Hist­amine Into­le­rance: Ever­ything about Testing and Getting Diagnosed.

The diagnosis of hist­amine into­le­rance is not easy, simply because too much hist­amine causes symptoms — even in healthy people! The ques­tion is always whether the observed reac­tion is normal, given the inge­sted hist­amine dose.

The following tests are used to diagnose hist­amine into­le­rance, although some are curr­ently still scien­ti­fi­cally contro­ver­sial and medical guide­lines do not recom­mend using them for now:

  • Hist­amine provo­ca­tion testing with a hist­amine solution.
  • DAO measu­re­ment in the blood (contro­ver­sial)
  • Hist­amine 50 prick test (rarely used)
  • Omis­sion test: hist­amine elimi­na­tion diet (recom­mended1)
  • Genetic testing for vari­ants with lower hist­amine degra­dation capa­city (DAO & HNMT polymorphisms)

Hist­amine Provo­ca­tion Testing

In some specia­lized outpa­tient clinics, a hist­amine provo­ca­tion test is performed by giving the test subjects a solu­tion with a defined amount of hist­amine to drink, depen­ding on their weight. However, there is a signi­fi­cant risk of life-threa­tening reac­tions (swel­ling of the respi­ra­tory tract, drop in blood pres­sure) that cannot be dismissed. Also, the signi­fi­cance of this test is limited because ever­yone reacts to hist­amine — the only ques­tion is how strongly. Previous consump­tion of alcohol, hist­amine-rich food, or other biogenic amines can also falsify the test result.

The German guide­line for hist­amine into­le­rance regards hist­amine provo­ca­tion testing as possibly helpful in estab­li­shing the diagnosis, if the change in diet has been successful.1

Diamine Oxidase Levels in the Blood

Diamine oxidase (DAO) mainly breaks down hist­amine inge­sted from food and is typi­cally found in the intes­tinal mucosa in the gastro­in­tes­tinal tract (see causes of hist­amine intolerance).

There­fore, the diamine oxidase level or DAO serum acti­vity in the blood is some­times used to diagnose hist­amine intolerance.

However, the current guide­line on hist­amine into­le­rance does not consider this measu­re­ment suffi­ci­ently evidence-based and there­fore does not recom­mend it.1

As things stand, it is also not yet clear to what extent the DAO level or acti­vity of diamine oxidase in the blood is related to the acti­vity and presence of diamine oxidase in the intes­tine, where the enzyme is most needed to break down biogenic amines.

In some studies, the DAO level in the control group of subjects was also below the defined thres­hold, although these people did not expe­ri­ence hist­amine into­le­rance symptoms. Also, the signi­fi­cance of DAO measu­re­ments in the blood as a marker for iden­ti­fying people who have symptoms after hist­amine consump­tion varies from study to study, leading to further doubts about these tests’ useful­ness.1

This article is about a health issue. It is important that you have your symptoms examined and treated by medical profes­sio­nals. This article is not intended to be, and cannot be, a substi­tute for the care and advice of medical profes­sio­nals that may be avail­able to you.

Hist­amine-50-Prick Test

In so-called prick tests performed by an aller­gist, a control prick test with hist­amine is usually done. The control patch serves as a compa­rison for a reac­tion to one of the other tested subs­tances. It is assumed that hist­amine usually causes a corre­spon­ding skin reac­tion, e.g., a wheal. The reac­tion (wheal, redness) on the skin then serves as a control.

In the Hist­amine 50 prick test, the hist­amine wheal from an allergy prick test is reas­sessed after 50 minutes. The under­lying assump­tion is that the wheal’s size should decrease over time due to the break­down of hist­amine. An unch­anged size would there­fore be indi­ca­tive of a hist­amine degra­dation disorder.1

Hist­amine Elimi­na­tion Diet: The Best Test & at the Same Time a Therapy.

