In brief: Histamine is a signaling molecule (mediator) that facilitates communication between cells and is present in every healthy person. We ingest histamine through food, which is broken down by the enzymes DAO and HNMT in our intestines. If these enzymes do not function properly, symptoms can occur in many parts of the body. In more detail:
1. Histamine is produced by bacteria (and fungi) from the amino acid histidine found in proteins, using their own enzyme (histidine decarboxylase). Aged, stale, smoked, fermented, preserved, sourdough, not fresh, several days old, not cold-processed, pickled, etc., products can contain higher amounts of histamine. If we cannot break down the histamine ingested with food, symptoms occur.
2. Additionally, there are foods, drinks, and additives that trigger the release of histamine from our own body.
3. Thirdly, there are foods, additives, and drinks that inhibit histamine-degrading enzymes (DAO, HNMT).
Diamine oxidase (DAO) breaks down histamine outside the cells, while histamine-N-methyltransferase (HNMT) functions within the cells. DAO plays the more important role. These two enzymes act as a barrier, preventing histamine from being absorbed through the intestinal wall.
If this barrier fails, histamine may trigger a cascade of reactions similar to allergy and inflammation. Additionally, internal histamine stores may also play a role in the condition.
Histamine is one of the most important signaling molecules in the immune response even in healthy individuals, allowing cells to "communicate" with one another.
In medical terminology, the term histamine intolerance is better replaced by the more widely accepted term histamine adverse reaction (or biogenic amine adverse reaction, though this latter refers to a broader category). The essence of a histamine adverse reaction is that histamine intake through food is not broken down properly due to primary or secondary causes. As a result, this mediator molecule causes pathological reactions through histamine receptors (H1–H4), potentially affecting multiple organ systems. It is possible, that this condition may only act as a predisposing factor and not as an independent disease.
OTHER biogenic amines
Simplified: Foods may also contain other substances similar to histamine, which can intensify symptoms in people with histamine intolerance. In more detail: Putrescine, tyramine, cadaverine (spermine/spermidine, phenylethylamine, agmatine, tryptamine) are biogenic amines similar to histamine. These are also produced by bacteria and fungi during the breakdown of amino acids in foods. They are mostly broken down by the DAO enzyme. This means that if these substances are present in food, DAO has less capacity to break down histamine. More histamine results in stronger intolerance symptoms.
Fruits, vegetables, spoiled fish (even after just a few hours), and meats can contain such substances. However, it is primarily histamine that causes symptoms, not the other biogenic amines, since histamine practically reaches the "toxic" dose more easily, while the other biogenic amines have relatively higher toxic thresholds.
Problems related to laboratory tests:
Histamine remains in the blood for a very short time due to its short half-life (minutes).
Other diseases can also cause elevated histamine levels.
The DAO enzyme level (concentration) is measured, whereas its function should be assessed.
HNMT level and function are not yet measurable.
Ideally, DAO function should be measured in the intestine (where it is produced).
DAO concentration values are often abnormal even in asymptomatic individuals.
No commercial test is available for histamine receptors.
Approximately 200 enzymes, proteins, and genes form a complex system that would need to be made easily measurable.
Unfortunately, none of the currently available tests in Hungary are suitable for diagnosis according to the valid German medical protocol (guideline).
Urine histamine test (Laborexpress), imidazole acetic acid, N-methylhistamine test (used to infer DAO, HNMT activity, approx. 30,000 HUF): The problem with this test is that, according to the literature, it is completely unreliable. Results can be abnormal in symptom-free individuals and normal in symptomatic patients. Many other conditions (allergy, anaphylaxis, inflammation, etc.) can cause urine abnormalities. If the value is abnormal, the patient may suffer from histamine intolerance (symptoms and lab results must be evaluated together). However, a normal result definitely does not mean the absence of histamine intolerance! Older Spanish research sources recommend this test, but the German guideline does not. I do not recommend it.
Fecal histamine level: Not suitable for diagnosis. For several reasons, for example, Lactobacilli that are part of the normal flora also secrete histamine.
Serum (blood) histamine level (Synlab, sample sent to Germany, approx. 22,000 HUF): Elevated levels can be found in asthmatics, urticaria patients, dermatological patients, allergy sufferers, etc. Histamine-intolerant individuals may also have normal values, and healthy people may have abnormal values. Plasma histamine levels fluctuate significantly within a single day; measurement is likely optimal around midday (see this article: doi: 10.1111/all.13361). Regardless, it may play a role in diagnosis, though not as a standalone test. I recommend testing with medical interpretation.
