Histamine intolerance

Medical condition

Histamine intolerance

Other names| Histaminosis
Specialty| Immunology

Histamine intolerance (HIT) is a medical condition characterized by an imbalance between histamine intake through the diet and the body's ability to metabolize ingested histamine. This imbalance leads to increased blood histamine concentration, which can cause adverse effects. HIT is considered a non-immunological disorder that results from reduced activity or levels of the enzymes that metabolize histamine: diamine oxidase (DAO) and histamine N-methyltransferase (HNMT). Besides histamine, other amines, such as histidine, contribute to the condition.[1][2]

The exact prevalence of HIT is unknown due to limited data and a lack of validated diagnostic methods. The diagnosis typically involves a thorough patient history, taking into account clinical manifestations associated with the ingestion of high-histamine foods as well as response to dietary changes such as low-histamine diets.[1][2]

## Signs and symptoms[edit]

HIT symptoms are wide-ranging and may affect various physiological systems, including the skin, gastrointestinal, cardiovascular, respiratory, and nervous systems. Common symptoms include abdominal distension, postprandial fullness, diarrhea or constipation, headaches or migraines, dizziness or lightheadedness, flushing or redness of the face, hives, itchiness, and runny nose. These symptoms are not specific to HIT and may overlap with other conditions or disorders.[1][2]

## Causes[edit]

The exact causes of HIT are not fully understood, but they can be multifactorial. One of the factors believed to cause HIT is an imbalance between uptake of histamine and other amines such as histidine through the diet and a diminished capacity to metabolize ingested amines, leading to an increased blood concentration of the amines which may potentially cause adverse effects. The primary cause of HIT is considered to be insufficient activity or reduced levels of the enzyme diamine oxidase (DAO), which normally metabolizes histamine in the gut. Factors that may contribute to HIT include endogenous overproduction of histamine due to allergies or mastocytosis, genetic inheritance resulting in reduced DAO activity or effectiveness, pathological factors such as intestinal diseases affecting DAO production or function, pharmacological factors like medications inhibiting DAO activity, and alterations in gut microbiota leading to increased levels of bacteria secreting biogenic amines.[1][3][4]

## Mechanism[edit]

The pathogenesis of HIT involves an imbalance between uptake of histamine and other amines through the diet and a diminished capacity to metabolize those amines. This can be due to insufficient activity or levels of the enzymes diamine oxidase (DAO), and histamine N-methyltransferase (HNMT), which are responsible for breaking down histamine. Of these two enzymes, DAO is responsible for breaking down ingested histamine and other amines in the intestines. In case of DAO deficiency, there is an increased concentration of blood amines, leading to adverse effects throughout the body. The exact mechanisms underlying DAO deficiency are not fully understood but may involve genetic factors, pathological conditions affecting DAO production, or medications that inhibit DAO activity. As for the HNMT, the exact mechanisms by which deficiency or impaired activity of HNMT causes HIT are also not fully understood, and may involve genetic factors, or medications that inhibit HNMT activity. Variations in genes encoding for HNMT have been identified as potential contributors to increased susceptibility to allergic diseases and more severe courses of conditions like atopic dermatitis and allergic rhinitis. While deficiencies in DAO are considered the primary cause of HIT, variations in both DAO and HNMT genes could play a role in its development. The interplay between these enzymes influences how effectively histamine is broken down and cleared from the body.[5][6]

The imbalance in histamine intolerance is between the synthesis and selective release of histamine from certain granulocytes (i.e., mast cells and basophils), versus the breakdown of histamine by the enzymes which metabolize it, such as diamine oxidase (DAO) and histamine N-methyltransferase (HNMT).[2]

In contrast, allergic reactions involving an immediate allergic response to an allergen are caused by anaphylactic degranulation, which is the abrupt and explosive release of "pre-formed mediators", including histamine, from mast cells and basophils throughout the body.[7]

## Diagnosis[edit]

The diagnosis of HIT is challenging due to its nonspecific symptoms and lack of validated diagnostic tools.[1][3][4]

There are no specific tests that can definitively diagnose HIT. The primary approach for diagnosing HIT is through a thorough evaluation of clinical symptoms and their improvement or resolution after following a low-histamine diet. An assessment should also be made to rule out other potential causes of similar symptoms, such as allergies, mastocytosis, gastrointestinal diseases, and medication-induced inhibition of diamine oxidase (DAO) enzyme activity. Additionally, genetic testing for single-nucleotide polymorphisms (SNPs) in genes related to DAO function may provide supportive evidence for the diagnosis but cannot confirm it on its own. Other complementary tests have been proposed but require further validation before being widely accepted as diagnostic tools for HIT. These include measuring plasma DAO activity levels and conducting intradermal skin allergy tests with histamine.[1][3][4]

While serum DAO activity determination offers additional diagnostic utility for HIT, supplementing clinical evaluation and assessment, it is cautioned that sole reliance on DAO activity measurements may not sufficiently establish the diagnosis due to the limited correlation between the result serum DAO activity measurement and the condition.[8]

## Treatment[edit]

Currently, a low-histamine diet is recommended as the primary approach for managing HIT symptoms. It is also recommended to avoid DAO-blocking medications and substances that may increase histamine levels, such as alcohol and certain food additives. Additional treatment options include antihistamines, mast cell stabilizers, supplementation with exogenous diamine oxidase (DAO), however, there is no solid research to validate effectiveness of these additional treatment options in HIT.[1][3][4]

