Always on antihistamines? Check your genes.
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Do you have problems with rashes, hives, frequent allergies, flushing, dizziness or headaches, or GI discomfort? Do you take antihistamine medications regularly? Then you might have histamine intolerance, and your genes might be playing a role.
What is histamine? Histamine is a compound produced by immune cells - mast cells and basophils. It’s an important molecule with a number of roles. It supports immune function, especially in response to allergens and parasites. It helps with the production of stomach acid, which aids digestion. It’s released in response to injury and to toxins, causing blood vessel dilation and increased permeability (which allows immune cells to get to areas of infection or injury). And it’s a neurotransmitter – it is important for maintaining wakefulness, attention, and other cognitive functions. [1–4]
But it has its down sides, too, some of which are very well known. Histamine plays a key role in allergic disease, and is involved in symptoms like asthma, itching, sneezing, and runny nose. It also plays a role in severe allergic reactions, or anaphylaxis. At high levels, it can lead to too much stomach acid production. This is what we have antihistamine medications for – to address the results of high histamine levels.[5] And this is a common thing people deal with. Over half of the population takes antihistamines.[6]
As with any molecule in the body, maintaining the right balance of histamine is important, and there are two main pathways involved in histamine metabolism. DAO, which stands for diamine oxidase, in an enzyme that breaks down histamine. DAO is part of one of these pathways (another enzyme, called HNMT, is involved in the other).
DAO is present throughout the body, but plays an outsized role in the GI tract, because while our body produces histamine, we can get it from the outside, too. Certain bacteria in the gut produce histamine, and we can get histamine from food. When this histamine isn’t broken down enough, histamine intolerance can develop, which is a condition with symptoms like headaches, gastrointestinal issues, and skin reactions.[7,8] High histamine levels in the gut may actually play a role in conditions like irritable bowel disease and even inflammatory bowel disease.[9,10]
If DAO is operating at full capacity, all is well and good with histamine management. But it’s actually quite common to have one of several genetic variants leading to decreased DAO function. And if you look at patients with symptoms of histamine intolerance, the variants are extremely common. In one study, 79% of individuals had gene variant associated with decreased DAO activity.
The way to know if you have a DAO variant is through genetic blueprint testing, which can provide insight into other genes involved in histamine metabolism as well.
If you do have a variant, then the question is whether or not it is causing issues. One way to do this is by testing your DAO levels. There are several tests available that do this, which work by measure the concentration and activity of DAO in the blood.
Another approach is to just see if you have symptoms that fit the picture, and then do what you can to support DAO activity as much as possible. One important way to support DAO activity is by supplying the factors that are needed for it to work. Copper is especially important for this, and it is easy to check copper levels with a blood test to make sure they are adequate. Another approach is limiting foods that are high in histamine, which can help take pressure off DAO. Some of these foods include fermented foods, like sauerkraut, kimchi, and miso. We usually think of these as very healthy – but if you have a histamine problem, they may not be the right move. Aged cheeses can also be an issue – these are things like parmesan, which have higher amounts of histamine-producing bacteria in the aging process. Fish and seafood are sometimes an issue, particularly those in the Scombridae family, like tuna and mackerel. In fact, if these aren’t stored properly, they can cause something called scombroid poisoning (which is caused by high histamine). Red wine and beer tend to have high histamine levels, as do certain vegetables like eggplants, spinach, and tomatoes. There are good low-histamine diet plans that can be followed that detail all of this.[12,13]
Some supplements can also help reduce histamine levels. Some probiotics, for example, can help break down histamine—one of these is lactobacillus plantarum. Other things, like quercetin and luteolin, can help reduce histamine levels by blocking the activation of mast cells (and preventing histamine release).[14] And taking DAO as a supplement may also be helpful – several studies have shown benefits of DAO for migraines, itching, and histamine intolerance.[15,16]
In summary, DAO deficiency is common, and is often associated with predisposing genetic variants. Testing for gene variants that are associated with DAO deficiency is straightforward with genetic blueprint testing, and it’s also possible to test DAO levels in the blood. If DAO is an issue, then low histamine diets and targeted supplementation with things like copper, DAO, and quercetin may be beneficial. DAO is usually not the only part of the picture, though. Symptoms related to histamine intolerance are often multifactorial, and understanding all the causes that may be contributing is important.
