nutrients

Review
Histamine Intolerance Originates in the Gut
Wolfgang J. Schnedl 1, * and Dietmar Enko 2

1 General Internal Medicine Practice, Dr. Theodor Körnerstrasse 19b, A-8600 Bruck, Austria
2 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz,
Auenbruggerplatz 15, A-8036 Graz, Austria; enko.dietmar@gmx.at
* Correspondence: w.schnedl@dr-schnedl.at; Tel.: +43-3612-55833; Fax: +43-3612-55833-22

Abstract: Histamine intolerance (HIT) is assumed to be due to a deficiency of the gastrointestinal (GI)
enzyme diamine oxidase (DAO) and, therefore, the food component histamine not being degraded
and/or absorbed properly within the GI tract. Involvement of the GI mucosa in various disorders
and diseases, several with unknown origin, and the effects of some medications seem to reduce
gastrointestinal DAO activity. HIT causes variable, functional, nonspecific, non-allergic GI and
extra-intestinal complaints. Usually, evaluation for HIT is not included in differential diagnoses of
patients with unexplained, functional GI complaints or in the here-listed disorders and diseases.
The clinical diagnosis of HIT is challenging, and the thorough anamnesis of all HIT-linked complaints,
using a standardized questionnaire, is the mainstay of HIT diagnosis. So far, DAO values in serum
have not been established to correlate with DAO activity in the gut, but the diagnosis of HIT may be
supported with determination of a low serum DAO value. A targeted dietary intervention, consisting
of a histamine-reduced diet and/or supplementation with oral DAO capsules, is helpful to reduce
HIT-related symptoms. This manuscript will present why histamine should also be taken into account
in the differential diagnoses of patients with various diseases and disorders of unknown origin,
but with association to functional gastrointestinal complaints. In this review, we discuss currently



increasing evidence that HIT is primarily a gastrointestinal disorder and that it originates in the gut.



Citation: Schnedl, W.J.; Enko, D. Keywords: histamine; diamine oxidase; gastrointestinal; biogenic amines; food intolerance;
Histamine Intolerance Originates in food malabsorption
the Gut. Nutrients 2021, 13, 1262.
https://doi.org/10.3390/nu13041262

Academic Editor: Iain A. Brownlee 1. Introduction

Chronic and unexplained, functional, gastrointestinal (GI) symptoms impact more
Received: 2 March 2021
than 20% of the population. In histamine intolerance (HIT), the impairment of GI histamine
Accepted: 9 April 2021
degradation causes functional, nonspecific, non-allergic GI complaints and extra-intestinal
Published: 12 April 2021
complaints [1]. An unbalanced and elevated quantity of histamine in HIT seems to be
the main consequence of the ingestion of histamine-containing foods [2]. Predominantly,
Publisher’s Note: MDPI stays neutral
in HIT, the intestinal enzyme diamine oxidase (DAO) has a reduced ability to metabolize
with regard to jurisdictional claims in
published maps and institutional affil-
and degrade histamine. Scientific evidence and studies to support this idea are increas-
iations.
ing [3]. However, in association with various different disorders and diseases listed here,
several with unknown underlying pathophysiologic mechanisms, the majority reports on
additional unexplained, functional GI symptoms. Nonetheless, reliable standardized evalu-
ations and/or laboratory tests for a definite diagnosis of HIT are still needed. HIT requires
detailed anamnesis and diagnostic examination with available tests [4]. Taking into account
Copyright: © 2021 by the authors.
the possible presence of additional GI diseases or disorders, the evaluation of all etiologic-
Licensee MDPI, Basel, Switzerland.
and symptoms-causing factors is essential [5]. Subsequently, a personalized treatment with
This article is an open access article
distributed under the terms and
the targeted dietary intervention for each patient with HIT, using a histamine-reduced diet
conditions of the Creative Commons
and/or oral supplementation with DAO, may help to provide sustained relief [6].
Attribution (CC BY) license (https:// Here we review various disorders and diseases with unexplained, functional, GI
creativecommons.org/licenses/by/ complaints, and their parallels to HIT. We describe emerging evidence, and with help of
4.0/).

Nutrients 2021, 13, 1262. https://doi.org/10.3390/nu13041262 https://www.mdpi.com/journal/nutrients

Nutrients 2021, 13, 1262 2 of 14

published studies, report on the link between reduced gastrointestinal DAO activity and
HIT, and why this association demonstrates that HIT originates in the gut.

