By Cody Bidlow
Histamine is produced from histidine by histidine carboxylase, and is metabolized by histamine methyltransferase and MAO. Histamine is a biogenic amine found in many foods, and released in cases of allergic reaction. Biogenic amines are one of five defined neurotransmitters, three of which are the catecholamines (which have a catechol moiety) dopamine, norepinephrine (noradrenaline) and epinephrine (adrenaline), and additionally the non-catecholamines histamine and serotonin.
High concentrations of histamine and histamine decarboxylase are found in the hypothalamus, and can project to nearly all regions of the central nervous system. These projections can mediate arousal in a manner similar to acetylcholine and norepinephrine. Some anti-histamines act as sedatives, likely due to these drugs dumbing down the arousing actions of histamine. Histamine is most commonly associated with its release in allergic reactions, but as with most physiological mechanisms, plays more than one role in homeostasis (or lackthereof).
Histamine intolerance results from an imbalance of histamine accumulation and a poor capacity for histamine degradation. Histamine is detoxified rapidly by amine oxidases, but persons with histamine intolerance generally have low amine oxidase activity and are thus at risk for histamine toxicity. Diamine Oxidase (DAO) is thought to be the primary amine oxidase responsible for scavenging extracellular histamine. On the intracellular level, N-methyltransferase is the enzyme responsible for inactivating histamine.
Histamine intolerance has been researched from a dietary standpoint, with some patients showing relief with the removal of dietary histamine. Foods with high levels of histamine can cause allergy-like symptoms, yet specific food allergy tests can come up negative. In general, many patients who show histamine intolerance can show improvements in their display of symptoms by reducing or removing dietary histamine intake. This includes removing foods such cured meats and sausages, cheeses, certain beans and nuts, shellfish, pickled or canned foods, and most importantly alcohol.
The DAO Deficiency <-> Histamine Intolerance Connection
DAO deficiency has become widely accepted by medical professionals to be a core issue in histamine intolerance. Diamine Oxidase (DAO) used to be referred to as Histaminase, due to its role in dealing with the removal/inactivation of excess histamine levels in the body. While it is pretty clear that if the enzyme responsible for getting rid of excess histamine in the body is underactive or deficient, then there will be issues with histamine levels being too high. The underlying pathways and causes though, are less conspicuous. Studies in humans, rats, and cows have shown that copper deficiency can lead to inadequate DAO activity.
Histamine and Stimulant Usage
There is a clear connection between stimulants and histamine release. From Caffeine promotes glutamate and histamine release in the posterior hypothalamus:
HPLC analysis and biosensor measurements showed a significant increase in glutamate levels beginning 30 min after caffeine administration. Glutamate levels remained elevated for at least 140 minutes. Gamma-amino butyric acid (GABA) levels did not significantly change over the same time period. Histamine level significantly increased beginning 30 min after caffeine administration and remained elevated for at least 140 minutes. Immunostaining showed a significantly elevated number of c-Fos labeled histamine neurons in caffeine treated rats compared to saline treated animals. We conclude that increased glutamate levels in the PH activate histamine neurons and contribute to caffeine-induced waking and alertness.
Histamine <-> Food Intake <-> Aphthous Ulcers
Changing gears a bit, let's take a look at some of the older material on the subject. As stated before, changes in dietary intake can have an effect on histamine release and associated allergic reactions. Here we have a look at food allergies and recurrent aphthous ulcers (aphthous stomatitis) from 1987 in the British Medical Journal. From Food allergy or intolerance in severe recurrent aphthous ulceration of the mouth:
Although the cause of oral aphthous ulcers is unknown, there is a well established association with coeliac disease.1 Wray et al suggested recently that recurrent aphthous ulceration may in some cases be due to gluten sensitivity in the absence of coeliac disease 2 and other authors have suggested allergy to various foods, including figs, cheese, and tomatoes3 and walnuts, tomatoes, and fruit.4 We tested the hypothesis that chronic aphthous stomatitis may be due to food allergy or intolerance, taking as our three most likely dietary suspects gluten, cows' milk protein, and azo dyes and preservatives.
Patients, methods, and results
Fifteen patients (11 women), mean age 29 (range 16-76) years, entered the trial. All had suffered severe oral aphthous ulcers most days for over a year and had normal serum vitamin B12, folate, red cell folate, and serum iron concentrations. A detailed medical history and examination was performed to exclude inflammatory bowel disease and Behcet's syndrome.
For each patient serum immunoglobulin concentration was estimated and biopsy specimens taken from both the buccal mucosa; under local anaesthesia, and the jejunum, using a Watson capsule. The small bowel biopsy specimens were examined histologically for coeliac disease, and mouth and intestinal biopsy specimens were screened by immunofluorescence techniques for local deposition of the immunoglobulin classes IgA, IgM, and IgG and also for the presence ofC3.
Each dietary exclusion period lasted 10 weeks and was followed by 10 weeks' return to normal diet. Patients were reviewed regularly by the doctor and dietitian. In the gluten free diet all sources of wheat, barley, rye, and oats were avoided; the milk free diet excluded all natural milk and milk products (soya milk as a substitute was allowed); the azo free diet excluded tartrazine (E102), sunset yellow (E10), new coccine (ponceau 4R; E124), and benzoic acid (E210).
A strict record was kept of the occurrence, duration, and frequency of ulcers. If a patient responded dramatically to the withdrawal of a specific food with relapse after returning to a normal diet the test was repeated and the response noted. Patients whose ulcers cleared on dietary restrictions were followed up on a long term basis and their progress recorded (table).
No patient had villous atrophy on intestinal biopsy examination, thus excluding coeliac disease. No significant abnormality was found in the results of serum immunoglobulin assays, and there was no increase in the deposition of immunoglobulins in the buccal or intestinal mucosal samples, apart from some IgA, which would be expected in the gastrointestinal tract. In five patients there was an unexpected finding on routine histological examination of the buccal mucosa, with noticeable cellular infiltrate and atrophy of the minor salivary glands found on biopsy examination. The importance of this change, more usually associated with autoimmune conditions such as Sjogren's syndrome.
Any investigation of allergy to food is complicated by the various possible clinical manifestations and the subjective nature these often take. The six patients who responded to a dietary withdrawal in this trial did so dramatically within a week of avoiding the incriminated food and after prolonged and relentless periods of ulceration, so that a causal relation with the foods seems likely. The buccal and small bowel biopsy examinations were unhelpful, and we intend to avoid performing these in future.
Double blind testing would require more patients than in this study and would have to be designed individually for each suspect foodstuff to accommodate its specific physical properties. This might best be achieved using a solid food, and we are experimenting with incorporation into biscuits.
From this study it appears that some benefit can come from eliminating wheat products (wheat, barley, rye, oats) as well as eliminating intake of azo products (artificial food coloring and preservative agents). Less benefit was seen from a milk-free diet. This study was limited by its small sample size, but is still something worth thinking about. One thing to note is that the subjects in the study who responded to wheat free diets did not have celiac disease.
This is interesting to me as Celiac Disease can manifest without significant digestive disorders, but show other symptoms on a regular basis. Skin rashes, canker sores, anxiety, bloating, anemia (iron deficiency), and other nutritional deficiencies (B-12, Folate).