Prof. Dr. med. Martin Raithel of the University Clinic of Erlangen (Germany) and his colleagues in Germany and Austria have worked on the subject of Histamine Intolerance for many years. Prof. Raithel has now given an exclusive interview. It should provide those searching for the cause of their symptoms with more information on how to get more reliable results concerning HIT. It is important not to fall into the trap of being given expensive long-term treatments. Please make sure to work with qualified medical professionals in your country. In the UK you can check if someone you don’t know holds a licence to practice (required by law) by checking the GMC Register or contacting the same institution.
This interview might be useful background information to print out and take along to your doctor or consultant.
Q 1: What, in your opinion, is the definition of Histamine Intolerance?
A: Definition of Histamine Intolerance Syndrome (HIS)
Histamine intolerance is defined as an acute or chronic non-immunologically mediated reaction to the intake of (generally tolerated) sub-toxic quantities of histamine. Such reactions, which proceed clinically similar to an allergy but which are not triggered by specific immune system mechanisms (for instance antigen-specific IgE antibodies or T-cells) , are currently recorded under the general heading of intolerance reactions.
Histamine Intolerance can thereby present variably, mono- oligo- or poly-symptomatic, with different organ manifestations and mainly affects post-adolescents or adults and is most prevalent in women.
Q 2: Which types of HIT have you seen at the University Clinic? E.g: low DAO levels caused by another illness that affects the intestine? Patients with Histamine Intolerance because of a defective/reduced HNMT? Patients with Histamine Intolerance because of defective/reduced DAO activity?
A: Overview of the multiple mechanisms of the Histamine Intolerance Syndrome (HIS) and a proposal for clinical classification.
HIS Group 1 (HIS-G1) through increased availability of histamine (“Histamine surplus” in the body)
HIS-G1A: Endogenous and/or genetically intensified histamine synthesis and release
e.g: mast cell activation syndrome (mastocytosis), leukaemia etc.
e.g: atopy*, allergies*, infections, NSAID Intolerance
HIS-G1B: Exogenously raised histidine or histamine intake (see (1))
e.g: food, wine, vinegar etc
e.g: blood products, tobacco smoke etc
HIS Group 2 (HIS-G2) through changes in the histamine receptors
HIS-G2A: Genetically caused changes in sensitivity on the histamine receptors.
e.g.: genetic polymorphism (epigenetic changes?)
HIS-G2B: Acquired changes in sensitivity on the histamine receptors
e.g: autoantibodies (?), infections, neurotransmitters, cytokines, etc.
HIS Group 3 (HIS-G3) through impaired enzymatic histamine degradation
HIS-G3A: Endogenous and/or genetically caused enzymatic disorder at the level of Diamine oxidase (HIS-G3A-DAO)
Histamine N-Methyltransferase (HIS-G3A-HNMT)
e.g: genetic polymorphisms (epigenetic changes?)
e.g: bacterial amine production (constitutional, endogenous intestinal flora)
HIS-G3B: Acquired enzymatic disorder at the level of Diamine oxidase (HIS-G3B-DAO)
Histamine N-Methyltransferase (HIS-G3B-HNMT)
e.g: alcohol, medication etc.
e.g: ingesting biogenic amines (putrescine)
e.g: bacterial amine production (small bowel overgrowth syndrome (SBOG))
HIS Group 4 (HIS-G4) through impaired cellular absorption (?)
The overview of the different possible individual mechanisms of histamine intolerance shows when and in which groups of patients histamine-induced symptoms in the sense of an intolerance (administration <200mg histamine) are to be reckoned with and which changes should be considered clinically or scientifically in individual cases.
* The allergen-specific induced liberation of histamine does not belong, by definition, to histamine intolerance;
(1) An administration of a quantity of histamine >200mg is classified as toxic and belongs, by definition, to the clinical picture of histamine intoxication (scromboid intoxication)
Q 3: How do you go about diagnosing HIT? Do you need several indicators?
A: The clinical picture of histamine intolerance has been diagnosed clinically up to now and should be either confirmed or definitely ruled out by means of the standardised provocation tests, embellished where appropriate by including co-factor triggers (such as physical stress), as otherwise too much uncertainty arises for the patient. Because, according to the current available data, there is no reliable laboratory test or laboratory constellation in blood or serum available for a definite diagnosis, several tests can be used (see fig.) in order to substantiate the suspicion of HIS.
Eventually, the diagnosis of a histamine intolerance is only confirmed after reproducible clinical symptoms from provocation tests. Oral histamine provocation is only undertaken in individual cases after ruling out other illnesses and relevant differential diagnoses as well as after seriously weighing up any contraindications (such as manifest obstruction of airways, cardio-vascular problems, cardiac arrhythmia, infections or other acute phases of illness with a danger of cardio-circulatory or respiratory insufficiency), after assessing concrete therapeutic consequences and, where necessary, under intensive medical monitoring.
The histamine intolerance is tested for according to a standardised protocol on a patient, who is required to fast overnight before the test, using a placebo-controlled oral histamine provocation with 50-150mg of histamine (0.25-1.5mg/kg body weight). Histamine chloride (1.6 mg is equivalent to 1mg of histamine) is given in a salt solution in a volume of 100ml, compared to the placebo (100ml NaCl), on different test days.
Chart: Histamine Intolerance diagnostics
– Anamnesis, physical examination
– Mediator diagnostic blood test (single determination)
Plasma histamine, ECP and tryptase in serum, cytokines if necessary
– Functional mediator diagnostics with at least 2 days of normal food and 2 – 14 days of hypo-allergenic, low histamine potato-rice diet:
Determination of combinations in normal diet and after potato-rice diet each to be compared (therapy effect)
Plasma histamine, plasma-DAO
ECP and tryptase in serum, cytokines if necessary
Histamine and methylhistamine in 12 hour urine
Histological assessment (mast cell density), DAO immune-histochemistry if necessary
Determination of histamine levels in tissues, further mediators if necessary
Determination of isolated enzyme activity of DAO, HNMT
Determination of biologically available total histamine degradation capacity
– Oral provocation testing with 50 – 150 mg histamine or placebo
On-call/emergency service (if necessary intensive-care monitoring)
Symptom score, cardiac monitoring, peak-flow measurement etc.
Mediator diagnostics for plasma histamine, if necessary DAO and other parameters.
Q 4: How can the DAO blood test help as an indicator? Is it just a snapshot view of that moment in time? Does it make sense to do it?
A: The DAO blood test is unfortunately not a satisfactory solution because the concentration in the blood is far too low compared with that in the intestine (1:>500) to allow a convincing diagnosis. In this respect, patients with lower DAO activity must be carefully diagnosed in spite of this. (see Histamine Intolerance Diagnostics diagram above as well as 5.).
Q 5: What can the General Practitioner (family doctor) do up ahead?
A: Ahead of an endoscopic examination, GPs can already put together the anamnesis (case history), identify or exclude the possible presence of an intolerance of carbohydrates, carry out a blood cell count test and look for inflammation. In addition they can make a start with the testing of urine for histamine and methylhistamine and refer the patient to an allergist or dermatologist so that skin tests and specific IgE antibody tests regarding foodstuffs, spices, moulds, environmental antigens (house dust, pollen, etc.) can be carried out.
Q 6: How important is it for the patient to have a diagnosis from a doctor before starting a low histamine diet?
Q 7: What can the consequences be for patients if they observe a low histamine diet without a diagnosis. Can you describe an example of such a patient?