Serum (blood) DAO enzyme concentration (Synlab) (approx. 20,000 HUF): This is the most important test! Not recommended alone (but NOT a useless test, worth doing!). All tests available in Hungary measure enzyme LEVELS, not FUNCTION! This is problematic because even if enzyme levels are good, its function may be impaired. Thus, a good lab result may mislead someone to think they do not suffer from the condition, while they are actually histamine sensitive. The German medical guideline does not recommend this test. Nevertheless, it is not useless, since no other tools exist. I suggest the following interpretation:
Bad result + symptoms = disease probable
Bad result + no symptoms = healthy
Good result = unfortunately, the test did not help diagnosis, as someone can still be histamine sensitive despite this
According to the currently valid German medical care protocol (guideline), the following tests are (approximately) reliable
Histamine-50 Prick test:
The usual prick skin allergy test's histamine control should be read at 20 and 50 minutes. If the diameter of the central, edematous (swollen) wheal exceeds 35 mm, it may indicate histamine intolerance (source: doi: 10.5402/2011/353045).
Measurement of enzyme activity in the intestines (endoscopy – biopsy during procedure):
DAO is primarily produced and utilized in the intestines. Histamine must be broken down here, as this is where it enters with food. Human serum (blood) DAO levels do not necessarily correlate with enzyme levels in the small intestine. This would be the most reliable method, but it is not performed in Hungary.
HNMT enzyme activity measurement:
Unfortunately, there is no such test available.
DAO enzyme ACTIVITY measurement (approx. 20,000 HUF, determined from blood serum) is not available in Hungary. It is performed by IMD Labor Berlin and Synlab in Germany. According to current scientific findings, this test would be the most important element for diagnosis. However, its value can be abnormal in healthy individuals, and there are further issues and difficulties with the test that doctors must consider.
Plasma (blood) histamine concentration (approx. 25,000 HUF, Synlab, sample sent to Germany): This can be an important diagnostic tool but cannot be interpreted alone. Many factors influence its level: allergies, other diseases (e.g., allergic asthma), food intake, time of day. Results may be normal in histamine intolerant individuals and abnormal in healthy people, and can also be normal during active histamine symptoms. Histamine breaks down very quickly in the blood, so the right moment for measurement may be missed. It has no significance as a sole test result.
Other testing option: Oral histamine challenge (histamine dissolved in water), performed with 75 mg histamine. This can only be done under hospital conditions because it can cause life-threatening complications/shock even in healthy individuals. The histamine preparations required for the test can only be obtained by doctors and are not commercially available.
How is the diagnosis established according to the German protocol?
1. Currently, the primary tool for diagnosis is the PATIENT INTERVIEW.
2. The suspicion is confirmed by measuring serum DAO ACTIVITY (or activity measurement in the intestine). The diagnosis is confirmed by genetic testing and can be supported by plasma histamine level measurement.
3. A trial diet is necessary (about 4 weeks, but the difference can be felt after just a few days).
4. Other tests are not suitable for diagnosis (e.g., a GOOD result in the DAO level measurement offered by Synlab does not exclude the disease, but a BAD result may support the suspicion of the disease).
5. After the trial diet, the patient must be re-challenged with foods to be avoided in a low-histamine diet to determine the individual tolerance level, as sensitivity varies from person to person.
Supplementary tests
Tryptase (Synlab, blood test) to rule out mastocytosis (a hematologic disease)
Vitamin B6 level or active vitamin B6 level (pyridoxal-5-phosphate, blood test, Synlab), which is a cofactor of the DAO enzyme (its deficiency may impair DAO function)
Serum copper (Cu) (Synlab, blood test) (and zinc, since high zinc levels may be associated with low copper), which is a cofactor of the DAO enzyme (its deficiency may impair DAO function)
Complete blood count, inflammatory markers, etc.
To be considered: colonoscopy, gastroscopy, and other specialist examinations
There are hundreds of mutations in the DAO and HNMT gene regions. However, the literature mentions only six that can significantly impair enzyme function (see below). These mutations can be tested abroad (e.g., IMD Laboratory, Berlin, with a medical referral). These are expensive tests (approx. 130,000 + 70,000 HUF).
If a person has one of these mutations, the condition is likely inherited (so other family members may also have similar complaints). However, many people with these mutations remain asymptomatic, so this test alone is not sufficient for diagnosis.
DAO mutations:
rs2052129, rs2268999, rs10156191, rs1049742 HNMT mutations:
rs1050891, rs11558538
Why hasn’t my doctor heard of this condition?
In short: It is likely not yet taught at universities. There is still no unified scientific consensus. At present, there is also no standardized, reliable diagnostic method.
In more detail: As long as a disease presents with symptoms that are difficult to detect, describe, or reproduce, representatives of evidence-based medicine are understandably skeptical — as I myself was. Fortunately, the role of histamine has been well described and continues to be extensively researched. However, when a histamine-sensitive patient is exposed to the same dose of histamine on two separate occasions, they may experience different symptoms each time — which are often subjective and hard to verify externally. The situation is further complicated by the wide range of diets people promote and experiment with, making it difficult to establish objective standards. In addition, unverified information spreading online adds to the confusion.
