What is histamine?
Histamine is a natural molecule that is found nearly everywhere in our body. It has a variety of key roles in the immune system, stomach, blood vessels, and nerve cells. Histamine is made from amino acids in our body by an enzyme called histidine decarboxylase (1). Although histamine is very important in our body, at high levels, it can cause symptoms such as runny nose, itchy eyes and more. As a result, we have two major enzymes that break it down and keep its levels in check: diamine oxidase (DAO) and histamine-N-methyltransferase (HNMT) (2). The table below summarizes the roles of these 2 enzymes.
Histamine Breakdown Enzymes (3) |
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Enzyme |
DAO |
HNMT |
% Histamine broken down |
50-80% |
15-30% |
Location |
Primarily outside of cells: breaks down histamine from foods or outside sources |
Primarily inside of cells: breaks down histamine made inside the cells |
What does histamine do?
Histamine can produce a wide variety of effects by binding to any one of four histamine receptors (homes) scattered all over the body. When histamine binds, each receptor produces a unique set of effects (1).
Histamine Receptors (1, 4, 5) |
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Receptor |
Receptor Location |
Effects |
H1R |
Brain, blood vessels, smooth muscle, and heart. |
|
H2R |
Mainly gut, but also smooth muscle and heart. |
|
H3R |
Throughout nervous system |
|
H4R |
Immune cells |
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What is histamine intolerance (HIT)?
We have discussed ways we obtain histamine from inside our body, but there are many foods that contain histamine as well. The environment surrounding us contains a lot of bacteria that are able to make histamine and release it. Much of this histamine ends up in the foods we eat, especially fermented food or food that is left out (6). Some examples include fish, cheese, fermented meat, vegetable derivatives, and fermented beverages (7). As histamine enters our gut, DAO is responsible for breaking it down. It turns out, the more DAO present in our gut, the more we are “protected” from this environmental histamine (3).
Histamine can become toxic when we get too much of it in our body. This phenomenon is known as histamine intolerance. It results from an imbalance between intake and breakdown of histamine (8). This imbalance is caused by high amounts of histamine in our food or inefficient DAO enzymes (9). In either case, histamine builds up in our body and we start to experience side effects like upset stomach, dizziness, headaches, breathing issues, and skin rashes (3).
How do genes play into histamine intolerance?
Scientists have identified variations in the DAO gene, called single nucleotide polymorphisms (SNPs), that can affect DAO. They can either change how much DAO we make or how efficient our enzyme is at breaking down histamine (9). Thus, depending on which variation of the DAO enzyme we have, we each have different chances of experiencing HIT. The table below summarizes some key SNPs in the DAO gene.
DAO Variations (3, 10, 11, 12) |
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SNP RSIDs |
Effect |
Ethnicity Affected |
rs2052129 |
Reduced amount of DAO enzyme made, leading to higher histamine levels |
Caucasians |
rs45558339 and rs35070995 |
Reduced amount of DAO enzyme made, leading to higher histamine levels |
Asians and Africans |
rs10156191, rs1049742, rs2268999, rs1049793 |
Decreased ability to break down histamine, leading to increased histamine levels |
Caucasians |
I suspect I have HIT, what should I do?
Histamine intolerance is difficult to diagnose because people experience it in different ways (3). If you suspect you have histamine intolerance, you first need to make sure you don’t have food allergies or gut problems. Once those are ruled out, start paying close attention to your diet, alcohol intake, and medications. It turns out, many foods and compounds (i.e. fermented foods) can affect histamine levels and DAO enzyme activity. Limiting alcohol intake can also be beneficial. Studies have found that alcohol can reduce DAO activity and lead to increased histamine levels (3, 13). On a similar note, certain medications (see table below) may also interfere with DAO activity (14). Thus it is a good idea to review your medications with your practitioner to make sure your medications aren’t contributing to the problem.
DAO enzymes are a great option to help you break down histamine. These are supplements that contain the enzymes your body may not be producing adequate levels. you try a low histamine diet for 1-2 months under the supervision of a nutritionist or trained practitioner (7). While you try a low histamine diet, it’s a good idea to create a detailed diary of all foods you eat. Be sure to take note of your side effects and track improvement/worsening of these symptoms. You can also give genetic tests a shot. Genetic tests are a great tool to help you find more definite answers sooner. Toolbox Genomics offers a histamine panel that can identify genetic variants in DAO that may cause histamine intolerance. We want to help you, please feel free to reach out to us for more information.
Sample Low-Histamine Diet (8,15,16,17) |
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Breakfast |
Lunch |
Dinner |
Supplements |
|
|
|
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High-Histamine Foods (8, 14) |
|
Food Item |
Examples |
Fish (frozen or canned) |
Mackerel, herring, sardine, tuna, anchovy |
Cheese |
Gouda, camembert, cheddar, emmental, swiss, parmesan |
Meat |
Fermented sausage, salami, fermented ham, pork, chicken |
Vegetables |
Sauerkraut, spinach, eggplant, tomato ketchup |
Vinegar |
Red wine vinegar |
Alcohol |
White wine, red wine, fermented beer, champagne |
Fermented Foods |
Fermented cabbage, radish, soy bean paste, red pepper paste, mayonnaise, yogurt |
Medications associated with higher histamine (14) |
|
Medication Class |
Examples |
Analgesics |
Morphine, NSAIDs, Aspirin |
Antihypertensives |
Alprenolol, dihydralazine, verapamil, clonidine |
Antibiotics |
Cefuroxime, Isoniazid, Clavulanic Acid, Chloroquine, |
Diuretics |
Amiloride |
Antidepressants |
Amitriptyline |
H2-Receptor Antagonists |
Cimetidine |
Muscle relaxants |
Pancuronium, alcuronium |
Revised References: