Published November 3 2014
Histamine is a chemical which plays a role in the inflammatory process, and also acts as a neurotransmitter. It is produced by certain white blood cells, specifically basophils and mast cells, although a few other cells can produce it as well, such as platelets and microglial cells. Some people have an intolerance to histamine, and as a result can experience symptoms such as itching, redness of the skin, hives, congestion or a runny nose, swelling, low blood pressure, arrhythmia, diarrhea, and other symptoms. In addition to talking about histamine intolerance in this article, I’ll also discuss how thyroid conditions can affect the production of histamine, and I’ll also talk about the relationship between histamine and autoimmunity.
I’d first like to talk briefly about histamine metabolism. Histamine is synthesized from the amino acid histidine. It is dependent on vitamin B6, and so a deficiency in this vitamin can in turn affect the production of histamine. Histamine exerts its effects by binding to its four receptors (1), which include histamine 1 receptor (H1R), H2R, H3R, and H4R. Histamine causes smooth muscle cell contraction, vasodilatation, increased vascular permeability and mucus secretion, tachycardia, alterations of blood pressure, it stimulates gastric acid secretion and nociceptive nerve fibers, and it has been known to play various roles in neurotransmission, immunomodulation, hematopoiesis, wound healing, and day-night rhythm (1).
What Is Histamine Intolerance?
Histamine intolerance is due to an imbalance between levels of released histamine and the ability of the body to metabolize it (2). In other words, there is a problem with breaking down histamine, which in turn leads to its accumulation. An enzyme called diamine oxidase (DAO) is primarily responsible for the metabolism of ingested histamine (3). Another enzyme called histamine N-methyl transferase (HNMT) also breaks down histamine, although it seems as if DAO has a greater impact. If someone is unable to metabolize histamine yet eats histamine-rich foods, then this can cause numerous symptoms related to excess histamine which I described in the opening paragraph. And in order to reduce symptoms it is necessary to eat a low-histamine diet and or take antihistamines, although as I’ll soon discuss, other factors can also be responsible for this condition and therefore needs to be addressed.
Why Do Some People Develop A Histamine Intolerance?
There can be a few different reasons why someone with a thyroid or autoimmune thyroid condition (or anyone else) has an intolerance to histamine. One reason can be due to genetic factors, as someone might have a polymorphism (genetic defect) in the DAO gene which in turn lowers DAO, and thus leads to problems breaking down histamine. However, this might be puzzling to someone who doesn’t experience histamine intolerance until adulthood. First of all, keep in mind that someone can have a genetic polymorphism which doesn’t become expressed until adulthood. But genetics isn’t the only factor, as a primary cause of histamine intolerance in many people is gut dysbiosis. What seems to happen is that there is an overgrowth of bacteria which produces histamine from undigested proteins from food. This doesn’t necessary mean that someone who has a histamine intolerance has small intestinal bacterial overgrowth (SIBO), although this is possible. For more information on SIBO you can check out my article entitled “SIBO and Thyroid Health“. Either way, histamine intolerance seems to be acquired mostly through the impairment of DAO activity caused by gastrointestinal diseases or through the inhibition of DAO (1).
Although I frequently recommend for my patients to eat fermented foods, some people who have a histamine intolerance will want to think twice about doing this. Fermented foods of course involve bacteria, which can actually increase the histamine content of foods during the process of fermentation. Keep in mind that I’m not talking about probiotic supplements, as most people with a histamine intolerance don’t have a problem taking these. But they might need to avoid or limit their consumption of fermented foods such as sauerkraut, kimchi, aged cheese, and even processed meat (which hopefully you’re trying to avoid regardless of whether you have a histamine intolerance or not). There are other foods which are histamine-rich, such as spinach and tomatoes. Even though citrus foods aren’t considered to be high in histamine, it seems that they can cause the release of histamine directly from tissue mast cells (1).
There are other potential causes of a histamine intolerance. For example, certain medications can act as DAO inhibitors, and this lead to the overproduction of histamine. Examples of drugs which can cause more histamine release include opiods such as morphine, codeine, and meperidine (4). As a result, if you shortly developed histamine intolerance after taking a certain medication then this is something to keep in mind. Drinking alcohol can also inhibit DAO (5), and this is especially true with regards to red wine.
