Autoimmune Thyroid Disease

An Unfortunate and Lengthy Adventure in Misdiagnosis

Histamine intolerance review

with 9 comments

Histamine and histamine intolerance is an excellent review.

Diamine oxidase (DAO) is the main enzyme for the metabolism of ingested histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator release. Conversely, histamine N-methyltransferase, the other important enzyme inactivating histamine, is a cytosolic protein that can convert histamine only in the intracellular space of cells.

DAO is more important than HNMT in histamine metabolism.

Ingestion of histamine-rich food (6), alcohol (7-9), or drugs (10-13) that release histamine or block DAO may provoke diarrhea, headache (14), congestion of the nose, asthmatoid wheezing (6, 8, 15), hypotension, arrhythmia, urticaria (16, 17), pruritus, flushing, and other conditions in these patients. Approximately 1% of the population has histamine intolerance, and 80% of those patients are middle-aged (18). Because of the multifaceted symptoms, the existence of histamine intolerance is frequently underestimated, or its symptoms are misinterpreted. Clinical symptoms and their provocation by certain foods and beverages appear similar in different diseases, such as food allergy and intolerance of sulfites, histamine, or other biogenic amines (eg, tyramine).

It’s virtually impossible to tell the difference between different food chemical reactions.

In mammals, DAO expression is restricted to specific tissues; the highest activities are shown for small bowel and colon ascendens (4, 5, 33) and for placenta and kidney (28, 31). Lower DAO activity has been discussed as a potential indicator of intestinal mucosa damage in inflammatory and neoplastic diseases (17, 24, 34) and in persons undergoing chemotherapy (35). HNMT is widely expressed in human tissues; the greatest expression is in kidney and liver, followed by spleen, colon, prostate, ovary, spinal cord cells, bronchi, and trachea (36). HNMT is regarded as the key enzyme for histamine degradation in the bronchial epithelium (37).

When these scientists talk about ‘intestinal mucosa damage’ they are not talking about intestinal dysbiosis. They are talking about Crohn’s disease, ulcerative colitis and coeliac disease, quite serious diseases.

Histamine can be metabolized by extracellular oxidative deamination of the primary amino group by diamine oxidase (DAO) (2) or intracellular methylation of the imidazole ring by histamine-N-methyltransferase (HNMT) (3). Therefore, insufficient enzyme activity caused by enzyme deficiency or inhibition may lead to accumulation of histamine. Both enzymes can be inhibited by their respective reaction products in a negative feedbackloop (4). N-Methylhistamine is oxidatively deaminated to N-methyl-imidazole acetaldehyde by monoamine oxidase B (MAO B) (5) or by DAO (6).

After histamine is methylated by HNMT, it still needs further metabolism by DAO or MAO B.

Recently, a potential genetic background of a reduced histamine metabolism has also been investigated. The human DAO gene spans {approx}10 kbp and is located on chromosome 7q35 (27) Various single-nucleotide polymorphisms (SNPs) in the DAO gene have been shown to be associated with inflammatory and neoplastic gastrointestinal diseases, such as food allergy (44), gluten-sensitive enteropathy, Crohn disease, ulcerative colitis, and colon adenoma (45-47). No significant difference in the distribution of the investigated HNMT alleles could be shown between patients with gastrointestinal diseases and control subjects (45, 47), but a functional relevant polymorphism of the HNMT gene (chromosome 2q22) has been described for white asthma patients (48). Conversely, this association could not be observed in Japanese (49), German pediatric (50), and East Indian (51) populations. Thus, histamine intolerance seems to be acquired mostly through the impairment of DAO activity caused by gastrointestinal diseases or through the inhibition of DAO, but the high interindividual variations in the expression of DAO in the gut and the association of SNPs in the DAO gene with gastrointestinal diseases provide evidence for a genetic predisposition in a subgroup of patients with histamine intolerance (27).

So impairments in DAO activity (whether genetic or acquired) are thought to be the main cause of histamine intolerance. I wonder whether that HNMT polymorphism in white asthma patients is actually interacting with another ‘white’ (i.e disproportionately present in caucasians) gene that causes it to be significant?