2. Histamine
Histamine [2-(4-imidazolyl)-ethylamine] is included in a group of biogenic amines
with putrescine, cadaverine, and tyramine, amongst others, produced by bacterial fermen-
tation [7]. The decarboxylation of the amino acid histidine results in histamine. Generally,
histamine was discovered more than 100 years ago. The understanding of the central
role of histamine in allergies and in immune regulations has led to the development of
antihistamine medications [8].
A disproportionate amount of histamine in the body is suspected to result from
the consumption of histamine-containing foods or drinks, and the reduced ability of en-
zymes to digest and degrade histamine. In foods, the manufacturing process,
the cleanliness of materials, the microbial composition, and the fermentation influence
the amount of histamine contained. The European Union allows the histamine content in
food up to a maximum of 200 mg/kg in fresh fish and 400 mg/kg in seafood products [9].
Histamine contents of more than 40 mg per meal (0.75 mg/kg body weight) considerably
increase the risk of scombroid poisoning [7]. However, this intoxication is in most cases
caused by the consumption of decaying sea animals, which are contaminated with bacteria
that cause high concentrations of histamine. Scombroid poisoning may also arise due to
spoiled food because cooking, smoking, or freezing does influence [10], but not eliminate
histamine. Usually, the consumption of low amounts of histamine and biogenic amines
does not cause health problems in humans. Nonetheless, HIT is clearly separated from food
allergies, like, e.g., peanut allergy [11], and is described as a non-allergic adverse reaction to
ingested food [3].

3. Histamine Intolerance (HIT)

The term “histamine intolerance” is used similarly to lactose intolerance (LIT). LIT,
with a deficiency of the enzyme lactase, shows parallels to the definition of HIT, with a
deficiency of the GI enzyme diamine oxidase (DAO). Occasionally, HIT is also defined as
“enteral histaminosis” or “sensitivity to dietary histamine” [2]. Although, HIT has also been
suggested to be a metabolic disease [12], the inadequate digestion seems to cause excess
histamine throughout the body that initiates a wide variety of symptoms. Nevertheless,
histamine is also involved in the etiology of many common diseases [13].
Genetic expression of DAO is mainly in the small intestine, the ascending colon,
the placenta, and the kidneys [14,15]. DAO activity, as shown in rats’ intestines, increases
from the duodenum to the ileum and is located in the intestinal villi [16]. It is synthesized
by mature intestinal enterocytes and is constantly released from the intestinal mucosa
into the gut as well as into the blood circulation, during digestion [17,18]. Ingested his-
tamine, clearly below the dose of scombroid poisoning [19], is alleged to cause HIT-related
symptoms. Human DAO and histamine N-methyl transferase, extra- and intracellular,
respectively, are enzymes which catalyse the oxidative deamination of mono-, di-, and
polyamines. Within the GI tract, DAO appears as the primary enzyme responsible for
degrading ingested or microbiota-generated histamine [20,21].
The clinical diagnosis of HIT is still challenging, as standardized diagnostic tests
are lacking. The thorough anamnesis of all HIT-linked complaints is the mainstay of HIT
diagnosis. So far, a HIT questionnaire for volunteers, who randomly attended an outpatient
clinic, has not proven useful for detection of HIT [22]. However, to evaluate patients
with unexplained functional, nonspecific, non-allergic GI and extra-intestinal symptoms,
suspected to have HIT, a questionnaire as shown in Table 1 may be helpful. We published
a survey which listed 23 HIT symptoms in four categories including gastrointestinal,
cardiovascular, respiratory, and skin complaints. This questionnaire contains questions
about symptoms and the severity of them that patients experience due to ingestion of
foods, and it is based on known symptoms related to the four histamine receptors [23]. In
Nutrients 2021, 13, 1262 3 of 14

this description the most common and most severe symptom indicated by HIT patients
in more than 90% was bloating. Other very commonly related GI symptoms included:
postprandial fullness and diarrhea (both in >70% of patients), abdominal pain (>65%),
and constipation (55%) [1]. This questionnaire shown in Table 1, may help to clinically
recognize and support the detection and diagnosis of HIT.

Table 1. Example of a standardized questionnaire for evaluation of patients with suspected histamine
intolerance (HIT).

