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Unfolding New Evidence on Histamine Intolerance

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A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Nutritional Epidemiology".

Deadline for manuscript submissions: closed (20 July 2022) | Viewed by 95896

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Dr. Mariluz Latorre-Moratalla

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Department of Nutrition, Food Sciences and Gastronomy, Food and Nutrition Torribera Campus, University of Barcelona, Spain.
Interests: dry-fermented sausages, biogenic amines, histamine, histamine intolerance, DAO

Dr. Oriol Comas-Basté

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Department of Nutrition, Food Sciences and Gastronomy, Food and Nutrition Torribera Campus, University of Barcelona, Spain.

Prof. Dr. M. Carmen Vidal-Carou

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Department of Nutrition, Food Sciences and Gastronomy, Food and Nutrition Torribera Campus, University of Barcelona, Barcelona, Spain
Interests: functional foods; bioactive compounds; food safety; food intolerances; biogenic amines; histamine; histamine intoxication; histamine intolerance; diamine oxidase (DAO) enzyme; tyramine; putrescine; cadaverine; polyamines; amino acid decarboxylase; fermentation; food-drug interactions

Special Issue Information

Dear Colleagues,

Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine, is a non-immune-mediated adverse reaction to food that arises from a reduced histamine degradation capacity in the intestine. Although the first scientific references to histamine intolerance date from the end of the 20th century, it is significant that almost 80% are from the last decade, reflecting the growing interest of researchers in this disorder.

A deficit of diamine oxidase (DAO), the primary enzyme responsible for scavenging histamine from food at the intestinal level, is recognized as the main etiologic factor that leads to histamine intolerance. This enzymatic deficit may have a genetic, pathological, or pharmacological origin, which causes the accumulation of histamine in plasma and the subsequent appearance of non-specific gastrointestinal and extraintestinal symptoms.

Currently, there is no consensual diagnostic algorithm for histamine intolerance and the treatment management is limited to the strict avoidance of dietary histamine and DAO enzyme supplementation. Recent and ongoing trials are focused on the study of the efficacy of low-histamine diets and/or DAO supplementation in the preventive treatment of symptoms, as well as on the potential link of this intolerance with other functional gastrointestinal disorders. Moreover, the potential role of microbiota in the pathophysiology of histamine intolerance needs to be elucidated.

The aim of this Special Issue is to review and unfold new evidence on the etiology, clinical presentation, diagnosis, and treatment of histamine intolerance. Articles dealing with strategies to control the occurrence of histamine and other biogenic amines in foods, as well as analytical methods to detect the presence of these compounds, are also within the scope of this Special Issue.

Dr. Mariluz Latorre-Moratalla
Dr. Oriol Comas-Basté
Prof. Dr. M. Carmen Vidal-Carou
Guest Editors

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Keywords

histamine
histamine intolerance
food intolerance
histaminosis
diamine oxidase (DAO)
DAO deficit
low-histamine diet
DAO supplementation
clinical manifestations
diagnosis
biogenic amines

Published Papers (9 papers)

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Research

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15 pages, 1523 KiB

Open AccessArticle

Pilot Study on the Prevalence of Diamine Oxidase Gene Variants in Patients with Symptoms of Histamine Intolerance

by Adriana Duelo, Oriol Comas-Basté, Sònia Sánchez-Pérez, M. Teresa Veciana-Nogués, Eva Ruiz-Casares, M. Carmen Vidal-Carou and M. Luz Latorre-Moratalla

Nutrients 2024, 16(8), 1142; https://doi.org/10.3390/nu16081142 - 12 Apr 2024

Viewed by 390

Abstract

A retrospective pilot study was carried out to investigate the prevalence of four variants of the diamine oxidase (DAO) encoding gene (AOC1) in Caucasian adults with symptoms of histamine intolerance. In a cohort of 100 patients and 100 healthy individuals, DAO-encoding gene non-synonymous Single Nucleotide Variations (SNVs) were genotyped by multiplex single-nucleotide primer extension (SNPE) and capillary electrophoresis, and serum DAO activity was analyzed with a radio-extraction assay. The study found that 79% of individuals with symptoms of histamine intolerance harbored one or more of the four SNVs associated with reduced DAO activity. No significant differences were found in the prevalence of any variant between the group of patients and healthy controls. However, when considering the status of the alleles associated with DAO deficiency, more homozygous alleles were observed in histamine-intolerant patients. Moreover, a slightly but statistically higher percentage of patients had a high genetic risk score, reflecting the cumulative effect of carrying multiple DAO deficiency-associated gene variants and a high load of risk alleles (homozygous). A relationship between serum DAO activity and the genetic load of one specific SNV was observed, with DAO activity being significantly lower in patients homozygous for rs2052129. These results potentially support that carrying multiple DAO deficiency-associated gene variants and a high load of risk alleles (homozygous) is more relevant than the mere presence of one or more SNVs. Further studies are needed to determine the predictive value of these DAO-encoding gene variants. Full article

