Histamine-Intolerance

Histamine intolerance is a symptom complex characterized by reduced Diamine Oxidase (DAO) activity or lack of the enzyme. Furthermore an increased availability of histamine can cause intolerance reactions.
The location of DAO in the intestinal mucosa, suggests histamine intolerance as a basically gastrointestinal disorder.
The high levels of DAO in the gastrointestinal tract describe the importance of metabolizing exogenous biogenic amines ingested with food. If not degraded in time, biogenic amines can enter the circulation, and cause various systemic symptoms, often similar to those in allergic reactions. When the enteral barrier is overwhelmed by histamine, an increase in plasma histamine levels can be observed due to the fact that histamine is resorbed.
High doses of ingested histamine can even cause problems in healthy subjects. Patients suffering from histamine intolerance may indicate one or more of the following symptoms after ingestion of histamine-rich food, alcoholic beverages or drugs inhibiting DAO: headache, facial flush, rhinopathia, bronchial asthma, gastric and bowl disorder, diarrhea and urticaria.

Biochemistry

Discovered in 1910 by Dale and Laidlaw histamine belongs to the biogenic amines, like putrescine, cadaverine, thyramine, spermine and spermidine.
Biogenic amines can be found in all living organisms and therefore are present in various foods like milk, fish, meat, fruits and vegetables.
Biogenic amines are natural catabolic products. They act as hormones and flavoring agents. All biogenic amines derive from metabolism of amino acids, basic components for nutrition:

Fig. 1: Creation of biogenic amines from the corresponding amino acid

Microbial denaturation in fish, meat and sausages as well as fermentation during the production process of cheese, wine, salami, increases the content of biogenic amines.

Fig. 2: Structural formula of histamine.

Histamin

The coherence between allergy and the mediation by histamine was discovered 1932.
Synthesis of histamine from the amine acid histidine is performed by histidine carboxylase. in e.g. mast cells, basophiles, platelets and histaminergic neurons. Intracellular stored histamine is released on stimulus. 

Beside the triggering of mast cell degranulation, histamine is involved in smooth muscle contraction, vasodilatation, allergic response and stimulation of gastric acid secretion as well as neuronal functions, like the sleep-wake-cycle, wound healing, hematopoiesis and cell proliferation are regulated by histamine.

Fig. 3: Various symptoms mediated by histamine.

Oxidative deamination by diamine oxidase and ring methylation by histamine-N-methyltransferase (HNMT) are two alternative pathways responsible for histamine inactivation. The type of degradation depends on the localization. DAO deaminates extracellular histamine, e.g. ingested with food, where else HNMT, a cytosolic protein, is responsible for degradation of intracellular histamine.

Histamine is present is various foods in variable concentrations. The content of histamine increases with longer fermentation and maturation processes.

A list of foods and beverages containing histamine can be found here.

Certain drugs were also reported to inhibit DAO:

Wirkstoff

Anwedung

Acetylcystein

Husten

Ambroxol

Hustein

Aminophyllin

Asthma

Amitriptylin

Antidepressivum

Chloroquin

Malaria

Clavulansäure

Antibiotikum

Isoniazid

Antibiotikum

Metamizol

Schmerzen

Metoclopramid

Übelkeit

Propafenon

Herzrythmusstörungen

Verapamil

Herz-Kreislauf Erkrankungen

Diamino Oxidase

Diamine Oxidase Diamine oxidase (DAO, EC 1.4.3.6) is a member of the copper-containing amine oxidases (CAOs) which metabolize primary amines into the corresponding aldehydes via oxidative deamination. The steps of this reaction are shown in Fig. 4:

Fig. 4: Reaction scheme of oxidative deamination

DAO consists of to identical subunits that form a so called homodimer, and can be found in all living organisms. Native DAO is highly glycosylated, type and degree of glycosylation depending on tissue and species.

The name DAO results from the substrate specificity for diamines (like histamine, putrescine and cadaverine).

Fig. 5: Ribbon illustration of Diamine oxidase with copper-ions in both active centers. [http://www.biology.leeds.ac.uk/centres/LIBA/cps/pherson.htm]

After synthesis DAO is stored in the base of the villus cells and released through the constitutive secretory pathway induced by heparin, if required.

Diagnosis

There are several ways of anamnesis whereas delayed or inconstant symptoms aggravate the diagnosis.

A temporary histamine-free diet following by stepwise testing of tolerated foods (elimination diet) or a very accurately recorded nutrition-diary used to be the only possibility to diagnose histamine intolerance. Furthermore skin- (prick test, rub test, intracutaneous test), and blood tests (RIST, RAST) were performed to eliminate possible allergies. Moreover the possibility of damine-oxidase activity testing in blood exists for some years now.

Therapy

A histamine-poor diet used to be the only therapie. Furthermore the ingestion of biogenic amines in common and histamine liberators should be avoided.

After appearance of symptoms, H1-blocker (antihistamine) can prevent worse.

For quite some time now it is also possible to substitute DAO, whereby DAO from a natural source is applied to the small intestine where the body’s own DAO can be supported. Exogenic histamine ingested with food is degraded properly and cannot enter the blood circulation whereby symptoms are reduced up to disappearance.