Severity of Complaints: No Symptoms (0), Mild (1) to Very Severe Complaints (5)
Gastrointestinal
0 1 2 3 4 5
Abdominal pain o o o o o o
Intestinal colics o o o o o o
Bloating o o o o o o
Diarrhea o o o o o o
Constipation o o o o o o
Nausea o o o o o o
Belching o o o o o o
Vomiting o o o o o o
Postprandial fullness o o o o o o
Menstrual cramps o o o o o o
Skin
0 1 2 3 4 5
Pruritus o o o o o o
Eczema o o o o o o
Reddened skin o o o o o o
Swollen, reddened
o o o o o o
eye lids
Cardiovascular
0 1 2 3 4 5
Headache o o o o o o
Dizziness o o o o o o
Hypotonia o o o o o o
Palpitations o o o o o o
Collapse o o o o o o
Respiration
0 1 2 3 4 5
Rhinorrhea o o o o o o
Nose congestion o o o o o o
Sneezing o o o o o o
Asthma o o o o o o
Additional Complaints (Please List Symptoms that Have Not Yet
Been Listed)
0 1 2 3 4 5
o o o o o o
o o o o o o
o o o o o o
Please tick complaints which you experience mainly after ingestion of food. Adapted according to reference [1].

There are 50 known non-synonymous single-nucleotide polymorphisms for the gene

which codes DAO [24] and the histamine receptors [25]. These seem associated with a
manifold of clinical symptoms and hundreds of symptom combinations [1]. Nonetheless,
this may help to explain the extensive individual variability of HIT-related GI and extra-
intestinal symptoms. Furthermore, this genetic variety in HIT might influence disease
expression and individual responses to diets or treatment. However, the functional and
Nutrients 2021, 13, 1262 4 of 14

clinical significance of these polymorphisms remains unknown. Another factor to consider

is that histamine content in food is frequently unknown [26], and that it varies geographi-
cally depending on ripeness, storage time, and processing [6]. All of these variables need
to be advised and may help to describe each person’s unique and occasionally changing
tolerance level.
However, a diagnosis of HIT may be supported with a low serum DAO value <10 U/mL
(normal >10 U/mL) [27]. GI symptoms, indicative of HIT, and a reduction of these when
following a histamine-reduced diet, help to support a successful diagnosis [3]. Although,
DAO values in serum are not established to correlate with DAO activity in the gut, a signif-
icant increase in serum DAO due to a strict histamine-reduced diet was demonstrated in
patients with HIT [28]. Subsequently, a correlation between low DAO values and symptoms
of HIT, and a response to histamine-reduced diet and/or to oral diamine oxidase supple-
mentation was shown [29,30]. Some findings suggested that serum DAO values agree with
symptoms of HIT [31]. In vitro and in vivo observations in mice, including administration
of DAO into the gut lumen, were found to be a valid treatment for histamine-induced
intestinal dysfunctions [32]. DAO made from the white pea (Lathyrus sativus) prevented
histamine toxicity in vitro in human epithelial colorectal adenocarcinoma cells [33].
Currently, serum DAO is being determined using a radio extraction assay. How-
ever, this analytical method has limitations because only a relative amount of DAO in
serum is quantified. With this method, a human DAO standard is not commercially avail-
able and absolute DAO quantities cannot be measured. Therefore, the development of
new assay methods have shown an enzyme-linked immunosorbent assay, using human
DAO as a standard, to be more accurate [34]. Nonetheless, the search for HIT diagnostic
tests continues.