(This article belongs to the Special Issue Unfolding New Evidence on Histamine Intolerance)

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13 pages, 1266 KiB

Open AccessArticle

Toward Oral Supplementation of Diamine Oxidase for the Treatment of Histamine Intolerance

by Lucas Kettner, Ines Seitl and Lutz Fischer

Nutrients 2022, 14(13), 2621; https://doi.org/10.3390/nu14132621 - 24 Jun 2022

Cited by 4 | Viewed by 3664

Abstract

A new diamine oxidase (DAO-1) was discovered recently in the yeast Yarrowia lipolytica PO1f and investigated for its histamine degradation capability under simulated intestinal conditions. DAO-1 was formulated together with catalase as a sucrose-based tablet. The latter (9 × 7 mm; 400 mg) contained 690 nkat of DAO-1 activity, which was obtained from a bioreactor cultivation of a genetically modified Y. lipolytica with optimized downstream processing. The DAO-1 tablet was tested in a histamine bioconversion experiment under simulated intestinal conditions in the presence of food constituents, whereby about 30% of the histamine was degraded in 90 min. This amount might already be sufficient to help people with histamine intolerance. Furthermore, it was found that the stability of DAO-1 in a simulated intestinal fluid is influenced distinctively by the presence of a food matrix, indicating that the amount and type of food consumed affect the oral supplementation with DAO. This study showed for the first time that a microbial DAO could have the potential for the treatment of histamine intolerance by oral supplementation. Full article

(This article belongs to the Special Issue Unfolding New Evidence on Histamine Intolerance)

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8 pages, 604 KiB

Open AccessArticle

Serum Diamine Oxidase Values, Indicating Histamine Intolerance, Influence Lactose Tolerance Breath Test Results

by Wolfgang J. Schnedl, Nathalie Meier-Allard, Simon Michaelis, Sonja Lackner, Dietmar Enko, Harald Mangge and Sandra J. Holasek

Nutrients 2022, 14(10), 2026; https://doi.org/10.3390/nu14102026 - 12 May 2022

Cited by 5 | Viewed by 4039

Abstract

Lactose intolerance (LIT) is one of the major causes of irritable bowel syndrome (IBS) spectrum complaints. Differences in inadequate lactose digestion are described as various LIT phenotypes with basically unknown pathophysiology. In LIT patients, we retrospectively assessed the effect of histamine intolerance (HIT) on expiratory hydrogen (H₂) during H₂ lactose breath tests. In a retrospective evaluation of charts from 402 LIT patients, 200 patients were identified as having only LIT. The other 202 LIT patients were found to additionally have diamine oxidase (DAO) values of <10 U/mL, which indicates histamine intolerance (HIT). To identify HIT, standardized questionnaires, low serum DAO values and responses to a histamine-reduced diet were used. Patients were separated into three diagnostic groups according to the result of H₂ breath tests: (1) LIT, with an H₂ increase of >20 parts per million (ppm), but a blood glucose (BG) increase of >20 mg/dL, (2) LIT with an H₂ increase of 20 ppm in combination with a BG increase of <20 mg/dL, and (3) LIT with an exhaled H₂ increase of <20 ppm and BG increase of <20 mg/dL. Pairwise comparison with the Kruskal Wallis test was used to compare the areas under the curve (AUC) of LIT and LIT with HIT patients. Exhaled H₂ values were significantly higher in H₂ > 20 ppm and BG < 20 mg/dL patients with LIT and HIT (p = 0.007). This diagnostic group also showed a significant higher number of patients (p = 0.012) and a significant higher number of patients with gastrointestinal (GI) symptoms during H₂ breath tests (p < 0.001). Therefore, low serum DAO values, indicating HIT, influence results of lactose tolerance breath tests. Full article

(This article belongs to the Special Issue Unfolding New Evidence on Histamine Intolerance)

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14 pages, 3693 KiB

Open AccessArticle

Intestinal Dysbiosis in Patients with Histamine Intolerance

by Sònia Sánchez-Pérez, Oriol Comas-Basté, Adriana Duelo, M. Teresa Veciana-Nogués, Mercedes Berlanga, M. Luz Latorre-Moratalla and M. Carmen Vidal-Carou

