Histamine Testing (and how it does and does not relate to Mast Cell Activation)

A common conversation that I have with my patients relates to the possibility that persistent immune activation is at least partly contributing to their chronic symptoms.

This might have resulted from triggers such as toxins, or infections; and sometimes these triggers are still present and need to be addressed. A lot of the time, the triggers are no longer present to any gainful extent and the resulting persisting immune activation or neurological dysfunction needs to be addressed.

One type of immune activation and dysregulation, discussed at length elsewhere here, is mast cell activation syndrome.

Testing for mast cell activation syndrome

The standard testing for mast cell activation syndrome (MCAS) is to look at a serum tryptase level. This is a relatively expensive test (~250 cad) and is typically done on a baseline day, as well as on a day when symptoms are triggered. The baseline helps to rule out an actual increased number of mast cells, vs an increased in reactivity. The hard part is doing the test when there is a reaction, as typically you want to run the test within 4 hours of a reaction.

I often run a 24 hour methylhistamine level in the urine. This is less affected by dietary histamine variations and is often used in other, possibly related conditions such as interstitial cystitis. It can be useful in mastocytosis and is better than urinary histamine levels for this purpose.

There are other tests available such as prostaglandin D2, but these are difficult for my patients to access with reliable shipping options.

Histamine Intolerance vs MCAS

Patients who have done their own research into their chronic symptoms often come with some understanding of histamine intolerance. They may have tried a low histamine diet, and found some reduction of inflammation. They may take an enzyme supplement called DAO, (diamine oxidase), which metabolizes histamine in the gut, and have some improvement in symptoms.

However, it should be noted that histamine intolerance and MCAS should not be considered interchangeable or equivalent. Mast cells release many different chemicals that mediate inflammation and symptoms. Only one of these is histamine.

Having said that, histamine modulation is one of the mainstays of MCAS treatment as it does treat symptoms. Histamine 1 receptor blockers (H1 blockers) and H2 blockers do help many patients after finding the right medication (sometimes one medication in the same family seems to work while others may not).

These H1 and H2 blockers also likely act to stabilize the mast cells and possibly prevent the release of histamine, as these receptors are also on the mast cells themselves.

Testing for Serum DAO (diamine oxidase) Levels

Another testing option that may be useful in some patients is to look at the levels of the enzyme that degrade and metabolize histamine. This test may be useful for both histamine intolerance as well as mast cell activation syndromes.

A report in 2011 showed:

Over the 3.5-year-long period we have recruited 316 patients with suspicion of histamine intolerance and excluded food allergy together with 20 healthy controls. Serum DAO activity was measured with Enzyme immunoassay for the quantitative determination of histamine-degradation activity by DAO in serum. Twenty patients with histamine intolerance and highly reduced initial activity of serum DAO (<40 data-preserve-html-node="true" HDU/ml) went to a histamine-free diet and after 6 to 12 months of histamine-free diet all clinical parameters and serum for determination of DAO activity were taken again.

We found that DAO activity was significantly lower in patients than in healthy control subjects (P<0.0001). data-preserve-html-node="true" Furthermore, 54 patients had highly reduced activity of DAO (<40 data-preserve-html-node="true" HDU/ml). The main symptoms involved the skin, gastrointestinal tract, respiratory system and eyes. In all 20 patients after the histamine-free diet the main clinical symptoms typical for histamine intolerance have disappeared. Furthermore, the measured values for activity of serum DAO have increased significantly (p<0.0001). data-preserve-html-node="true"

More recently a study in 2022 found that with histamine intolerance (HIT):

HIT is characterized by typical symptoms and low levels of DAO activity. Symptom severity was associated with the degree of DAO deficiency. Patients with DAO values between 3 and 10 U/mL show the best response to treatment (low-histamine diet and/or DAO supplementation).

Serum DAO levels may be a practical test also. Similar to 24 hour levels of urinary methylhistamine, histamine rich meals do not change DAO levels immediately.

Other Conditions and DAO Levels

Histamine intolerance may affect other conditions as well.

There are reduced DAO levels found in migraine patients. This may indicate that some migraine patients may benefit from stabilizing histamine releasing mast cells, and identifying non-traditional migraine triggers such as foods.

Other studies have found that elevated blood histamine levels may be present with premenstrual syndrome, and symptoms can be alleviated by increasing serum DAO activity with things like magnesium.

Intestinal dysbiosis (imbalances in bacteria) may be relieved by a low histamine diet and DAO supplementation. In such cases, treatment might be aimed at reducing the relative abundance of histamine-secreting flora such as Staphylococcus, Proteus, Pseudomonas spp., Aspergillus spp.). I have written also on how dysbiosis and SIBO can contribute to other symptoms such as impaired cognition."

Other histamine degradation testing and pathways

It is also worth noting when thinking about histamine intolerance, and thus the body's ability to degrade histamine, that there is another pathway other than DAO that comes into play.

Histamine can also be degraded by histamine N-methyltransferase. Thus, some labs offer a test called THAK or total histamine degradation capacity. There is less data on this than serum testing of DAO, but it certainly is plausible that it may be a useful test. It does cost about twice as much as DAO typically though.