4. Histamine Intolerance (HIT) Associated with Gastrointestinal (GI) Disorders

The various disorders and diseases, of which several are with unknown etiology,
listed here are mainly presented with unexplained functional, nonspecific, non-allergic GI
symptoms. Predominant symptoms are abdominal pain, bloating, and diarrhea. The GI
symptoms include multiple individual combinations, which are also indicated by patients
with HIT, with or without extra-intestinal symptoms.
However, DAO activity has been proposed as a marker of the integrity of intestinal
mucosa. A recent study analyzed the molecular effects of histamine in human ileal neu-
roendocrine tumor cells, which are a model for gut enterochromaffin cells. The results
indicated that enterochromaffin cells participate in intestinal intolerance or allergic reac-
tions to food constituents associated with elevated histamine levels [35]. In inflammatory
bowel diseases, reduced DAO activity was related to the degree of mucosal damage [36].
In Crohn’s disease, DAO was discussed as a marker for disease assessment [37]. Moreover,
histamine content and secretion were found to be significantly increased in affected mucosa
in Crohn’s disease and in ulcerative colitis [38]. Intestinal mucosa diamine oxidase activity
was shown to reflect intestinal involvement in Crohn’s disease. Additionally, histamine
was concluded to contribute to the mucosal reactions in the intestine and to reflect the
degree of colonic inflammation [39]. Measurement of gut DAO activity was stated as a
biologic marker of colorectal proliferation [40] and histamine catabolism was reported
to be lower in the colonic mucosa of patients with colonic adenoma [41]. According to
reports, in oncologic patients receiving chemotherapy, DAO activity may be a predictor of
intestinal mucosal damage [42]. Serum DAO activity was reported to be a predictor of GI
toxicity and malnutrition due to anticancer drugs [43]. Some results in children support
the hypothesis of DAO being a marker of small intestinal functional integrity [44].
Histamine and DAO measurements, in vivo and in vitro, beyond any doubt need
further investigation to shed light on the changes in gut tissues during various diseases
and disorders.
Nutrients 2021, 13, 1262 5 of 14

4.1. Irritable Bowel Syndrome (IBS)-Like Disorders

Functional dyspepsia (FD), IBS, and small intestinal bacterial overgrowth (SIBO) are
commonly reported, but solely symptom-oriented conditions. These clinical syndromes
continue to be imprecise and were therefore re-named to “IBS-like” disorders [45]. They
have no established pathophysiology, however, emerging evidence suggests that this
paradigm may need revision [46]. In general, there is a lack of specificity of symptoms.
Symptoms alone or symptom complexes can rarely, if ever, be used diagnostically. How-
ever, 80% of IBS patients identified food, including histamine, to be triggers for their GI
symptoms [47]. Currently, IBS is defined using—and discussed within—the Rome IV crite-
ria [48]. Furthermore, histamine was recently named to act as a key mediator in IBS [46].
FD is with absence of an organic disease a disorder with heterogeneous symptoms in the
epigastric region. Patients with HIT report abdominal pain and postprandial fullness to
be prominent symptoms and these are described in FD also as main symptoms. SIBO
occurs with an abnormal increase in the overall bacterial population in the small intestine.
Bloating and abdominal pain are primary symptoms in SIBO, very much comparable
to HIT complaints [1]. However, there is an imprecise clinical overlap between IBS, FD,
SIBO, and IBS-like disorders [49], and it is suspected that a number of different pathogenic
mechanisms may be responsible. Dietary nickel (Ni) was described as a possible etiology
for GI complaints in patients with IBS-like symptoms [50]. Remarkably, several foods
described as containing Ni are also not well digested by HIT patients because of their high
histamine content.
Since there are symptom correlations in FD, IBS, and SIBO with HIT, determination of
serum DAO values in well-defined patients may help to elucidate this link.

4.2. Non-Celiac Gluten Sensitivity (NCGS)

Due to all of these disorders being increasingly discussed in the media, a growing
number of people are changing their diets. Currently, approximately 20% of the population
are avoiding gluten in food because of a self-diagnosed, new clinical condition, referred to
as non-celiac gluten sensitivity (NCGS). Unproven hypotheses of supposed health benefits
due to gluten-free eating are wide-spread [51]. There are no medical tests available for the
diagnosis of NCGS, and patients were also named “people without celiac disease avoiding
gluten” [52]. Mainly, they are self-diagnosed and perform self-treatment with a gluten-free
diet. It has been proposed that NCGS patients are a certain group of patients with IBS.
Recently, a newly created term “non-celiac wheat sensitivity” has been suggested as a more
accurate definition [53]. Moreover, widely used gluten-containing bakery goods and beers
are prepared with histamine-producing yeast [54,55]. Additionally, foods like pasta, pizza,
and bulgur are very commonly consumed with histamine-containing tomatoes [56] and
seasonings. Generally, several gluten-free foods are low in histamine [57] and an increasing
number of gluten-free products, including breads, are already labeled gluten-free and
yeast-leavened [58]. Furthermore, we reported that in NCGS the GI and extra-intestinal
symptoms resemble those found in HIT [59]. However, the reduction of gluten-containing
food and drinks cuts the quantity of parallel consumed histamine. This may help to explain
the current extraordinary popularity of gluten-free food. Lastly, the pathophysiology of
these symptom-oriented disorders are unknown and HIT, with its plethora of symptoms,
may play a role.