Nutrients 2022, 14(9), 1774; https://doi.org/10.3390/nu14091774 - 23 Apr 2022

Cited by 23 | Viewed by 9930

Abstract

An underlying cause of histamine intolerance is diamine oxidase (DAO) deficiency, which leads to defective homeostasis and a higher systemic absorption of histamine. Impaired DAO activity may have a genetic, pharmacological or pathological origin. A recent proposal also suggests it can arise from an alteration in the gut microbiota, although only one study has explored this hypothesis to date. A greater abundance of histamine-secreting bacteria in the gut could lead to the development of histamine intolerance. Thus, the aim of this study was to characterize the composition of the intestinal microbiota of patients with histamine intolerance symptoms and compare it with that of healthy individuals. The study was performed by sequencing bacterial 16S rRNA genes (V3-V4 region) and analyzing the data using the EzBioCloud Database. Dysbiosis of the gut microbiota was observed in the histamine intolerance group who, in comparison with the healthy individuals, had a significantly lower proportion of Prevotellaceae, Ruminococcus, Faecalibacterium and Faecablibacterium prausnitzii, which are bacteria related to gut health. They also had a significantly higher abundance of histamine-secreting bacteria, including the genera Staphylococcus and Proteus, several unidentified genera belonging to the family Enterobacteriaceae and the species Clostridium perfringens and Enterococcus faecalis. A greater abundance of histaminogenic bacteria would favor the accumulation of high levels of histamine in the gut, its subsequent absorption in plasma and the appearance of adverse effects, even in individuals without DAO deficiency. Full article

(This article belongs to the Special Issue Unfolding New Evidence on Histamine Intolerance)

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8 pages, 271 KiB

Open AccessArticle

Basal Serum Diamine Oxidase Levels as a Biomarker of Histamine Intolerance: A Retrospective Cohort Study

by Valentina Cucca, Giuseppe A. Ramirez, Patrizia Pignatti, Chiara Asperti, Marco Russo, Emanuel Della-Torre, Daniela Breda, Samuele E. Burastero, Lorenzo Dagna and Mona-Rita Yacoub

Nutrients 2022, 14(7), 1513; https://doi.org/10.3390/nu14071513 - 05 Apr 2022

Cited by 13 | Viewed by 4492

Abstract

Background: Histamine Intolerance (HIT) is a multifaceted pseudoallergic disorder possibly due to defective histamine metabolism. Diamine oxidase (DAO) contributes to histamine degradation and can be measured in the serum. The role of DAO measurement in the diagnostic work-up of HIT still remains unclear, and conflicting results have been reported in the literature. Therefore, we aimed to evaluate the possible clinical usefulness and consistency of DAO value ranges as provided by the assay manufacturer and verify whether they could predict the response to treatment. Methods: We retrospectively analyzed 192 outpatients with HIT symptoms and measured serum DAO values at baseline. Patients were prescribed either with low-histamine diet and/or enzymatic supplementation according to symptom severity and re-evaluated six to eight months later. Patients were stratified into three groups according to DAO levels: <3 U/mL, 3–10 U/mL, and >10 U/mL. HIT severity was assessed on a scale of 1 to 5 before and after treatment. Results: A total of 146 patients completed the study. Gastrointestinal and cutaneous symptoms, often associated with headache, were more frequent in subjects with DAO < 10 U/mL. Symptom severity and DAO ranges were correlated. Patients with intermediate DAO levels (3–10 U/mL) showed a more complex clinical phenotype but also a more significant improvement in symptom severity (score reduction 50%, interquartile range (IQR) = 33–60%) when compared to patients with low DAO (40%, IQR = 20–60%; p = 0.045) or high DAO (33%, IQR = 0–50%; p < 0.001). Complex clinical phenotypes were also more frequent in patients with intermediate DAO levels. Conclusions: HIT is characterized by typical symptoms and low levels of DAO activity. Symptom severity was associated with the degree of DAO deficiency. Patients with DAO values between 3 and 10 U/mL show the best response to treatment (low-histamine diet and/or DAO supplementation). DAO value could arguably be considered as a predictor of clinical response to treatment. Prospective studies are needed to confirm these data. Full article

(This article belongs to the Special Issue Unfolding New Evidence on Histamine Intolerance)

10 pages, 1017 KiB

Open AccessArticle

Low-Histamine Diets: Is the Exclusion of Foods Justified by Their Histamine Content?

by Sònia Sánchez-Pérez, Oriol Comas-Basté, M. Teresa Veciana-Nogués, M. Luz Latorre-Moratalla and M. Carmen Vidal-Carou

Nutrients 2021, 13(5), 1395; https://doi.org/10.3390/nu13051395 - 21 Apr 2021

Cited by 18 | Viewed by 21697

Abstract

A low-histamine diet is currently the most advised strategy to prevent the symptomatology of histamine intolerance. Conceptually, these diets should be founded on the exclusion of histamine-containing foods, although a certain disparity is found within the list of excluded foods in accordance with the different low-histamine diets available in the literature. This study aimed to critically review low-histamine diets reported in the scientific literature, according to the histamine and other biogenic amine contents of the excluded foods. A total of ten scientific studies that provided specific recommendations on the foods that must be avoided within the framework of a low-histamine diet were found. Overall, the comparative review brought out the great heterogenicity in the type of foods that are advised against for histamine intolerant individuals. Excluded foods were, in most cases, different depending on the considered diet. Only fermented foods were unanimously excluded. The exclusion of 32% of foods could be explained by the occurrence of high contents of histamine. The presence of putrescine, which may interfere with histamine degradation by the DAO enzyme at the intestinal level, could partly explain the reason why certain foods (i.e., citrus fruits and bananas) were also frequently reported in low-histamine diets. Finally, there was a range of excluded foods with an absence or very low levels of biogenic amines. In this case, certain foods have been tagged as histamine-liberators, although the mechanism responsible has not yet been elucidated. Full article