References
1. Weltman JK. Update on histamine as a mediator of inflammation. Allergy Asthma Proc. 2000;21(3):125-128. doi:10.2500/108854100778148954
2. Jutel M, Akdis M, Akdis CA. Histamine, histamine receptors and their role in immune pathology. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2009;39(12):1786-1800. doi:10.1111/j.1365-2222.2009.03374.x
3. Nomura H, Shimizume R, Ikegaya Y. Histamine: A Key Neuromodulator of Memory Consolidation and Retrieval. Curr Top Behav Neurosci. 2022;59:329-353. doi:10.1007/7854_2021_253
4. Jutel M, Blaser K, Akdis CA. Histamine in allergic inflammation and immune modulation. Int Arch Allergy Immunol. 2005;137(1):82-92. doi:10.1159/000085108
5. The role of histamine in allergic diseases - PubMed. Accessed June 12, 2024. https://pubmed.ncbi.nlm.nih.gov/1699987/
6. Common allergy medications used among adults U.S. 2021. Statista. Accessed June 12, 2024. https://www.statista.com/statistics/1243257/common-allergy-medications-us/
7. Arih K, Đorđević N, Košnik M, Rijavec M. Evaluation of Serum Diamine Oxidase as a Diagnostic Test for Histamine Intolerance. Nutrients. 2023;15(19):4246. doi:10.3390/nu15194246
8. Beltrán-Ortiz C, Peralta T, Ramos V, et al. Standardization of a colorimetric technique for determination of enzymatic activity of diamine oxidase (DAO) and its application in patients with clinical diagnosis of histamine intolerance. World Allergy Organ J. 2020;13(9):100457. doi:10.1016/j.waojou.2020.100457
9. Fiorani M, Del Vecchio LE, Dargenio P, et al. Histamine-producing bacteria and their role in gastrointestinal disorders. Expert Rev Gastroenterol Hepatol. 2023;17(7):709-718. doi:10.1080/17474124.2023.2230865
10. Mou Z, Yang Y, Hall AB, Jiang X. The taxonomic distribution of histamine-secreting bacteria in the human gut microbiome. BMC Genomics. 2021;22(1):695. doi:10.1186/s12864-021-08004-3
11. Structure and Inhibition of Human Diamine Oxidase | Biochemistry. Accessed June 12, 2024. https://pubs.acs.org/doi/10.1021/bi9014192
12. 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):1395. doi:10.3390/nu13051395
13. Wantke F, Götz M, Jarisch R. Histamine-free diet: treatment of choice for histamine-induced food intolerance and supporting treatment for chronic headaches. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 1993;23(12):982-985. doi:10.1111/j.1365-2222.1993.tb00287.x
14. Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N, Nagai H. Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2000;30(4):501-508. doi:10.1046/j.1365-2222.2000.00768.x
15. Yacoub MR, Ramirez GA, Berti A, et al. Diamine Oxidase Supplementation in Chronic Spontaneous Urticaria: A Randomized, Double-Blind Placebo-Controlled Study. Int Arch Allergy Immunol. 2018;176(3-4):268-271. doi:10.1159/000488142
16. Izquierdo-Casas J, Comas-Basté O, Latorre-Moratalla ML, et al. Diamine oxidase (DAO) supplement reduces headache in episodic migraine patients with DAO deficiency: A randomized double-blind trial. Clin Nutr Edinb Scotl. 2019;38(1):152-158. doi:10.1016/j.clnu.2018.01.013