Histamine is a biogenic amine that can be synthesized by L-histidine decarboxylase (HDC) from histidine amino acid and it is also synthesized by mast cells, basophils, platelets, histaminergic neurons and enterochromophins, where it is stored in intracellular vesicles and released after stimulation.1
Histamine exerts its effects by binding to four receptors (HIR, H2R, H3R and H4R) in certain cells of different tissues, generating smooth muscle contraction, vasodilatation, increased vascular permeability, mucus production, tachycardia, blood pressure changes, arrhythmias, gastric acid secretion and stimulation of nocioceptive nerve fibers.2
Histamine can be metabolized in two ways: by oxidative deamination mediated by diamine oxidase (DAO) in the extracellular medium or by methylation mediated by histamine-N-methyltransferase (HNMT) in the intracellular space.3
Histamine can also be introduced to the body from exogenous sources, through the intake of certain types of foods with high concentrations of histamine.4
Different fermenting bacteria are able to decarboxylate histidine, forming histamine. The two key factors for histamine accumulation in food are the presence of bacteria with decarboxylase activity and the availability of the reaction’s substrates. Thus, foods that are most likely to contain histamine are those with a high protein load and those fermented foods and beverages in which lactic acid bacteria are involved.5
Many foods have been considered capable of inducing the release of histamine from tissue mast cells, even if these contain low concentrations of histamine. In vitro studies of patients with a history of pseudoallergic reactions with food have shown massive degranulation of duodenal mast cells in the presence of certain histamine-releasing substances. However, clinical studies using oral provocation tests are required to support this hypothesis.6 Figure 1.
Histamine intolerance (HIT) is a pathology in which there is an imbalance between the intake of histamine through the digestive tract and the ability of the body to degrade it. This results in an excessive accumulation of histamine that determines the appearance of symptoms when it binds to its respective receptors. It is estimated that the prevalence of HIT is approximately 1% of the population, with a predominance of middle-aged women. However, it is very likely that the prevalence is underestimated due to the wide variety of symptoms that are often misinterpreted by physicians and patients.7
DAO is continuously being secreted into the intestinal lumen, so that under normal conditions histamine from food and generated by bacteria in the intestine is satisfactorily degraded by it.8 Thus, HIT may be a condition secondary to a quantitative deficit of DAO or a functional deficit of DAO.9
The quantitative deficit of DAO may be due to genetic defects—intestinal pathologies that damage enterocytes—that result in a decrease in DAO production; while the functional deficit may be due to the DAO inhibition by other biogenic amines, alcohol or drugs. A decrease in DAO activity has also been observed in patients with chronic kidney disease, viral hepatitis, cirrhosis, and chronic urticaria.10
Genetic polymorphisms influence both the expression and the function of DAO, but alone are not sufficient to generate HIT. The presence of environmental factors such as the use of concomitant DAO-inhibiting drugs is of paramount importance. Thus, HIT is caused by the sum of genetic and environmental factors.11 The functional deficit of DAO can also be secondary to the deficit of its co-factors: vitamin B6, vitamin C, copper and zinc, being a reversible cause of HIT.12
Because histamine is the main mediator of the classic symptoms of IgE-mediated allergic reactions, it is difficult to differentiate a true allergy from HIT since it has basically the same clinical manifestations. An important key is that unlike the IgE-mediated reactions in which even small amounts of antigen trigger the onset of symptoms, in HIT the accumulation of high concentrations of eaten histamine plays a fundamental role in the onset and severity of symptoms.13
The diagnosis of this pathology is complex because of the diversity of histamine-mediated symptoms and the lack of a reliable biomarker to date. Faced with a suspicion of HIT, the diagnostic algorithm should begin by recording a diary of symptoms associated with food intake. Potential food allergies should then be excluded through skin test or specific IgE determination for food allergens and a hidden systemic mastocytosis by measuring basal serum tryptase levels. Finally, the clinical response to the introduction of a histamine-free diet is essential in the diagnostic process.14-15 Figure 2.
A double-blind, placebo-controlled histamine provocation has been proposed for the definitive diagnosis of HIT, in addition to the determination of plasma histamine concentration and the objectivation of clinical parameters. Other diagnostic methods include the measurement of DAO's intestinal activity, the analysis of its genetic polymorphisms in order to determine a possible genetic predisposition to HIT, and the measurement of DAO concentration and activity in peripheral blood. The latter are low-cost, easy-access, non-invasive tests.16-17
OBJECTIVE: Describe the clinical characteristics of patients with HIT, apply an ELISA assay to determine serum DAO concentration, and analyze the proportion of patients with a diagnosis of HIT with a deficit of this enzyme in comparison with healthy individuals.