(This article belongs to the Special Issue Unfolding New Evidence on Histamine Intolerance)

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9 pages, 1225 KiB

Open AccessArticle

Increasing Expiratory Hydrogen in Lactose Intolerance Is Associated with Additional Food Intolerance/Malabsorption

by Wolfgang J. Schnedl, Nathalie Meier-Allard, Sonja Lackner, Dietmar Enko, Harald Mangge and Sandra J. Holasek

Nutrients 2020, 12(12), 3690; https://doi.org/10.3390/nu12123690 - 30 Nov 2020

Cited by 8 | Viewed by 3309

Abstract

Single and/or combined food intolerance/malabsorption may cause nonspecific, functional gastrointestinal (GI) complaints. In lactose-intolerant patients we evaluated the influence of additional food intolerance/malabsorption with hydrogen (H₂) breath tests. In a retrospective analysis of charts from 279 lactose-intolerant patients, we found 128 patients with only lactose intolerance (LIT). Then, we identified 106 LIT patients with additional histamine intolerance (HIT). Additionally, 45 LIT and HIT patients also had fructose malabsorption (FM). A hydrogen (H₂) breath test was performed to evaluate LIT and FM. A serum diamine oxidase value of <10 U/mL and a response to a histamine-reduced diet was used to identify HIT. Using pairwise comparison with the Kruskal–Wallis test to associate the area under the curve (AUC) of LIT patients and, LIT with HIT, to LIT with HIT and FM it was found, that the exhaled hydrogen values were significantly higher in patients with two-fold and triple combined food intolerance/malabsorption (p < 0.004 and p < 0.001, respectively). Within the pool of 170 LIT patients with >20 ppm increase of expiratory H₂ from baseline, there were 74 LIT-only patients, 60 LIT with HIT patients, and 36 LIT patients with additional HIT and FM. With the Kruskal–Wallis test AUCs demonstrated a significant difference between all three groups (p = 0.024). In patients with LIT, the presence of additional food intolerance/malabsorption, significantly increases expiratory H₂ values. We demonstrate evidence, which may suggest HIT to embody an own GI disorder as food intolerance/malabsorption. Full article

(This article belongs to the Special Issue Unfolding New Evidence on Histamine Intolerance)

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Review

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21 pages, 1426 KiB

Open AccessReview

Histamine Intolerance—The More We Know the Less We Know. A Review

by Martin Hrubisko, Radoslav Danis, Martin Huorka and Martin Wawruch

Nutrients 2021, 13(7), 2228; https://doi.org/10.3390/nu13072228 - 29 Jun 2021

Cited by 38 | Viewed by 25019

Abstract

The intake of food may be an initiator of adverse reactions. Food intolerance is an abnormal non-immunological response of the organism to the ingestion of food or its components in a dosage normally tolerated. Despite the fact that food intolerance is spread throughout the world, its diagnosing is still difficult. Histamine intolerance (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. Manifestations may be caused by various pathophysiological mechanisms or a combination of them. The problem with a “diagnosis” of HIT is precisely the inconstancy and variety of the manifestations in the same individual following similar stimuli. The diagnosing of HIT therefore requires a complex time-demanding multidisciplinary approach, including the systematic elimination of disorders with a similar manifestation of symptoms. Among therapeutic approaches, the gold standard is a low-histamine diet. A good response to such a diet is considered to be confirmation of HIT. Alongside the dietary measures, DAO supplementation supporting the degradation of ingested histamine may be considered as subsidiary treatment for individuals with intestinal DAO deficiency. If antihistamines are indicated, the treatment should be conscious and time-limited, while 2nd or 3rd generation of H₁ antihistamines should take precedence. Full article

(This article belongs to the Special Issue Unfolding New Evidence on Histamine Intolerance)

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14 pages, 317 KiB

Open AccessReview

Histamine Intolerance Originates in the Gut

by Wolfgang J. Schnedl and Dietmar Enko

Nutrients 2021, 13(4), 1262; https://doi.org/10.3390/nu13041262 - 12 Apr 2021

Cited by 35 | Viewed by 18284

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. Full article

(This article belongs to the Special Issue Unfolding New Evidence on Histamine Intolerance)

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