Impaired resolution of wheals in the skin prick test and low diamine oxidase blood level in allergic patients
Aneta Wagner1, Krzysztof Buczyłko2, Hanna Zielińska-Bliźniewska1, Waldemar Wagner3
1Allergology and Respiratory Rehabilitation Department, Medical University of Lodz, Lodz, Poland
2NZOZ Allergology Center, Lodz, Poland
3Laboratory of Cellular Immunology, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
Adv Dermatol Allergol 2019; XXXVI (5): 538–543
Introduction: Histamine is the major mediator of IgE- and non-IgE-mediated allergic reactions upon allergen or
hapten contact. Reduced histamine degradation capacity was associated with atopic eczema as well as with nonimmunological
histamine intolerance. Higher blood serum histamine level concomitant with decreased intestinal
diamine oxidase activity were observed in patients with food allergy.
Aim: To evaluate the relationship between patients’ blood diamine oxidase (DAO) activity/histamine status and
their reactivity to time-resolved histamine skin prick test in respect to vulnerability to allergic diseases.
Material and methods: Fifty-three patients were examined with skin prick tests (SPT) and patch tests for suspected
presence of either IgE- or non-IgE-mediated allergy. All individuals were skin prick tested with histamine and the
resolution of the wheal was monitored for 50 min. Blood DAO activity and histamine concentration were measured
with a radio-extraction radioimmunoassay.
Results: Time-resolved histamine skin prick testing revealed presence of wheals which were 35% larger in diameter
in 47% of examined subjects at 20 min of the test. These patients exhibited significantly compromised time-course
wheal resolution (wheal ≥ 3 mm at 50 min) compared to a group of patients with the normal-rate of wheal resolution
(wheal = 0 mm at 50 min). Within a group of subjects exhibiting impaired wheal resolution, 61% of patients
were diagnosed allergic compared to 50% in a group of patients with a normal rate of wheal resolution. Finally,
allergic patients were characterized by a significantly lower DAO activity and higher histamine content compared
to healthy subjects.
Conclusions: The results of this study indicate that patients with IgE- or non-IgE-mediated allergy are likely to
have low DAO blood activity and may concomitantly suffer from histamine intolerance. Furthermore, our results
suggest that allergic patients are more likely to develop an excessive SPT reaction. Our results emphasize caution
in interpretation of the SPT results in allergic patients with diagnosed histamine intolerance or histamine/DAO
The past 20 May was published in the European Journal of Neurology an article in which the doctors Wolfgang J Schnedl and Robert Queissner stated that there was apparently a greater relationship between the cause of migraines and histamine rather than with ethanol present in alcoholic beverages.
In the letter to the editor that have published both doctors, reflect on another recent publication of Onderwater et al, in the same magazine, in which it is intended to show by epidemiological studies a causal relationship between ethanol of alcoholic beverages and the development of migraines in people who consume.
However, both doctors argue that no one has been identified as specific pathophysiologic mechanism that correlate the alcohol intake with migraines and headaches (being the red wine the alcoholic beverage that has been related in the study population of Onderwater et al with migraine).
They argue, in contrast, that greater evidence exists so far as a cause of migraines and headaches are the deficit of the enzyme diamine oxidase (DAO) (alteration in the main route of metabolism of dietary histamine and can be present as a heritable genetic alteration) and the effects that generate exogenous histamine and other biogenic amines (such as tyramine, phenylethylamine, putrescine, cadaverine, spermidine, serotonin, tryptamine, agmatin) when they accumulate in plasma after being ingested.
The results of measurement of these amines into alcoholic beverages show that has been quantified higher concentrations in red wine (with concentrations >2,200 μg/L), being double the concentration that can be found in the white wine ( ~900 μg/L), and much higher even than in distilled spirits such as vozka. This difference in concentration also has been related to a lower incidence of migraine in studies in which the population consumed vozka than in the population that consumed wine.