Headache can be induced dose-dependently by histamine in healthy persons as well as in patients with migraine (53, 61). Histamine-induced headache is a vascular headache caused mainly by nitrate monoxide (62). Histamine releases endothelial nitrate monoxide upon stimulation of H1R, which is also expressed in the large intracranial arteries (63). In migraine patients, plasma histamine concentrations have been shown to be elevated both during headache attacks and during symptom-free periods.

Everyone is adversely affected by a dose of histamine that exceeds their own personal tolerance levels.

Besides headache, gastrointestinal ailments including diffuse stomach ache, colic, flatulence, and diarrhea are leading symptoms of histamine intolerance. Elevated histamine concentrations and diminished DAO activities have been shown for various inflammatory and neoplastic diseases such as Crohn disease (17), ulcerative colitis (67), allergic enteropathy (39), food allergy (33, 68, 69), and colorectal neoplasmas (24). In the colonic mucosa of patients with food allergy, a concomitant reduced HNMT (70) and an impaired total histamine degradation capacity (THDC) (69) have been found (33), so that the enzymes cannot compensate each other. Therefore, an impaired histamine metabolism has been suggested to play a role in the pathogenesis of these diseases.

During or immediately after the ingestion of histamine-rich food or alcohol, rhinorrea or nasal obstruction may occur in patients with histamine intolerance; in extreme cases, asthma attacks also may occur. Reduced HNMT activity has been shown for patients with food allergy (70) and asthma bronchiale (71).

Possibly a methylation cycle related connection for some but not all individuals.

In addition to histamine-rich food, many foods such as citrus foods are considered to have the capacity to release histamine directly from tissue mast cells, even if they themselves contain only small amounts of histamine (Table 4). In vitro studies of persons with a history of pseudoallergic reactions to food have shown a fragility of duodenal mast cells with massive degranulation in the presence of histamine-releasing substances that is significantly greater than that shown by control subjects (85). However, clinical studies using oral challenge tests to support the hypothesis for the histamine-releasing capacity of foods are required (22).

You don’t need to have a problem with salicylates to have a reaction to citrus fruits!

Alcohol, especially red wine, is rich in histamine and is a potent inhibitor of DAO (9, 86). The relation between the ingestion of wine, an increase in plasma histamine, and the occurrence of sneezing, flushing, headache, asthma attacks, and other anaphylactoid reactions and a reduction of symptoms by antihistamines has been shown in various studies (7, 8, 14, 65, 87, 88). However, among the multitude of substances contained in wine, other biogenic amines such as tyramine (80) and sulfites (89) have been supposed to contribute to symptoms summarized as “wine intolerance” or “red wine asthma” (19, 89, 90).

How about red wine-violently-throwing-up-sickness? I’ve never been able to tolerate more than a small glass.

In the female genital tract, histamine is mainly produced by mast cells, endothelial cells, and epithelial cells in the uterus and ovaries. Histamine-intolerant women often suffer from headache that is dependent on their menstrual cycle and from dysmenorrhea. Besides the conctractile action of histamine, these symptoms may be explained by the interplay of histamine and hormones. Histamine has been shown to stimulate, in a dose-dependent manner, the synthesis of estradiol via H1R; meanwhile, only a moderate effect on progesterone synthesis was observed (117). The painful uterine contractions of primary dysmenorrhea are mainly caused by an increased mucosal production of prostaglandine F2{alpha} stimulated by estradiol and attenuated by progesterone. Thus, histamine may augment dysmenorrhea by increasing estrogen concentrations. And, in reverse, estrogen can influence histamine action. A significant increase in weal and flare size in response to histamine has been observed to correspond to ovulation and peak estrogen concentrations (118). In pregnancy, DAO is produced at very high concentrations by the placenta (119, 120), and its concentration may become 500 times that when the woman is not pregnant (120). This increased DAO production in pregnant women may be the reason why, in women with food intolerance, remissions frequently occur during pregnancy (14).

Interesting, because oestrogen also decreases monoamine oxidase activity. I’ve thought for ages that I have too much oestrogen.

I’ve also noticed that some women who are usually complete crazy bitches seem perfectly sweet and lovely during pregnancy, whilst other women who seem like perfectly lovely people go nuts. Coming from a family who were closely involved in the administration of a fibromyalgia support network, I’m familiar with the anecdotal ‘fibromyalgia sufferers always get better during pregnancy then relapse again’ phenomenon.