In the hist­amine elimi­na­tion diet, hist­amine-rich foods are consist­ently avoided for 14 days. If this leads to a clear impro­ve­ment of the symptoms, then one can assume a hist­amine into­le­rance. In a second step, one should expand the diet step by step to find the personal limit.1,2

In the case of a strict elimi­na­tion diet, it may also be helpful to omit other foods contai­ning biogenic amines. These require the same enzymes for degra­dation in the body as hist­amine, like diamine oxidase (DAO).2

histamine hmnt dao degradation
Degra­dation of Hist­amine & Biogenic Amines via DAO and HNMT

Genetic Testing in Cases of Suspected Hist­amine Degra­dation Disorder

In the case of severe symptoms, genetic tests can be carried out to see whether varia­tions in the genes that are jointly respon­sible for hist­amine break­down in the body are present. These varia­tions, called poly­mor­phisms, occur natu­rally, and many are not clas­si­fied as patho­lo­gical and disease-causing.

But certain genetic varia­tions in the DAO gene, for example, in the sequence vari­ants rs2052129, rs2268999, rs1049742, and rs10156191, are asso­ciated with reduced DAO acti­vity. Thus, the body is less able to break down the hist­amine produced.3–5

In addi­tion to diamine oxidase, hist­amine methyl­trans­ferase, or HMNT, is respon­sible for degra­ding hist­amine. Poly­mor­phisms can also be present here. The HNMT C314T geno­type results in a 30–50% reduc­tion in hist­amine methyl­trans­ferase acti­vity and is more common in people with aspirin into­le­rance (AERD), for example.6,7

Depen­ding on the cause of the hist­amine into­le­rance syndrome (HIS), the treat­ment approa­ches differ. In the case of genetic poly­mor­phisms, it is often sensible to ensure that the hist­amine-degra­ding enzymes DAO and HNMT are not addi­tio­nally blocked in their acti­vity by certain drugs, if not medi­cally necessary.

Fecal Hist­amine Testing: Non-Specific and rather a Dysbiosis Marker

Hist­amine in stool is gene­rally not a specific marker for hist­amine into­le­rance. There may be hist­amine or other biogenic amine-forming bacteria in the intes­tine that produce high hist­amine levels in stool depen­ding on their compo­si­tion or if the bacteria have over­grown.8

There­fore, a high hist­amine level in the stool is more indi­ca­tive of a possibly unfa­vor­able compo­si­tion of the intes­tinal flora and does not necessa­rily have to be asso­ciated with hist­amine intolerance.

However, an over­growth of hist­amine-forming bacteria can increase the amount of hist­amine produced in the body and over­load the degra­dation capa­city. These unfa­vor­able processes, in turn, can lead to hist­amine-mediated symptoms.8

Urinary Methyl­hist­amine: Elevated in Gastro­in­tes­tinal Aller­gies and Mast Cell Disease.

Urinary methyl­hist­amine is also not a specific marker for hist­amine into­le­rance and does not help diagnose hist­amine into­le­rance. Instead, elevated methyl­hist­amine may indi­cate an allergy in the gastro­in­tes­tinal tract or mast cell dise­ases, such as mast cell acti­va­tion syndrome (MCAS) or masto­cy­tosis.9

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Who is affected by hist­amine intolerance?

Around 80% of pati­ents affected by hist­amine into­le­rance are female, and between 25 and 45 years old. Affected women often report a cycle-depen­dency of their symptoms, so a link to sex hormones is assumed.1,2

In severe cycle-depen­dent symptoms, gyne­co­lo­gists some­times prescribe “the pill” in the long-term cycle with fewer breaks to regu­late or stop the monthly bleeds. However, it is not uncommon that oral contracep­tives (“the pill”) are not well tole­rated in sensi­tive women with intolerances.

