Histamine intolerance and the low histamine diet

Chloe Hall discusses the challenges faced by those with histamine intolerance and how we can help to support our patients.

After years of likely underdiagnosis and very little research on the condition, over the last few years there have been a growing number of research studies looking at histamine intolerance, and the public interest in the area is ever growing. However, we still have a long way to go to fully understand the condition and how we can best manage it.

What is histamine?

Histamine is a biogenic or vasoactive amine and is one of the many chemical mediators produced by our mast cells.^1-3 It is also found in food and drinks that as a result of bacterial degradation during fermentation, storage or decay.^4-6

In our bodies, histamine acts as a chemical messenger and there are four different types of histamine receptors found throughout the body.³ In view of this, histamine has a wide range of physical effects and plays an important role in numerous processes including gastric acid secretion, inflammation, changes in blood pressure and muscle contraction.^1-3

What is histamine intolerance?

Plasma histamine levels are usually very tightly regulated, and normal plasma levels are 0.3-1.0ng/mL, at which level it would cause no symptoms.² Histamine intolerance (HIT) is a ‘disequilibrium of accumulated histamine and the capacity for degradation’, which causes these plasma levels to rise above normal levels and cause a range of distressing symptoms.²

Histamine is broken down in the body by two enzymes:

Diamine Oxidase (DAO) – Stored in in epithelial cells within the small intestine, placenta, kidneys, thymus and seminal plasma and released into the circulation on stimulation.^{3, 7} Primary enzyme for breaking down the histamine in the food and drink that we consume^8-10

Histamine- N-Methyltransferase (HNMT) – Found in the cytoplasm of cells.¹¹ Can only break down histamine inside of cells¹²

What are the symptoms of histamine intolerance?

HIT is a whole-body condition and can involve each body system.^{2, 3} Symptoms can include migraines, dizziness, anxiety, insomnia, tachycardia, irregular heartbeat, low blood pressure, shortness of breath, rhinitis, sore throat, painful periods and gut symptoms. Those with HIT have often seen multiple specialist consultants without a clear diagnosis as often symptoms are looked at individually. It can share some of the symptoms of an allergy so it is important that a primary igE allergy is ruled out before a diagnosis of HIT is made.³

What causes histamine intolerance?

It is thought that there are two main reasons why people may experience HIT.

1.  An overproduction of internal histamine, due to conditions such as Mast Cell Activation Syndrome (MCAS), mastocytosis, allergies and gut dysbiosis²
2. Reduced or slowed histamine breakdown, which is proposed to be due to an impairment or deficiency in DAO.^{2, 3, 13} This has been associated with certain medications,¹⁴ genetics,² hormones¹⁵ and gastrointestinal diseases such as inflammatory bowel disease.¹⁶

Another cause, which is potentially reversible, is competitive inhibition of DAO, which prevents histamine breakdown by the following:

a) Other biogenic amines such as cadaverine and putrescine as DAO breaks these down preferentially and can become saturated leaving little room for histamine breakdown.¹⁷ Biogenic amines such as histamine, cadaverine and putrescine are often found together in food products such as fish and soy sauce and therefore most low histamine diets eliminate foods high in all biogenic amines.¹⁸

b) Medications such as cimetidine and ibuprofen. Other medications can also interfere with

histamine metabolism and distribution such as metoclopramide, doxycycline and many others.³

c) Alcohol. Alcohol is not only usually high in histamine but it also slows histamine breakdown so those with HIT can often be particularly sensitive to alcohol-containing food and drinks.¹⁹

In practice, many dietitians specialist in this area are also seeing a link between women’s health and histamine intolerance. Women are presenting during the menopause with either new onset or an exacerbation of histamine intolerance. Although there is a lack of studies that have looked at this directly, there is some data that looks at the relationship between hormones and histamine. It has been noted that during the premenstrual phase there seems to be an increased sensitivity to histamine.² Oestrogen also appears to influence the action of histamine by increasing the amount produced.²⁰

How is histamine intolerance diagnosed?

There is currently no conclusive biomarker that can diagnose HIT.²¹ Serum DAO can be measured and, although this may add to the evidence that someone has the condition, serum DAO doesn’t always correlate with the activity of the enzyme in the gut, so therefore cannot be used as a definitive diagnostic tool.²²

Diagnosis can be confirmed through an elimination of high histamine foods for two to four weeks followed by a gradual re-introduction to identify individual tolerance to histamine.³ We would consider suggesting this to our patients if they presented with more than two symptoms of histamine intolerance.^{8, 21} It is essential that dietitians are able to effectively support people following the low histamine diet as it can be socially and nutritionally restrictive.

What is the low histamine diet and what foods does it exclude?

There is no gold standard food list for the low histamine diet and these lists can vary widely, making it extremely confusing for patients.²¹ In addition to this, it is impossible to completely eliminate histamine from the diet.²³ There is, however, consensus on some foods, such as fermented foods and tomatoes.²¹ Freshness, storage and manufacturing processes do affect the histamine content of food so discussions around this with patients are key.²¹ Aside from food, the ‘bucket theory’ is often used in relation to HIT, and there are many other factors that may ‘fill up the bucket’.^{24, 25}

Conclusion

HIT can be an extremely challenging condition for patients in terms of following a low histamine diet and also in terms of getting a diagnosis. It is important that we are able to identify the symptoms of HIT and support our patients practically by following a modified histamine diet.