4.3. Food Intolerance/Malabsorption

There is growing public interest in adverse reactions to food that may influence
and impair digestion. Food intolerance/malabsorption and people who experience GI
reactions to food are reported to affect 20% of populations. Particularly the sugars (lactose
and fructose), proteins (gluten), and biogenic amines (including histamine) are widely
consumed and trigger GI reactions to food. However, quantity, type, and composition of
dietary carbohydrates and proteins influence digestion and the metabolic output of gut
Nutrients 2021, 13, 1262 6 of 14

microbiota [60]. In patients with HIT, a deranged gut flora and a change of the intestinal
bacterial composition was demonstrated [61].
One or a combination of various food components cannot be degraded and/or ab-
sorbed properly within the gut. Combinations of LIT and fructose malabsorption were
reported in >30% of patients with a carbohydrate intolerance/malabsorption [62]. In
lactose-intolerant patients, the effect of HIT with different perceptions of functional, non-
specific, non-allergic GI symptoms was described [63]. During H2 breath tests of patients
with LIT, the presence of additional fructose malabsorption and HIT significantly increased
expiratory H2 values. This indicated that HIT embodies a separate GI disorder as food
intolerance/malabsorption [64]. We described the fact that 55% of the patients with carbohy-
drate intolerance/malabsorption have serum DAO values below 10 U/mL as an indicator
for HIT [5]. Further studies and descriptions of food intolerance/malabsorption, includ-
ing the changes of the microbiota, in various combinations of intolerance/malabsorption,
including HIT, are certainly needed.

4.4. Medications
Due to the increased release of histamine, or an inhibition of DAO, a variety of medi-
cations may influence HIT-related complaints or induce HIT [1,65,66] (Table 2). Approxi-
mately 20% of Europeans use DAO-inhibiting drugs on a regular basis, which significantly
increases their susceptibility to adverse effects of ingested histamine [67]. Several of these
drugs, including high-dose acetylsalicylic acid and nonsteroidal anti-inflammatory drugs,
are available over the counter. However, they may cause GI side effects, including, with
prolonged and high-dose use, an increased risk for GI bleedings [68]. Particularly, when
exploring HIT-related symptoms, long-term treatments with these drugs need assessment,
as well as reflection concerning the estimation of serum DAO values.

Table 2. Medications which may influence diamine oxidase and/or histamine.

Medications Generic Name

Analgesics Acetylsalicylic acid, Metamizole, Morphines, Nonsteroidal anti-inflammatory drugs, Pethidine
Antiarrhythmics Propafenon
Antibiotics Cefuroxime, Cefotiam, Isoniazid, Pentamidine, Clavulanic acid, Chloroquine
Antidepressants Amitriptylline
Antifungal Pentamidine
Antihypertensives Verapamil, Alprenolol, Dihydralazine
Antihypotensives Dobutamine
Antimalarial Chloroquine
Broncholytics Aminophylline
Cytostatics Cyclophosphamide
Diuretics Amiloride
H2 receptor antagonists Cimetidine
Local anesthetics Prilocaine
Motility agents Metoclopramide
Mucolytics Acetylcysteine, Ambroxol
Muscle relaxants Pancuronium, Alcuronium, D-Tubocurarin
Narcotics Thiopental
Radiological contrast
media
Vitamines Ascorbic acid, Thiamine
Adapted according to references [2,62].