During pregnancy, an impro­ve­ment in hist­amine into­le­rance-related symptoms can often be observed, as diamine oxidase, respon­sible for the break­down of hist­amine, incre­ases many times over. This increase protects the unborn child from hist­amine excess.10

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  1. Reese I, Ballmer-Weber B, Beyer K, et al. German guide­line for the manage­ment of adverse reac­tions to inge­sted hist­amine: Guide­line of the German Society for Aller­go­logy and Clinical Immu­no­logy (DGAKI), the German Society for Pediatric Aller­go­logy and Envi­ron­mental Medi­cine (GPA), the German Asso­cia­tion of Aller­go­lo­gists (AeDA), and the Swiss Society for Aller­go­logy and Immu­no­logy (SGAI). Allergo J Int. 2017;26(2):72–79. doi:10.1007/s40629-017‑0011‑5
  2. Maintz L, Novak N. Hist­amine and hist­amine into­le­rance. Am J Clin Nutr. 2007;85(5):1185–1196. doi:10.1093/ajcn/85.5.1185
  3. García-Martín E, Martínez C, Serrador M, et al. Diamine Oxidase rs10156191 and rs2052129 Vari­ants Are Asso­ciated With the Risk for Migraine. Headache: The Journal of Head and Face Pain. 2015;55(2):276–286. doi:https://doi.org/10.1111/head.12493
  4. Agúndez JAG, Luengo A, Herráez O, et al. Nonsyn­ony­mous poly­mor­phisms of hist­amine-meta­bo­li­sing enzymes in pati­ents with Parkinson’s disease. Neuro­mole­cular Med. 2008;10(1):10–16. doi:10.1007/s12017-007‑8017‑7
  5. Meza-Veláz­quez R, López-Márquez F, Espi­nosa-Padilla S, Rivera-Guillen M, Ávila-Hernández J, Rosales-González M. Asso­cia­tion of diamine oxidase and hist­amine N‑methyltransferase poly­mor­phisms with presence of migraine in a group of Mexican mothers of children with aller­gies. Neuro­logia. 2017;32(8):500–507. doi:10.1016/j.nrl.2016.02.025
  6. Kim S‑H, Kang Y‑M, Cho B‑Y, Ye Y‑M, Hur G, Park H‑S. Hist­amine N‑methyltransferase 939A>G poly­mor­phism affects mRNA stabi­lity in pati­ents with acetyl­sa­li­cylic acid-into­le­rant chronic urti­caria. Allergy. 2009;64:213–221. doi:10.1111/j.1398–9995.2008.01795.x
  7. Parejo PA, García-Agúndez JA, Cornejo-Garcia JA, et al. Asso­cia­tion Study of Func­tional Poly­mor­phisms in Genes Involved in Hist­amine Home­o­stasis and Multiple NSAID–Triggered Urti­caria and/or Angio­e­dema and Anaphy­laxis in Pati­ents without Pre-Exis­ting Chronic Urti­caria (MNSAID-UA). Journal of Allergy and Clinical Immu­no­logy. 2013;131(2):AB169. doi:10.1016/j.jaci.2012.12.1266
  8. Schink M, Konturek PC, Tietz E, et al. Micro­bial patterns in pati­ents with hist­amine into­le­rance. J Physiol Phar­macol. 2018;69(4). doi:10.26402/jpp.2018.4.09
  9. Raithel M, Hagel A, Albrecht H, et al. Excre­tion of urinary hist­amine and N‑tele methyl­hist­amine in pati­ents with gastro­in­tes­tinal food allergy compared to non-allergic controls during an unrestricted diet and a hypo­al­ler­genic diet. BMC Gastro­en­te­ro­logy. 2015;15(1):41. doi:10.1186/s12876-015‑0268‑4
  10. Maintz L, Benfadal S, Allam J‑P, Hage­mann T, Fimmers R, Novak N. Evidence for a reduced hist­amine degra­dation capa­city in a subgroup of pati­ents with atopic eczema. J Allergy Clin Immunol. 2006;117(5):1106–1112. doi:10.1016/j.jaci.2005.11.041


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Natur­o­path, hypno­the­ra­pist, owner of an immune system gone crazy with various auto­im­mune special effects. She likes reading through medical papers and is an avid learner of all things regar­ding the human immune system. When her joints and body allow it: enthu­si­astic do-it-your­selfer around the house.

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