A Q 6&7: Before HIS is diagnosed a rigorous differential diagnosis should be carried out so that other illnesses (inflammation, malabsorption, tumors, mastocytosis, etc.) can be definitely ruled out. This usually means an examination by an allergist, dermatologist, internist, gastroenterologist and possibly other specialists (for instance a cardiologist) depending on the main symptoms. In all cases, a hasty diagnosis of histamine intolerance is to be avoided, because the consequences could be that another illness that could easily be treated might not be recognised, the diagnosis would be delayed and that irreversible organ damage might then develop. As an example, there is the case of an overhasty diagnosis of histamine intolerance in a young female patient with a variety of food intolerances. Despite a low histamine diet and anti-histamines the patient was not symptom-free and continued to suffer from abdominal pains, nausea and vomiting. A fresh admission to hospital then led to my carrying out a thorough ileocoloscopy which revealed that there was a small length of inflammation located at the junction of the small and large intestine which indicated Morbus Crohn. That, of course, required a completely different therapy from that of an histamine intolerance and the patient was then treated with a medicinal acute-phase therapy.
Q 8: How many patients at the University Clinic with other intolerances or food allergies have you diagnosed with also suffering from HIT? Many or few?
A: As far as the question of frequency regarding histamine intolerance is concerned, you can’t refer to your own daily patient flow because we get many patients referred to us which would mean overestimating the frequency. This can best be deduced from research where patients have been included prospectively and have been tested on the basis of hard diagnostic criteria. We recorded a research project in Erlangen by Giera et al involving a double-blind histamine provocation with people suffering from gastro-intestinal symptoms which showed histamine intolerance in around 5.9%, while in the case of another group of patients (neurodermatitis) Maintz et al registered a histamine intolerance in 19 – 23%. This shows that the actual frequency is also determined by the patient group or the underlying disease. Further examples of provoked histamine reactions carried out by Jarisch et al in bronchial constriction in asthma patients, the induction of headaches in migraine patients or by atopic dermatitis show a frequency of 3 – 10%. In this respect, we can assume an average frequency for histamine-induced intolerance symptoms within the general population of 5 – 8%, whereby not all of those affected seek doctor’s advice.
Q 9: There are people who take an IgG test, or a hair test, or a Vega test, in order to determine whether or not they have a food intolerance. What is your view of this?
A: Seen from the internist-gastroenterologist point of view, with unspecific gastrointestinal diseases (for instance post-infectious, carbohydrate malabsorbtion, diarrhoea associated with antibiotics, pancreatic insufficiency, lambliatis infestation, etc.) there is already frequently an increase of the IgG antibody level against foodstuffs that relates to other, often very unspecific patho-pysiological indications of impaired intestinal permeability, a shift in the intestinal bacterial species and unspecific signs of infection (for instance Lactoferrin). As has been described in the literature, there is no indication in the Erlangen inter-disciplinary data register for an IgG–induced clinical gastrointestinal reaction in oral provocation testing within 48 hours (unpublished observations). However, in individual IgG-positive patients, a local intestinal IgE production could be detected in the endoscope-regulated intestinal lavage, creating the impression that a rise in IgG antibodies occurs consecutively as the result of an unspecific barrier disorder of the gastrointestinal tract. Since the barrier disorder generally results in specific symptoms, it is recommended that certain targeted differential diagnoses (as described above) are systematically carried out and that ultimately endoscopic and histological tissue tests are performed.
Q 10: Is there anything else you would like to say on the subject of histamine intolerance?
A: In the case of every form of food intolerance, whether it is simple (for instance lactose intolerance) or complex (for instance gastrointestinal allergy or histamine intolerance in mastocytosis) a medical diagnosis is advisable which positively diagnoses the medical condition and which excludes other possible illnesses, so that the patient can follow specific therapeutic measures without further concern, so that no psychological after-effects arise, and patients can receive specific, targeted instructions about their condition. We have achieved the best long-term results in these cases. For this reason, in the new edition of the book Histaminintoleranz (Thieme Verlag, published by Jarisch, Raithel, Wantke) all the new and up-to-date aspects of histamine intolerance in many different clinical pictures will be precisely described (for instance irritable bowel, arrhythmia, migraine and many others).