4.5. Disorders Associated with Mast Cells

Mast cells are essentially involved in immunity and inflammation. Endogenous
histamine is stored mainly in mast cells and basophils. The mast cells’ histamine release
appears linked to GI-involving diseases like celiac disease (CD), eosinophilic gastroenteritis
(EGE), and mast cell activation syndrome (MCAS) [4].
Nutrients 2021, 13, 1262 7 of 14

CD is a well-defined autoimmune disorder characterized by a gastrointestinal mu-

cosal reaction to ingested gluten proteins. An overlap between CD and irritable bowel
syndrome (IBS) exists and an improvement of symptoms with gluten restrictions in IBS was
reported [69]. Mast cells releasing histamine and other inflammatory mediators have been
linked with CD, showing that mast cells infiltrating the mucosa were associated with the
severity of mucosal damage [70]. HIT was found in 55% of non-responsive CD patients and
seems to play an important role in CD [71]. Originally, the Mas-related G protein-coupled
receptor family (Mrgprs) members were identified as itch receptors in cutaneous sensory
neurons. Now, they have become a target in abdominal pain research. Recently, a function
for Mrgprs in the mouse gut nociceptive innervation and through Mrgprs elevation of
histamine was found [72]. Given these functions of Mrgprs in humans, these findings
deserve future research and may help to elucidate pathophysiology of HIT.
The underlying mechanisms of EGE are remain unknown. EGE is characterized by
eosinophilic infiltration into the gastrointestinal mucosa. With the eosinophil–mast cell axis,
which is involved in functional GI disorders, mast cells induce eosinophils and eosinophils
activate mast cells in a co-dependent manner. Several symptoms in EGE, including GI
complaints [73] resemble complaints in HIT [1]. It was suggested that cytokines combined
with proliferation of eosinophils and histamine-releasing mast cells are involved in EGE [74].
The influence of a histamine-reduced diet on gastrointestinal symptoms in EGE remains
to be discovered.
Mast cell activation disorders have a certain relation of GI and extra-intestinal com-
plaints with HIT. It was questioned whether HIT patients, some or all, could be seen within
the mast cell activation disorders spectrum [75]. However, HIT mainly causes GI symp-
toms. A coexistence of the hypermobility spectrum disorder, Ehlers-Danlos syndrome, and
the postural tachycardia syndrome exists [76]. Individuals with these syndromes have
frequently functional GI disorders fulfilling criteria according to Rome IV [77] and present
complex clinical challenges. The postural orthostatic tachycardia syndrome is associated
with increased occurrence of IBS-like symptoms and is described according to abnormal
increase in heart rate occurring after sitting or standing up. Future studies need to eluci-
date the pathophysiology of hypermobility spectrum disorders and postural orthostatic
tachycardia, including evaluation of HIT in these syndromes. The role of histamine and a
therapeutic effect of a histamine-reduced diet, and the effect of oral DAO capsules, remain
to be determined.

4.6. Helicobacter Pylori (H.p.) Infection

In patients with unexplained functional GI symptoms, an H.p. infection needs to be
considered. Accordingly, if it is detected, an eradication therapy is required [78]. Gastrin
and histamine are the main stimulants of gastric acid secretion, and they, combined with
H.p., influence acid secretion [79]. Although the involvement of H.p. in functional dyspepsia
is controversial, some studies from areas with a high prevalence of H.p. reported that
eradication improves dyspepsia. Some association of H.p. infection and CD was reported
because CD patients had significantly lower rates of gastric H.p. infection [80]. This argues
that evaluations of GI infection with H.p., the most prevalent human pathogen, with HIT
are also needed.

5. Histamine Intolerance (HIT) Associated with Other Disorders

In various disorders and diseases, of which several are of unknown etiology, no clear
link from headache and urticaria complaints to dyspepsia can be established. However,
several patients in evaluations of described disorders were reported with unexplained
functional, nonspecific, non-allergic GI symptoms.

5.1. Headache
A specific pathophysiologic mechanism of headache is still unknown and migraines
are defined as an untreatable disease [81]. Biogenic amines in wine, including histamine,
Nutrients 2021, 13, 1262 8 of 14

tyramine, and putrescine [82], have relevance for headache and histamine-related symp-
toms [83]. Red wines contain clearly more than double the histamine concentrations with
>2200 µg/L, compared to white wines (~900 µg/L histamine) [6]. An increased risk for
migraines was demonstrated in patients with some DAO genotypes and allelic variants [84].
A high incidence of DAO deficiency at nearly 90% was observed in migraine patients [85].
Recently, a study demonstrated that oral ingestion of capsules with DAO significantly
reduces headaches in migraine patients [86]. Subsequently it was shown that headaches
in HIT patients—as one of the many symptoms in HIT—were considerably reduced due
to oral DAO supplementation [30]. The organic wine industry was reported to lower
the amount of histamine in wine. This decreases headaches and other adverse effects
usually provoked by drinking wine [87]. Associations between migraine, celiac disease,
non-celiac gluten sensitivity, and low activity of DAO were hypothesized. It was stated
that patients with low serum DAO values were more severely impacted by migraine than
healthy persons with normal DAO activity [88]. Bloating with headache was mentioned by
63% of HIT patients as one of the most common HIT-related symptom combinations [1].
Thus, the histamine content of consumed food may play a key role in triggering migraines
and headaches, and there are certainly additional evaluations necessary.

