Histamine intolerance results from a disequilibrium of accumulated histamine and the capacity for histamine degradation. Histamine is a biogenic amine that occurs to various degrees in many foods. In healthy persons, dietary histamine can be rapidly detoxified by amine oxidases, whereas persons with low amine oxidase activity are at risk of histamine toxicity. Diamine oxidase (DAO) is the main enzyme for the metabolism of ingested histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator release. Conversely, histamine N-methyltransferase, the other important enzyme inactivating histamine, is a cytosolic protein that can convert histamine only in the intracellular space of cells. An impaired histamine degradation based on reduced DAO activity and the resulting histamine excess may cause numerous symptoms mimicking an allergic reaction. The ingestion of histamine-rich food or of alcohol or drugs that release histamine or block DAO may provoke diarrhea, headache, rhinoconjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritus, flushing, and other conditions in patients with histamine intolerance. Symptoms can be reduced by a histamine-free diet or be eliminated by antihistamines. However, because of the multifaceted nature of the symptoms, the existence of histamine intolerance has been underestimated, and further studies based on double-blind, placebo-controlled provocations are needed. In patients in whom the abovementioned symptoms are triggered by the corresponding substances and who have a negative diagnosis of allergy or internal disorders, histamine intolerance should be considered as an underlying pathomechanism.

Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine, is a disorder associated with an impaired ability to metabolize ingested histamine that was described at the beginning of the 21st century. Although interest in histamine intolerance has considerably grown in recent years, more scientific evidence is still required to help define, diagnose and clinically manage this condition. This article will provide an updated review on histamine intolerance, mainly focusing on its etiology and the existing diagnostic and treatment strategies. In this work, a glance on histamine intoxication will also be provided, as well as the analysis of some uncertainties historically associated to histamine intoxication outbreaks that may be better explained by the existence of interindividual susceptibility to ingested histamine.

Histamine in food at non-toxic doses has been proposed to be a major cause of food intolerance causing symptoms like diarrhea, hypotension, headache, pruritus and flush ("histamine intolerance"). Histamine-rich foods such as cheese, sausages, sauerkraut, tuna, tomatoes, and alcoholic beverages may contain histamine up to 500 mg/kg. We conducted a randomized, double-blind, placebo-controlled cross-over study in 10 healthy females (age range 22-36 years, mean 29.1 +/- 5.4) who were hospitalized and challenged on two consecutive days with placebo (peppermint tea) or 75 mg of pure histamine (equaling 124 mg histamine dihydrochloride, dissolved in peppermint tea). Objective parameters (heart rate, blood pressure, skin temperature, peak flow) as well as a total clinical symptom score using a standardized protocol were recorded at baseline, 10, 20, 40, 80 minutes, and 24 hours. The subjects received a histamine-free diet also low in allergen 24 hours before hospitalization and over the whole observation period. Blood samples were drawn at baseline, 10, 20, 40, and 80 minutes, and histamine and the histamine-degrading enzyme diamine oxidase (DAO) were determined. After histamine challenge, 5 of 10 subjects showed no reaction. One individual experienced tachycardia, mild hypotension after 20 minutes, sneezing, itching of the nose, and rhinorrhea after 60 minutes. Four subjects experienced delayed symptoms like diarrhea (4x), flatulence (3x), headache (3x), pruritus (2x) and ocular symptoms (1x) starting 3 to 24 hours after provocation. No subject reacted to placebo. No changes were observed in histamine and DAO levels within the first 80 minutes in non-reactors as well as reactors. There was no difference in challenge with histamine versus challenge with placebo. We conclude that 75 mg of pure liquid oral histamine--a dose found in normal meals--can provoke immediate as well as delayed symptoms in 50% of healthy females without a history of food intolerance.

Background: Histamine intoxication, initially described as scombroid fish poisoning, is now recognized as histamine intolerance (HIT), a condition associated with impaired histamine metabolism, often due to diamine oxidase (DAO) deficiency. HIT presents with nonspecific gastrointestinal and systemic symptoms, frequently overlooked in clinical practice. While extraintestinal manifestations are well-documented, oral findings have not been previously described.

Objective: This short communication presents the first reported cases of HIT diagnosed through oral lesions, providing a brief review of this emerging condition.

Materials And Methods: Five patients (2022-2024) were evaluated based on clinicopathological findings and dietary anamnesis, focusing on histamine-rich food intake. A thorough oral examination was conducted, and diagnostic criteria and differential diagnoses were reviewed.

Results: All cases exhibited persistent oral burning, sensitivity to acidic foods, and erythematous velvety macules on oral mucosa. Symptoms correlated with histamine intake and improved with dietary restriction and antihistamines. Differential diagnoses included food allergies, plasma cell mucositis, fungal infections, lupus, and oral lichen planus. A familial case suggests a genetic component of DAO deficiency.

Conclusions: Recognizing oral lesions as potential HIT manifestations may improve diagnostic accuracy in patients with unexplained mucosal symptoms. Further research is needed to establish standardized diagnostic criteria and optimize clinical management.

Histamine (HA) is a pleiotropic biogenic amine synthesized exclusively by histidine decarboxylase (HDC) in most mammalian tissues. The literature on the role of HA within the male gonad has expanded over the last years, attracting attention to potential unexpected side-effects of anti-histamines on testicular function. In this regard, HA receptors (HRH1, HRH2 and HRH4) have been described in Leydig cells of different species, including human. Via these receptors, HA has been reported to trigger positive or negative interactions with the LH/hCG signaling pathway depending upon its concentration, thereby contributing to the local control of testicular androgen levels. It should then be considered that anti-histamines may affect testicular homeostasis by increasing or decreasing steroid production. Additionally, HRH1 and HRH2 receptors are present in peritubular and germ cells, and HRH2 antagonists have been found to negatively affect peritubular cells and reduce sperm viability. The potential negative impact of anti-histamines on male reproduction becomes even more dramatic if we consider that HA has also been associated with human sexual behavior and penile erection. What is more, although testicular mast cells are the major source of locally produced HA, recent studies have described HDC expression in macrophages, Leydig cells and germ cells, revealing the existence of multiple sources of HA within the testis. Undoubtedly, the more we learn about the testicular histaminergic system, the more opportunities there will be for rational design of drugs aimed at treating HA-related pathologies, with minimum or nule negative impact on fertility.

Although histamine has been suggested to be involved in the control of male sexual function, including the induction of penile erection, its role in the human corpus cavernosum penis is still poorly understood. The aim of our study was to evaluate the course of histamine plasma levels through different stages of sexual arousal in the systemic and cavernous blood of healthy male subjects. Thirty four (34) healthy men were exposed to erotic stimuli to elicit penile erection. Blood was aspirated from the corpus cavernosum and a cubital vein during the penile conditions flaccidity, tumescence, rigidity and detumescence. Blood was also collected in the post-ejaculatory period. Plasma levels of histamine (ng ml(-1)) were determined by means of a radioimmunoassay. Histamine slightly decreased in the cavernous blood when the penis became tumescent. During rigidity, histamine decreased further but remained unaltered in the phase of detumescence and after ejaculation. In the systemic circulation, no alterations were observed with the initiation or termination of penile erection, whereas a significant drop was registered following ejaculation. Results are not in favour of the hypothesis of an excitatory role of histamine in the control of penile erection. Nevertheless, the amine might mediate biological events during the post-ejaculatory period.