References

1. Vlieg-Boerstra BJ, van der Heide S, Oude Elberink JN, Kluin-Nelemans JC, Dubois AE. Mastocytosis and adverse reactions to biogenic amines and histamine-releasing foods: what is the evidence? Neth J Med. 2005;63(7):244-9.
2. Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007;85(5):1185-96.
3. Hrubisko M, Danis R, Huorka M, Wawruch M. Histamine Intolerance-The More We Know the Less We Know. A Review. Nutrients. 2021;13(7).
4. Bodmer S, Imark C, Kneubühl M. Biogenic amines in foods: histamine and food processing. Inflamm Res. 1999;48(6):296-300.
5. Jansen SC, van Dusseldorp M, Bottema KC, Dubois AE. Intolerance to dietary biogenic amines: a review. Ann Allergy Asthma Immunol. 2003;91(3):233-40; quiz 41-2, 96.
6. Skypala IJ, Williams M, Reeves L, Meyer R, Venter C. Sensitivity to food additives, vaso-active amines and salicylates: a review of the evidence. Clin Transl Allergy. 2015;5:34.
7.  Schwelberger HG, Hittmair A, Kohlwein SD. Analysis of tissue and subcellular localization of mammalian diamine oxidase by confocal laser scanning fluorescence microscopy. Inflamm Res. 1998;47 Suppl 1:S60-1.
8. Comas-Basté O, Sánchez-Pérez S, Veciana-Nogués MT, Latorre-Moratalla M, Vidal-Carou MDC. Histamine Intolerance: The Current State of the Art. Biomolecules. 2020;10(8).
9. Pugin B, Barcik W, Westermann P, Heider A, Wawrzyniak M, Hellings P, et al. A wide diversity of bacteria from the human gut produces and degrades biogenicamines. Microb Ecol Health Dis. 2017;28(1):1353881.
10. Smolinska S, Jutel M, Crameri R, O’Mahony L. Histamine and gut mucosal immune regulation. Allergy. 2014;69(3):273-81.
11. Brown DD, Tomchick R, Axelrod J. The distribution and properties of a histaminemethylating enzyme. J Biol Chem. 1959;234:2948-50.
12. Küfner MA, Ulrich P, Raithel M, Schwelberger HG. Determination of histamine degradation capacity in extremely small human colon samples. Inflamm Res. 2001;50 Suppl 2:S96-7.
13. Tuck CJ, Biesiekierski JR, Schmid-Grendelmeier P, Pohl D. Food Intolerances. Nutrients. 2019;11(7).
14. Sattler J, Hesterberg R, Lorenz W, Schmidt U, Crombach M, Stahlknecht CD. Inhibition of human and canine diamine oxidase by drugs used in an intensive care unit: relevance for clinical side effects? Agents Actions. 1985;16(3-4):91-4.
15. Hamada Y, Shinohara Y, Yano M, Yamamoto M, Yoshio M, Satake K, et al. Effect of the menstrual cycle on serum diamine oxidase levels in healthy women. Clin Biochem. 2013;46(1-2):99-102.
16. Schmidt WU, Sattler J, Hesterberg R, Röher HD, Zoedler T, Sitter H, et al. Human intestinal diamine oxidase (DAO) activity in Crohn’s disease: a new marker for disease assessment? Agents Actions. 1990;30(1-2):267-70.
17. Sánchez-Pérez S, Comas-Basté O, Rabell-González J, Veciana- Nogués MT, Latorre Moratalla ML, Vidal-Carou MC. Biogenic Amines in Plant-Origin Foods: Are They Frequently Underestimated in Low-Histamine Diets? Foods. 2018;7(12).
18. Doeun D, Davaatseren M, Chung MS. Biogenic amines in foods. Food Sci Biotechnol. 2017;26(6):1463-74.
19. Zimatkin SM, Anichtchik OV. Alcohol-histamine interactions. Alcohol Alcohol. 1999;34(2):141-7.
20. Kalogeromitros D, Katsarou A, Armenaka M, Rigopoulos D, Zapanti M, Stratigos I. Influence of the menstrual cycle on skinprick test reactions to histamine, morphine and allergen. Clin Exp Allergy. 1995;25(5):461-6.
21. Sánchez-Pérez S, Comas- Basté O, Veciana-Nogués MT, Latorre-Moratalla ML, Vidal Carou MC. Low-Histamine Diets: Is the Exclusion of Foods Justified by Their Histamine Content? Nutrients. 2021;13(5).
22. Schnedl WJ, Enko D. Histamine Intolerance Originates in the Gut. Nutrients. 2021;13(4).
23. Kohn JB. Is there a diet for histamine intolerance? J Acad Nutr Diet. 2014;114(11):1860.
24. Giannetti A, Filice E, Caffarelli C, Ricci G, Pession A. Mast Cell Activation Disorders. Medicina (Kaunas). 2021;57(2).
25. Afrin LB, Ackerley MB, Bluestein LS, Brewer JH, Brook JB, Buchanan AD, et al. Diagnosis of mast cell activation syndrome: a global “consensus-2”. Diagnosis (Berl). 2021;8(2):137-52.