5.2. Urticaria
Urticaria is a relapsing-remitting skin disease with unknown etiology. The majority
of cases are called idiopathic or autoreactive. It has a significant impact on affected
patients and reduces their quality of life. The mainstay of medical therapy is symptom
management, including the use of H1 antihistamines. Histamine-releasing mast cells and
basophils are known as primary inflammatory cells in urticaria. Degranulation and release
of vasoactive substances, including histamine and other pro-inflammatory mediators,
causes vasodilation, sensory nerve activation, plasma extravasation, dermal edema, and
wheals. Although further evaluations are needed, it appears that some patients have
dietary triggers contributing to this skin disease and a number of food ingredients have
been reported to worsen symptoms [89]. In patients suffering from urticaria, accompanied
by functional GI symptoms, a histamine-reduced diet was demonstrated therapeutically
useful, simple, and economically efficient. The diet decreased symptoms and increased
quality of life in urticaria patients [90]. Additionally, oral DAO supplementation was found
to improve the degree of urticarial activity score, which was inversely correlated with the
levels of serum DAO [91]. Dietary intervention in urticaria patients with histamine-reduced
diet and/or oral DAO capsules obviously needs additional investigations.

5.3. Further Diseases and Disorders

Occurrence of HIT, causing GI complaints, was described in some patients with
rare diseases, such as primary epiploic appendagitis, beta-thalassemias minor, and Gullo
syndrome [92]. However, it has also has been reported in several other cases and fur-
ther groups of patients with HIT-related symptoms. In all of these examples, the re-
duction of histamine in food with initiation of a histamine-reduced diet was helpful to
decrease complaints.
Recently, a patient with already performed Nissen fundoplication had recurring
gastroesophageal reflux symptoms with coughing and increased throat clearing. Lung
function and gastroesophageal reflux disease were tested but not found as the cause of
these symptoms. After a successful diagnosis of HIT, a histamine-reduced diet resulted in
apparent improvement of the patient’s complaints [93].
In a female patient with anorexia nervosa, HIT-related symptoms arose. After she
followed a histamine-reduced diet, she experienced weight gain and improvement of GI
symptoms [94].
Drinking wine with high histamine content caused coughing and wheezing with
bronchoconstriction in patients with HIT [95].
Nutrients 2021, 13, 1262 9 of 14

Etiology and triggers of atopic dermatitis are still under debate. The treatment of
atopic dermatitis, in a patient who also had HIT-related GI symptoms, was successful with
a histamine-reduced diet [96].
Interestingly, histamine secretion from bacteria within the gut of mice was shown to
have immunological consequences within the lung [97]. On the other hand, a pilot study
reported on a histamine-reduced diet, which might have had an active and direct impact
on asthma symptoms in children, without known HIT [98].
Somewhat conflicting results are reported on DAO and histamine values in patients
with multiple sclerosis (MS), an autoimmune disease of the central nervous system. In-
compatible low DAO and low histamine serum levels have been documented in MS [99].
However, the pathogenesis and an association to HIT are unknown, but this again docu-
ments the need for further investigations.
Usually, GI endoscopy with histologic evaluation of GI mucosa and radiological
evaluation, including ultrasound, of the abdomen are valuable additional options for
examination of patients, especially aged >55 years, with functional, nonspecific, non-
allergic GI symptoms [100]. If signs of GI infection are evident, then specific anti-microbial
or anti-parasitic treatments, that may reverse the disease, need consideration.

