medicaments, such as N-acetylcysteine, ambroxol, verapamil, propafenone, amiloride, cefuroxime, clavulanic acid or non-steroidal anti-inflammatory drugs, metamizole, as well as radiological contrast agents (
Figure 3) [
13,
31]. We summarize an extended list of substances possibly interfering with the activity of DAO in
Table 2.
HNMT is a cytosolic enzyme whose role is to regulate intracellular histamine levels [
6]. The inactivation of intracellular histamine is mediated by the methylation of the imidazole nucleus; this metabolite is subsequently oxidized [
13]. Although it is also found in the gastrointestinal tract, it is unlikely to play a major role in the degradation of exogenous histamine or histamine produced by the gut microbiome [
9].
1.3. Biogenic Amines in Food
Biogenic amines may be present in greater or lesser amounts in any food. Processing and storage are generally inevitable in cases where the ingredients spoil quickly and/or are rich in proteins. Storage raises the risk of accumulation of biogenic amines. It seems that their accumulation is totally dependent on the microorganisms that create histamine during food storage (especially in case of foods with a high L-histidine content) [
35]. Overall, the fresher the food, the lower the probability of biogenic amine formation.
Amines are classified as monoamines, diamines and polyamines, depending on how many amine groups they contain. Among the most important biogenic amines found in food are monoamine tyramine, diamines histamine, putrescine and cadaverine, as well as the polyamines spermine and spermidine [
36].
In the context of HIT syndrome, of clinical significance is tyramine, which may be present in excessive amounts in certain types of ripening cheeses. In sensitive people, this is related to increased blood pressure and the consequent occurrence of migraine pains [
37].
Biogenic amines may contribute to histamine toxicity by saturating enzymes responsible for the degradation of histamine in the mucosa (DAO, HNMT). The diamines putrescine and cadaverine are considered to be the amines with the greatest influence on the metabolism of histamine. This is due to the fact that the DAO enzyme breaks down them preferentially [
13,
23,
36]. Foods with a high biogenic amine content are generally considered as risky and should be omitted from low-histamine diets [
9,
23].
Values of Biogenic Amines and Histamine in Foods
A diet that ensures the complete elimination of histamine is unattainable [
38]. The content of biogenic amines and histamine in foods differs in dependence on their source, freshness, types, pH, salt content, content of proteins (and L-histidine), processing and storage [
13,
23,
39]. The wide range of content of histamine and/or other biogenic amines for individual foods makes these parameters inconclusive and so we do not regard the listing of specific value intervals per 100 g of food as authoritative. In
Figure 4, we present a list of foods that are most often recommended to be excluded from diet in case of suspected HIT.
In
Table 3, we list foods that in usual quantities are considered safe from triggering HIT symptoms.
In general, biogenic amines are thermostable. If they are already present in the food, heat treatment does not significantly degrade them [
36]. However, boiling in water can reduce the biogenic amines content in certain types of vegetables, most likely by transferring them from the food to the water. Boiling spinach reduced the histamine level by 83% when compared to raw spinach, while analysis confirmed the transfer of the histamine from the spinach to the water (Latorre-Moratalla et al., 2015, in [
23]). Heat treatment needs not always lead to a reduction of the biogenic amines contained in the food however. Heat treatment in the form of boiling and grilling showed an increase of the biogenic amines content in mg/100 g in aubergine, green and yellow beans [
41,
42]. In a work by Chung, the histamine content in mg/100 g in grilled seafood and meat increased, whereas boiling these foods reduced the histamine content in the meat. Boiling the vegetable had no influence on the content of histamine or reduced it only minimally [
43].
1.5. Microbiome and HIT
In 2018, Schink compared microbial patterns from 33 healthy individuals with 33 persons with suspected HIT, 8 of whom had decreased DAO enzyme activity in serum. In comparison with those patients suspected of HIT presence, the healthy people showed a greater abundance of the
Bifidobacteriaceae family, with a median of 0.3% [
44]. To this family belongs the
Bifidobacterium genus, which confers health benefits to the host [
45]. In persons having decreased DAO activity in serum, a greater abundance of the
Proteobacteria genus was observed. The higher ratio in favour of
Proteobacteria genus, which competes with strict anaerobes (including bacteria of the genus
Bifidobacterium), may predict dysbiosis and/or impaired intestinal epithelial function [
44]. If the bifidobacteria were used as a starting culture in the production of fermented sausages, the end products contained lower amounts of biogenic amines [
46].
Some bacterial strains also have an enzyme that ensures endogenous histamine synthesis in the human body. It should be emphasized that the presence of bacterial L-histidine decarboxylase is strain-, not species-, specific [
47]. Accordingly, it is not possible to extrapolate this property from one strain to another, although within the same species. Hence, it is imperative to always assess independently the amount of produced histamine for the individual strains of bacterial species.
Certain strains which are considered potentially probiotic, for example
Lactobacillus saerimneri 30a, produce a significant amount of histamine and other biogenic amines [
48,
49,
50]. In the wide commercially used bacteria
Limosilactobacillus reuteri DSM 17938, the presence of genes responsible for the synthesis of this enzyme was not proven [
51]. From the 15 strains of the bacteria
Lactobacillus acidophilus,
Lacticaseibacillus casei,
Lactobacillus delbrueckii ssp.
bulgaricus,
Lactobacillus lactis ssp.
lactis,
Lactococcus lactis ssp.
lactis and
Lactiplantibacillus plantarum, only two strains,
L. casei TISTR 389 and
L. bulgaricus TISTR 895, appeared to be potentially histamine-producing [
47].
Certain strains of the following bacteria, yeasts and moulds genera and species have the capacity for histamine formation. In
Table 4, we summarize microbial genera and species in which the presence of gene for the L-histidine decarboxylase was demonstrated.
The presence of such bacteria in the gastrointestinal tract could for certain individuals increase sensitivity to ingested histamine. In a study from 2013, the effect of the histamine-producing strain of the
Lacticaseibacillus rhamnosus species was studied in mice. Frei et al. came to the conclusion that alteration of the innate immune response (e.g., dendritic cells) may be mediated through the H
2 receptor not only by endogenous histamine, but also by histamine produced by the microbiome [
53]. The
L. rhamnosus LGG and
L. rhamnosus Lc705 strains suppressed the expression of the H
4 receptor of mast cells and decreased mast cell activation and IgE response [
54].
Since microorganisms play a crucial role in histamine formation; they have been studied for their ability to degrade biogenic amines in foods, particularly histamine and tyramine [
55,
56,
57]. The
Lactiplantibacillus plantarum D-103 strain was able to degrade histamine up to 100% in histamine MRS broth [
57]. Although the microbial catabolic activities responsible for histamine degradation have yet to be completely elucidated, microbial copper-containing amine oxidases, such as histamine oxidase, are most likely involved [
55,
57]. The capacity of microorganisms to degrade biogenic amines is strain-specific [
55]. In the future, eligible strains could be exploited to control the accumulation of biogenic amines in certain foods (e.g., cheese, wine, miso) [
55,
56,
57]. This approach would require an excellent knowledge of the microbial metabolism, since some by-products of the enzymatic reactions (e.g., hydrogen peroxide) are not desirable [
55]. Moreover, some strains could have properties for concomitant degradation and production of biogenic amines [
56].