Written by alienrobotgirl

27 April, 2008 at 10:21 am

Posted in The Science of FCI

9 Responses

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  1. I’ve read this paper too. Do you think that a congenital DAO deficiency could be the root cause of early onset eczema, food allergies and ulcerative colitis? By early onset, I mean eczema pretty much at birth, food allergies at 15 months and UC at age 4, but starting to pass just mucus in stools at age 3.

    Do you think that taking a DAO supplement would help to mitigate (or cure?) colitis in this case? I’m thinking DAOsin by Sciotec, if it’s indeed what it claims to be.


    25 May, 2008 at 11:57 pm

  2. Hi beegirl, I hadn’t heard of DAOsin, but it sounds revolutionary! If it works – a big if – it would make a huge difference to people with histamine intolerance.

    It isn’t always possible to figure out the exact cause of the symptoms you describe – they could be caused by any or all of the food chemicals that are problematic to failsafers and might have other possible causes too. It would certainly be worth trying though (unlike nofenol and similar products). Has the failsafe diet not worked well enough, or haven’t you tried it yet?


    10 June, 2008 at 12:58 am

  3. if a shortage of DAO or MAO is a problem with amines/histamine, has anyone looked at copper supplementation. Copper is a component of both DAO and MAO, and it appears from research that a copper deficiency (common) can cause a shortage of DAO and MAO enzymes. I just started taking some copper today.



    26 August, 2008 at 1:44 am

  4. Hi John

    Afraid I know a few people who have tried it and no one has claimed it has helped – me included. I suspect that copper may not be the rate-limiting factor for people with life-long FCIS. I suspect there are many genes involved and that MAO may be limited by other genes and by hormones.


    29 August, 2008 at 10:57 pm

  5. Hi there, I have recently been diagnosed as histamine intolerant by a microbiologist called Dirk Budka, at the Hale Clinic in London, after years of GI probs. He has himself been involved in a new drug called histrelief which is a DAO supplement. I have started taking it but have had no improvement as of yet. Has anyone tried the Sciotec version mentioned by Beergirl?


    13 July, 2009 at 10:40 pm

  6. hi larabara, how did u get on with DAO supplements? I to, have been to see Dirk Budka but so far he’s only put me on a low histamine diet. Would be good to know if they’ve helped others before I try them. Thanks, cybersmiler


    15 December, 2009 at 3:04 am

  7. Hi

    I was diagnosed with histamine intolerance almost 5 months ago and am on my 4th Histrelief bottle…I can say that although at the beginning it was better, now it is worth – it feels like my stomach got so sensitive to everything and is not coping on its own or in fact with this Histrelief…
    I was told that I need to have more patience and wait. Apparently Dirk has a lot of experience with these things, so I am still hoping it will work…
    If you are aiming to achieve balance in your health nowadays (especially digestion) it takes a lot of time if you are not using some heavy medicine.
    Altough it would be nice to know if it actually helped someone yet ?


    16 June, 2010 at 4:50 pm

  8. larabara, how are you?

    i too am seeing Dirk…but not got any great results yet…how are you? has his advice helped you?


    21 June, 2010 at 7:36 pm

  9. Guys, please try to understand that histamine intolerance is just a little part of the problem with the majority of the patients. It is too easy to put it all down to an allergic reaction to foods high in histamines.
    Histamines (as an inflammatory marker) can be found in your heart, in your brain, in your lungs. Severe rheumatoid arthritis is related to histaminosis (a far better word than the harmless sounding “Histamine Intolerance”), Schizophrenia, Chronic Fatigue… you name it… it is all related to histamines.
    It is easy to place a list of histamine rich foods on the web (most of the lists are actually wrong). If avoiding these foods does the job 100%, nobody would blog here any more.
    That’s why we change the recipe of HistRelief all the time.
    Please note, that so far 244 patients have used HistRelief (length: between 1 month and 12 month or even longer).
    Approc. 140 patients are seaying that it helped a lot! 50 are saying that it helped at least a bit. The rest… sorry. No success yet.
    Also bare in mind: the ones who are happy do not blog any more… 🙂
    We keep on working…big promise. So far the development of this drug has cost us over £ 150000 and we are not allowed to make any profits…
    Best wishes
    Dirk Budka
    Immune Clinic London


    1 July, 2010 at 4:55 pm

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