With regard to the pathophysiologic mechanism of the cause of migraines by DAO deficiency, certain genotypes of the enzyme DAO and its allelic variants (all of them involved in a deficit of the enzyme activity) have shown association with increased risk of migraine. On the other hand, recent studies consisting of double-blind randomized trials in which a population of migraine patients were treated with supplements of DAO, have shown a reduction in the number, frequency, and intensity of migraines. States of these results, other studies of supplementation with DAO on patient population with intolerance to histamine (HIT), has shown a reduction of headaches and the rest of the symptoms related to this pathology.
Outside the interest and data and studies shown about people affected with a diagnosis of DAO deficiency and intolerance to histamine, this letter to the editor does not mention the inhibitory role of ethanol on the activity of the diamine oxidase, which explains the syndrome of the hangover after the acute intake of alcohol in people without a diagnosis of HIT or DAO deficiency.
Dr. Wolfgang J Schnedl is professor of internal medicine and doctor in the General Internal Medicine Practice Theodor Könerstrasse (Austria), and Dr. Robert Queissner is a professor in the Department of Psychiatry and Psychotherapeutic Medicine of the Medical University of Graz (Austria).
Next Monday 17 June (2019), will take place from 14.00 to 16.00 hours in the University Rovira i Virgili (Edifici N5 Sustainable Chemistry, Assembly Hall.Marcel.li Sunday, 2-4-6, Sescelades Campus 43007-Tarragona, Spain) the training activity “DAO deficiency and the role of the pharmacist in the diagnosis and treatment” (language: Spanish).
This training is organized by DR Healthcare, Spanish biomedical company leader in research and development in deficit of DAO, by the Col·legi Oficial de Farmacèutics of Tarragona and by the University Rovira i Virgili (URV), and endorsed by the International Society of DAO Deficiency, maximum scientific authority at the international level in DAO Deficiency.
It is a free training and in which you can obtain a certificate of attendance issued by the International Society of DAO Deficiency.
The training focuses on the role of the pharmacist in the diagnosis and treatment of the DAO deficiency, as it is a metabolic alteration that affects a 16% of the population and is involved in the cause of chronic diseases highly disabling as migraine, fibromyalgia and irritable bowel, as well as a wide range of neurological, dermatological, rheumatologic and gastrointestinal disorders.
Below shows the programming and the speakers of the training.
We wait for you
Migraines appear more likely to be caused by histamine rather than ethanol.
Eur J Neurol. 2019 May 20. doi: 10.1111/ene.14003. [Epub ahead of print]
1General Internal Medicine Practice, Dr. Theodor Körnerstrasse 19b, 8600, Bruck, Austria.2Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Auenbruggerplatz 36, 8036, Graz, Austria.
We read with interest the manuscript by Onderwater et al. that reported on alcoholic beverages as a trigger factor for migraines . Although, epidemiological studies have found a correlation between alcohol intake and headaches, a specific pathophysiologic mechanism of this headache remains unidentified . Particularly red wine was documented as the most common trigger for migraines in this evaluated population . Most commonly found biogenic amines in wine – histamine, tyramine, phenylethylamine, putrescine, cadaverine, spermidine, serotonin, tryptamine, agmatine – and, flavonoids have suspected relevance for migraines and this implies that ethanol seems not to be the main culprit for the headaches . This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Alcohol; Diamine oxidase; Headache; Histamine intolerance; MigrainePMID: 31106460 DOI: 10.1111/ene.14003
According to a study the 90% of migraines can be treated with the enzyme DAO – Interview of RTVE to Juanjo Duelo, CEO of DR Healthcare
7/3/2013 – interview to Juanjo Duelo in rtve 24h. Language: Spanish
These last hours has been spoken about migraines, from which has been made public that the fifteen percent of the world’s population suffers from these tremendous headaches that go beyond a headache. Juanjo Duelo, in addition to suffering from migraines, directs a research team that assures to be able to determine the causes of migraines and most importantly, their solution.
“Our market is the world and we began to be an international reference” – interview in eduscopi to Juanjo Duelo, CEO of DR Healthcare
8/5/2019 – original interview published in eduscopi
The patient Congressman
Affected by strong migraines for many years, Juanjo Duelo, who was dedicated to the world of finance, decided to start to learn first-hand the latest research about this symptom who accompanied him from quite young.
He began to attend medical conferences that addressed the topic of migraine and compared the information he received to that provided by the tests conducted on him his self as a patient at home.