6. Discussion
Generally, the growing number of scientific studies has led to a better understanding of
the role of food ingredients causing GI complaints. If biogenic amines, including histamine,
cannot be absorbed and digested properly in HIT then this causes non-allergic, functional,
nonspecific GI and extra-intestinal complaints. GI bacteria use catabolic enzymes to
degrade and ferment carbohydrates and proteins from ingested food [101], as well as in
HIT, a changed intestinal bacterial composition was reported.
Although there is limited availability of sufficiently sensitive and specific diagnostic
procedures, it seems essential to assess HIT individually with the currently available
methods. The thorough anamnesis of all HIT-linked complaints is the mainstay of HIT
diagnosis. However, for evaluation of patients with symptoms, suspected to have HIT,
the questionnaire indicated here (Table 1) may be helpful. Medical personnel should
be aware that a large number of HIT patients have, to a certain extent, GI complaints.
However, distinct patients may present only single symptoms like, e.g., postprandial
vertigo or headache. Additionally, several studies demonstrate the growing importance of
serum DAO determinations. So far, some studies conducted report on an insufficient low
number of patients. This demonstrates the need for further evaluations of HIT in clearly
defined and larger patient groups.
After detailed diagnosis of HIT, the GI complaints and extra-intestinal symptoms
can be decreased by reducing the consumption of histamine and/or oral DAO supple-
mentation. Capsules containing DAO seem helpful but there is an ongoing discussion
about the therapeutically helpful dosage [102]. Each patient’s tolerance level should also
be considered, when recommending dietary restrictions for long-term symptom reduction.
Nonetheless, the permanent compliance with a locally-available, histamine-reduced diet,
is challenging for patients. Certainly, this represents the future need of the histamine
content indication on food labels. Improvements and developments of new methods for
the determination of histamine and biogenic amines in food will allow this [103–105].
A strong association of histamine and HIT with functional GI complaints in various
disorders and diseases is assumed, several of these with a so-far unknown origin. Thera-
peutically helpful, in many ways, is the reduction of the food histamine load. However, if
HIT is present, an experienced, a registered dietician may help to design an individually
tailored diet. The reduction of ingested histamine with a histamine-reduced diet is helpful
for HIT-related symptoms and available at low cost. This seems to positively influence the
pathophysiologic process, including inflammation, and accomplish symptom reduction.
The oral supplementation with DAO capsules represents an additional therapeutic option
to lower HIT-related symptoms. So far, an agreement for dosing of oral DAO supplements
Nutrients 2021, 13, 1262 10 of 14

has not been established. Commercially available capsules contain 4.2 mg extracted pig kid-
ney proteins with 0.3 mg DAO. These are suggested up to three times per day before meals.
Although, it was reported that a higher activity of DAO seems required for a satisfactory
histamine degradation [102]. The dietary intervention with histamine-reduced diet and/or
oral supplementation of DAO clearly needs additional investigations. Interdisciplinary
management is necessary, so that all etiologic and therapeutic possibilities are included
in the evaluation of patients with HIT [4,106]. The diagnosis of HIT helps patients to put
their symptoms into context, to reduce complaints and to improve their quality of life. This
shows why additional scientific evaluations in these demonstrated diseases and disorders
are certainly necessary. Nonetheless, the development of new laboratory methods will
improve determination of DAO and histamine in serum, and histamine in food.

7. Conclusions
In conclusion, HIT seems to play a more significant role in GI disorders and complaints,
and in several extra-intestinal disorders, than so far anticipated. Overall, scientific evidence
of histamine involvement and HIT in the demonstrated diseases and disorders is scarce
but increasing. A detailed diagnosis of HIT, with currently available methods and tests,
including the questionnaire (Table 2), is helpful and necessary to evaluate each patient with
HIT-related GI and extra-intestinal complaints. With the increasing scientific evidence, we
demonstrate, that HIT is primarily a GI disorder and that it originates in the gut.

Author Contributions: W.J.S. and D.E.—Collection, analysis, and interpretation of studies and data;
conception; design; and writing. Both authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: Wolfgang J. Schnedl received speaking honoraria from Sciotec. Dietmar Enko
has no conflict of interest.

Abbreviations

CD Celiac Disease
DAO Diamine oxidase
EGE Eosinophilic gastroenteritis
FD Functional dyspepsia
GI Gastrointestinal
H.p. Helicobacter pylori
HIT Histamine intolerance
IBS Irritable bowel syndrome
LIT Lactose intolerance
MCAS Mast cell activation syndrome; Mrgprs, Mas-related G protein-coupled receptor family
NCGS Non-celiac gluten sensitivity
SIBO Small intestinal bacterial overgrowth

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