## Epidemiology[edit]

The exact prevalence of HIT is unknown due to limited data and a lack of validated diagnostic methods. The diagnosis typically involves a thorough patient history, taking into account clinical manifestations associated with the ingestion of high-histamine foods as well as response to dietary changes such as low-histamine diets. There is some prediction that incidence of HIT in the general population is estimated to be about 1%, with 80% of them being middle-aged. Still, these figures are likely incorrect and cannot be relied upon because this prevalence estimate is not supported by robust scientific evidence or validated diagnostic methods. Because HIT symptoms can mimic those seen in other conditions such as food allergies or intolerance to sulfites and biogenic amines like tyramine, there is often confusion in differentiating the causal agent responsible for adverse reactions. This further complicates accurate diagnosis and estimation of disease burden. There is limited evidence from double-blind placebo-controlled provocations (DBPC) studies on adverse reactions to histamine-containing foods or other agents associated with HIT. Therefore, solid date focused on understanding pathophysiology, clinical presentation, and improved diagnostic tools is needed before reliable estimates can be made regarding epidemiological aspects of HIT.[2]

## See also[edit]

* Mast cell
* Basophil
* Food intolerance
* Red wine headache
* Scombroid food poisoning

## References[edit]

1. ^ a b c d e f g Zingone F, Bertin L, Maniero D, Palo M, Lorenzon G, Barberio B, Ciacci C, Savarino EV (November 2023). "Myths and Facts about Food Intolerance: A Narrative Review". Nutrients. 15 (23): 4969. doi:10.3390/nu15234969. PMID 38068827.
2. ^ a b c d e Maintz, L.; Novak, N. (2007). "Histamine and histamine intolerance". American Journal of Clinical Nutrition. 85 (5): 1185–96. doi:10.1093/ajcn/85.5.1185. PMID 17490952.
3. ^ a b c d Shulpekova YO, Nechaev VM, Popova IR, Deeva TA, Kopylov AT, Malsagova KA, Kaysheva AL, Ivashkin VT (September 2021). "Food Intolerance: The Role of Histamine". Nutrients. 13 (9): 3207. doi:10.3390/nu13093207. PMC 8469513. PMID 34579083.
4. ^ a b c d Schnedl WJ, Enko D (April 2021). "Histamine Intolerance Originates in the Gut". Nutrients. 13 (4): 1262. doi:10.3390/nu13041262. PMC 8069563. PMID 33921522.
5. ^ Zhao Y, Zhang X, Jin H, Chen L, Ji J, Zhang Z (March 2022). "Histamine Intolerance-A Kind of Pseudoallergic Reaction". Biomolecules. 12 (3): 454. doi:10.3390/biom12030454. PMC 8945898. PMID 35327646.
6. ^ Hrubisko M, Danis R, Huorka M, Wawruch M (June 2021). "Histamine Intolerance-The More We Know the Less We Know. A Review". Nutrients. 13 (7): 2228. doi:10.3390/nu13072228. PMC 8308327. PMID 34209583.
7. ^ Moon TC, Befus AD, Kulka M (2014). "Mast cell mediators: their differential release and the secretory pathways involved". Front Immunol. 5: 569. doi:10.3389/fimmu.2014.00569. PMC 4231949. PMID 25452755. "This release of pre-formed mediators enables not only rapid anaphylactic reactions and allergic responses but also initiates recruitment of leukocytes to sites of pathogen invasion, activation of innate immune processes, and inflammatory responses (1). ... Two types of degranulation have been described for MC: piecemeal degranulation (PMD) and anaphylactic degranulation (AND) (Figures 1 and 2). Both PMD and AND occur in vivo, ex vivo, and in vitro in MC in human (78–82), mouse (83), and rat (84). PMD is selective release of portions of the granule contents, without granule-to-granule and/or granule-to-plasma membrane fusions. ... In contrast to PMD, AND is the explosive release of granule contents or entire granules to the outside of cells after granule-to-granule and/or granule-to-plasma membrane fusions (Figures 1 and 2)."
Figure 1: Mediator release from mast cells
Figure 2: Model of genesis of mast cell secretory granules
Figure 3: Lipid body biogenesis
Table 2: Stimuli-selective mediator release from mast cells
8. ^ Arih K, Đorđević N, Košnik M, Rijavec M (October 2023). "Evaluation of Serum Diamine Oxidase as a Diagnostic Test for Histamine Intolerance". Nutrients. 15 (19): 4246. doi:10.3390/nu15194246. PMC 10574399. PMID 37836530.

## Literature[edit]

* Abbot, Lieners, Mayer, Missbichler, Pfisterer, Schmutz: Nahrungsmittelunverträglichkeit (Histaminintoleranz). HSC, Mauerbach 2006, ISBN 3-9502287-0-5.
* Reinhart Jarisch: Histamin-Intoleranz, Histamin und Seekrankheit. Thieme 2004, ISBN 3-13-105382-8.
* Nadja Schäfers: Histaminarm kochen – vegetarisch. pala-Verlag, Darmstadt 2009, ISBN 978-3-89566-263-8.
* Anja Völkel: Gesunde Küche: bewusst genießen – schmackhaft & lecker. AVA-Verlag, 2013, ISBN 978-3-944321-13-4.
* I. Reese: Streitthema Histaminintoleranz. (CME zertifizierte Fortbildung) In: Der Hautarzt. 65, 2014, S. 559–566, doi:10.1007/s00105-014-2815-2.

## External links[edit]

Classification|

* ICD-10: T78.1

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Authority control databases: National |

* Czech Republic

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