He began to control his diet and saw that between the food and the migraine had some kind of relationship. Determined to find a solution to his problem and for millions of people, looked for researchers that endorse his hypothesis. Twelve years after he created DR Healthcare company with more than 80 patents and now it is a reference on the study of the DAO enzyme.
What prompted the creation, twelve years ago, of DR Healthcare?
We were born as a start-up of the University of Barcelona (UB), always linked to the Department of Nutrition and we seek in the world of academia if there was any research team with interest in our project. We wanted to find some scientific basis that will find the relationship between food and migraine, because until then we had no physiological or chemical explanation to explain this relationship.
Our market is the world and we began to be an international reference” – Juanjo Duelo, CEO of DR Healthcare
What was behind your research?
Doing research on histamine , which is a key molecule in our body because it regulates many functions. The problem is that the same molecule also forms in most of the foods from the diet, and the histamine that everyday we consume with food does not have a physiological function such as the produced by the body. This makes that when it reaches the intestine being degraded, metabolized and eliminated and not absorbed. In this context, a key enzyme in the metabolism of histamine is called Diamine Oxidase (DAO).
There are people who by a motive, mainly genetic, cannot degrade the histamine that ingest from food, and, like is not metabolised, it is absorbed through the intestinal epithelium and then enters the bloodstream and accumulates in the blood. There are individuals who accumulate histamine in the blood faster than others, and there are several others who suffer symptoms earlier than others. But it was never linked before to food because the relationship between you eat the food and the appearance of symptoms does not occur immediately.
In the year 2010 we published the first study that showed that more than 90% of migraine patients had a genetic variation that produces a deficiency in the activity of diamine oxidase enzyme.
Is it being a very productive line of research?
The field of migraine is where we have generated more scientific evidence, that is our main concern. We move in the field of medical nutrition, which is to tackle diseases through nutrition, and we need scientific evidence before looking for the clinical evidence. After publishing many studies on migraine and headaches, now we focus a lot on fibromyalgia or ADHD (Attention Deficit Hyperactivity Disorder).
What is the solution the company offers to those affected by migraine headaches or symptoms associated to the DAO deficiency?
From a clinical point of view, people who have a DAO deficiency, their track therapy is twofold: on the one hand dietetic, controlling the intake of histamine and other secondary amines. And, depending on the activity level of DAO, other path is, at least in the first stage, restore, replace or complement DAO. And this is where we work in the DAO form animal, plant or biotechnology origin. We speak of very prevalent diseases (migraine, ADHD, fibromyalgia…) and we treat them as symptoms.
Over these 12 years of life where has evolved DR Healthcare?
Now we have abandoned the main focus of migraine and guide our research to the DAO and its role as a biomarker.
And you have decided to get out of Barcelona and seek alliances with the University Rovira i Virgili (URV) through a new R&D&i center in Tarragona
Accurate. The relationship with the UB is really satisfactory for us, but now we have also been attracted by the dynamism of the URV and we think that complement each other well . And in front of the need for growth of the company, we saw that we needed to boost an ambitious center with pilot tests with this enzyme, always with the premise that we didn’t want to leave Catalonia. We are an innovative company that begins to be an international reference and we believe that the relationship with the URV is a good option. With the URV Foundation we want to promote research projects jointly with other areas or departments of the University, always linked to the DAO. This is why who is leading this project is Jaume Bori, a graduate in biotechnology at the URV. He directs the Center for R+D+i and works to turn it into a reference center from where we will promote various projects. Over the years we have become a singular company, since we are the only specialists in DAO and its mainly deficiency and associated symptoms.
We have generated more than 80 patents, all with the enzyme DAO, and we are the only company that has this asset.
What functions assumes the center of Tarragona?
We want to complement the investigation initiated in the UB on DAO of plant origin, and also recombinant DAO. And the more immediate objectives are to begin looking for connectivities in the campus and within the scope of the University in order to find synergies and projects in other areas. At the moment, the forecast is to dedicate a 70% of the activity to research and a 20% to the production of the enzyme.
Which is your market?
Our market is the world. We have generated more than 80 patents, all with the enzyme DAO, and we are the only company that has this asset.