Having problems with methylation can lead to high histamine levels, which can be problematic for someone who has a histamine intolerance. Proper methylation is important for breaking down histamine. In fact, if you recall, one of the enzymes which helps to break down histamine is called N-methyl transferase (HNMT), which uses S-adenosyl-L-methionine (SAMe) as the methyl donor and transfers this methyl group to the histamine molecule (6). As a result, impaired methylation can lead to greater levels of histamine.
Histamine, Thyroid Health, and Autoimmunity
There have been a few studies involving histamine and thyroid health. One study conducted on neonatal rats showed that the thyroid hormones could be involved in the regulation of the levels of brain histamine by regulating the number of brain mast cells (7). Another study looked at the effects of histamine H1- and H2-receptor antagonists on the pituitary-thyroid axis, and showed that histamine might be able to physiologically regulate TSH and prolactin secretion through H2 receptors in the anterior pituitary (8).
With regards to autoimmunity, histamine has an effect on dendritic cells, immunoregulatory cells, T-cell polarization and cytokine production, and thus can play a role in immune system disorders, including autoimmune conditions (9). Another journal article discusses how histamine can play a role in the pathogenesis of autoimmune conditions (10). Histamine apparently affects the Th1/Th2 cytokine balance (11). I have spoken about this in a past blog post entitled “The Role of Cytokines In Autoimmune Thyroid Conditions“, as I discussed how Hashimoto’s Thyroiditis is typically a Th1 dominant condition, while Graves’ Disease is usually a Th2 dominant condition. In any case, this study has to do with atopic asthma, which is associated with an increase in the number of Th2 cytokines and a decrease in the number of Th1 cytokines, and the authors mentioned that histamine enhances the secretion of Th2 cytokines and inhibits the production of Th1 cytokines. So based on this information it is possible that increased histamine levels might shift the balance towards Th2 dominant conditions such as Graves’ Disease. I did come across one older study which showed that there may be an abnormality in the H-2 receptors in Graves’ disease suppressor T lymphocytes, which can play a role in the development of Graves’ Disease (12).
In addition, histamine may have an impact in the pathogenesis of brain diseases which are associated with inflammatory conditions, such as multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease, possibly by increasing pro-inflammatory cytokines, as well as levels of something called inducible nitric oxide synthase, also known as iNOS (13). This form of nitric oxide can in turn lead to the formation of free radicals which can damage neurons ((13). Just to summarize, histamine can lead to neuroinflammation due to the release of pro-inflammatory cytokines and nitric oxide.
Is There a Natural Treatment Solution For Histamine Intolerance?
If someone has a histamine intolerance, they should try to minimize their consumption of foods high in histamine. In addition, taking certain nutritional supplements can help to minimize the effects of histamine. One of these is vitamin C, which is a cofactor for DAO. And so in addition to eating foods high in vitamin C, supplementing with vitamin C can be a safe and effective method of minimizing the effects of histamine. Other cofactors of DAO include vitamin B6 and copper (14). But probably the most effective in helping with histamine intolerance is quercetin, as there is plenty of evidence which shows that quercetin effectively blocks histamine (15) (16) (17). In fact, one study showed that quercetin is potent enough to suppress the anaphylactic reaction associated with peanuts (18). Keep in mind that this study was conducted on rats, and so if you or anyone you know has a peanut allergy and think that taking quercetin will allow you to safely eat peanuts I would think twice before trying this.
Of course eating low histamine foods and taking nutrients such as vitamin C, vitamin B6, copper, and quercetin won’t cure the histamine intolerance. As I mentioned earlier, intestinal dysbiosis could be the cause of histamine intolerance. And so if someone has problems with dysbiosis then this needs to be corrected, and doing so might correct the histamine intolerance. I also briefly mentioned how methylation is important to break down histamine, and so if someone has impaired methylation then this needs to be addressed.
In summary, histamine is a chemical which plays a role in inflammation, and numerous factors can lead to higher histamine levels than one can tolerate. The enzyme diamine oxidase (DAO) is the main enzyme which breaks down histamine, and so factors which inhibit this enzyme can cause high levels of histamine. Intestinal dysbiosis and impaired methylation are factors which need to be considered for anyone who has histamine intolerance. Thyroid hormones can potentially regulate the levels of histamine by effecting the number of mast cells, and so this also needs to be considered. In addition, there is some evidence that histamine can play a role in the pathogenesis of autoimmune conditions, and might be more common in Th2 dominant conditions.