To access the original interview in catalan clic here.
The biomedical company DR Healthcare installs a research center and production plant on the Campus of Rovira i Virgili University – Indicador d’Economia
The center will dedicate 75% of the activity in research and a 25% in the production of the enzyme DiAmine Oxidase (DAO) as an ingredient in functional foods
DR Healthcare has invested 500,000 euros in this new center for research and in the production plant, both located in the Sescelades Campus of the URV (Tarragona, Spain). This biomedical company manufactured in Tarragona the enzyme that is the essential ingredient of its innovative product indicated for the dietary treatment of migraine.“The URV is a dynamic university and in Tarragona we hope to generate many synergies with different research groups located in the same campus” explains Juanjo Duelo, founder and CEO of DR Healthcare.
DR Healthcare was founded 12 years ago as a emergent company (start up) of the Universitat de Barcelona to investigate the relationship between diet and migraine. In 2010 published one of the first studies, which demonstrated the relationship between the DAO deficiency and the triggering of migraine. In these years the company, with headquarters in Barcelona, has focused the activity to generate scientific and clinical evidence about the deficit of diaminooxidase, the key enzyme in the metabolism of histamine. This deficiency leads to a series of associated disorders that, in addition to migraine, include fibromyalgia, dermatological problems, rhinitis, irritable bowel syndrome or Attention Deficiency- Hyperactivity Disorder (ADHD).
The dietary product of DR Healthcare for the treatment of migraine obtained last year the official certificate of the European Union that categorizes it as “new food with therapeutic objective.” This new recognition should definitely boost the marketing of the DAO enzyme as “food for special medical purposes,” according to Duelo, beyond the 500 pharmacies in within the Spanish state that they have participated in a pilot test.
The goal of the new plant of DR Healthcare
The company has generated more than 80 patents and the aim of the Tarragona plant is to continue with the production of DAO of animal origin for marketing, in addition to do research to lead to other modalities of this enzyme, such as that of plant and biotechnology origin. “We are the only company specialized in DAO deficiency and in the treatment of its associated symptoms, and we want that the plant of Tarragona to become a center of reference from where we will promote various research projects in collaboration with other departments of the University,” explains Juanjo Duelo, founder and director of the company.The plant has been installed in the building N5 of the Sescelades Campus and will be managed by Jaume Bori, holds a bachelor’s degree in Biochemistry and Biotechnology by the URV and PHD in Environmental Engineering. His figure will depend on the scientific department of the company, and will be devoted to seek synergies in the environment of the URV and launch projects with different areas of the University.The incorporation of this new company in the campus is in the line of the University, who wants to promote the relationship with the company and to promote the transfer of knowledge for the benefit of society.
Other arguments in favor of this location, according to Duelo is that “we are looking for partners to be able to expand all over the world. If we have to use the airport of Tarragona or the Prat, we will obtain the same as if we are in Barcelona.”
Objective of the URV: The attraction of companies of high technological value
The attraction of companies of high technological value is a strategic objective for the URV, who currently maintains advanced negotiations with another company in the health sector. “This type of companies are very interesting because with their level of specialization cause interaction, mutual learning and generate new opportunities and projects. Contribute to raise the bar of the research that we do in the university,” explains Lourdes Jane, director of the Center for Transfer of Technology of the Foundation URV.
Data of interest
The Technology Transfer Center of the Foundation URV managed 318 collaboration contracts with companies and institutions the year 2018. Transfer contracts allow to create applicable solutions, and from the research results that are generated in the university. Of the 190 clients with whom collaborated the URV last year, 85 are private companies. The rest are public entities, associations, foundations and cooperatives. The sum of the value of contracts was supposed to the university 5.6 million euros of income.
Access the original new through here.
Published on 28-3-2019 – Infosalus.com – Language: Spanish.
From the Spanish Society of Allergology and Clinical Immunology (SEAIC), Dr. Pedro Ojeda in an interview to the Media Infosalus indicates that there is a clinical non allergic picture, hereinafter referred to as ” non-allergic histaminosis” or “DAO deficiency”, in which alcohol inhibits the function of the intestinal enzyme diamine oxidase (DAO), causing symptoms such as pseudoallergics itching , redness, abdominal pain and migraine.
If this enzyme is deficient, and in addition is inhibited by alcohol, the person who suffers from this disorder can manifest symptoms pseudoallergics to alcohol consumption, such as itching, redness or abdominal pain” – Dr. Pedro Ojeda of the Spanish Society of Allergology and Clinical Immunology (SEAIC).
In response to the question of whether you may be allergic to alcohol, Dr. Ojeda explains that a person may not be allergic to alcohol, if by alcohol is used to mean “ethanol molecule”. However if you may be allergic to alcoholic beverages by its components. As an example, you may be allergic to proteins in barley, wheat or hops from beer, rage allergy symptoms immediately after the first shot.
In the non-allergic histaminosis produced by DAO deficiency, symptoms appear over time as a result of the silent accumulation of histamine and its effects in tissues and organs. On the other hand these non-allergic reactions can affect people of any age range, although they tend to occur in middle-aged and older.
Possible symptoms of non-allergic histaminosis DAO deficit after consuming alcohol
Dr. Ojeda points out that “in the case of non-allergic histaminosis, the symptoms are usually skin redness, itching skin, and sometimes migraine and hangover.”
For the treatment of this symptomatology, the expert of the SEAIC recommends “avoid alcoholic beverages. There are products on the basis of exogenous Diamino Oxygenase that help alleviate the situation.”
Get access to the original publication here.
The International Society of DAO Deficiency debuts new website and we are delighted that you form part of its members. If you aren`t jet members you can send your request through the next link and enjoy of great benefits.
But before we would like to show you all the news…
¡New Social Network!
Now our membership directory (only accessible for registered users) is a great social network: you can publish content in your wall, make comments in the rest of accounts, send private messages to other members, make your professional profile… all the tools for networking and lead to the development of new projects.
¡News in Communication!
because our mission is to keep you informed
An updated list of scientific publications, congresses, conferences, thesis, studies and clinical trials on DAO Deficiency and its symptoms.
List of innovation projects developed and in progress.
Know the entities involved and access the directory of companies, research centers, universities, institutes and associations of patients who collaborate with us.
Events and activities
Events and activities directory (congresses, conferences and courses) in which you can be informed of the next dates, locations and topics.
Press Room and Blog
Articles, interviews, press releases and audiovisual materials published in the media.
¡We are Science! ¡We are communication!
The Team and the Community of the International Society of DAO Deficiency is waiting for you.
Join and form part of the advancement in the treatment and prevention of this metabolic disorder for which so many population is affected.
30ytantos, ONDACERO – WITH PEPA GEA – Language: Spanish.
@Pepagea |@30ytantosondac1 | medicepepa.es
In this interview from the ONDACERO radio station in its program 30ytantos, Roser Sala, responsible for marketing of SYNLAB (european leader in management and services of clinical and pathological anatomy laboratories), explains what is histamine intolerance, which are their most common symptoms and how it is diagnosed.
Here is the link to the podcast of the interview.
Causes of intolerance to histamine
The histamine intolerance is a disorder whose causes can be genetic, pharmacological or pathological and which produces diverse symptoms throughout the body.
- The genetic causes are due to mutations in the gene of the diamine oxidase (DAO), an enzyme that metabolizes histamine in the intestine, as a part of which is exogenous: from food, thus preventing to be absorbed by the bloodstream. These mutations discovered on the gene of the DAO reduce or prevent its activity, generating an accumulation of histamine.
- The pharmacological factors are related with the use of certain drugs that cause a deficit in the activity of the enzyme diamine oxidase, such as analgesics (aspirin) and tranquilizers (Diazepam).
- Certain inflammatory bowel diseases such as Crohn’s disease, Ulcerative Colitis and colon cancer make decrease the activity of the diamine oxidase to affect parts of the intestinal mucosa that produce it.
All of these can be causes related to the different symptoms involving the histamine intolerance by DAO Deficiency, let`s now to know its symptoms.
Symptoms of DAO deficiency
Migraines and vascular headaches are one of the most notable symptoms, since they are highly disabling diseases and in which is involved the deficit of DAO. According to clinical studies the deficit of DAO is involved in up to 87% of cases of migraine patients.
This intolerance also causes effects on the rest of the systems, triggering a rash, urticaria, dry skin, or atopic dermatitis; hot flashes, dizziness, muscle fatigue, fibromyalgia; indigestion, heartburn, bloating, diarrhea, vomiting… and all the latest studies show that is also involved in the development of the Attention Deficit Hyperactivity Disorder (ADHD), due to the neuronal functions of histamine in the brain.
The histamine is a molecule that we can be found in different food, but which we also manufacture within our cells and it is involved in various regulatory processes in our body. In fact the histamine is involved in the process of inflammation, in the regulation of the immune system, in the neuronal connections (acts as a neurotransmitter in the brain) and one of its most visible negative effects are allergies.
With regard to its origin, as we have already commented the source of histamine is not only internally, but also externally, because it comes from the foods we eat and our digestive process. Rich histamine foods like chocolate, ripe cheeses, monosodium glutamate , the skin of fish, some fruits and nuts, fermented products or pickles, yeast and cured meats or processed contain it in large quantities. On the other hand, alcoholic beverages block the activity of DAO, preventing that it metabolice histamine in the intestine.
In this way, there are people that in order to different causes (genetic, pharmacological or pathological) accumulate histamine in their body, triggering a series of symptoms such as migraine headaches, fibromyalgia, different gastrointestinal and skin disorders, and attention deficit and hyperactivity disorder.
Diagnosis of intolerance to histamine by DAO deficiency
There are no tests to detect the allergy to histamine. What is done in hospitals is a measurement of the diamine oxidase activity in the body by the test MigraTest, Designed to know what level of enzyme activity the patient has and if it is within normal or pathological ranges.
Measures to prevent and treat DAO Deficiency
Patients should be placed in the hands of a doctor and nutritionist. This is the way to control the medication and diet of the patient, to receive recommendations and guidelines to avoid, to the extent possible, certain drugs and foods that are triggering or exacerbating symptoms caused by the DAO deficiency. This joint action allows a correct custom design of treatments that the patient requires for its particular pathological condition to the time that is deployed a diet that will try to feed properly and complete nutrition.
To ensure the benefits of good management of feeding and nutrition for patients, there are dietary supplements of the DAO enzyme , which are functional foods that help to the metabolization of histamine in a natural way, without any side effect, and preventing it from to trigger all symptoms resulting from intolerance to the histamine by DAO deficiency.
Some of these nutraceuticals have been designed and formulated for the specific treatment of certain diseases, such as migraine, fibromyalgia, intestinal dysbiosis, gastrointestinal and skin disorders or attention deficit and hyperactivity disorder.
Other causes of intolerance to the histamine by DAO deficiency
On the other hand, other causes of the DAO deficiency are related with the processes of the intestinal dysbiosis. The intestinal dysbiosis is the alteration of the microbiota of our intestines, the set of microorganisms that live and carry out their functions in our intestines naturally, and that in certain conditions are affected in the tasks involved. Among them we can highlight: the proper absorption of nutrientsa and its function as a barrier of defense against external pathogens such as parasites and viruses. The deterioration of the intestinal micriobita loses the integrity of the intestinal mucosa and can cause malnutrition, and in some cases malnutrition must be controlled from the beginning to avoid illness and highly negative effects.
The intestinal dysbiosis can be caused by overconsumption of antacids, since these unbalance the intestinal pH (increasing it, making alkaline) causing an overgrowth of species that are not inherent in our intestine. The stress and overuse of antibiotics can also cause these processes of deterioration and alteration of our intestinal microbiota.
In this way, due to the complexity of the variety of factors acting in these diseases, from the first moment patients should be in the hands of specialized doctors and nutritionists, make a diagnosis of DAO deficiency and perform a continuous control of both the medication, diet and living habits of the patients, since all of them are involved in the origin and worsening of these pathologies and their symptoms.
Finally, if is diagnosed a intolerance to histamine by DAO deficiency should be to supplement the diet with nutraceuticals that include diamine oxidase.
This is a council of the International Society of DAO Deficiency.