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Histamine Intolerance: Emerging Evidence

 
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Histamine intolerance (HIT) continues to be a topic of in-creasing clinical interest with scientific research continuing into  its  prevalence,  aetiology,  pathophysiology,  clinical  presentation,  and  comorbidities  along  with  the  most  appropriate therapeutic assessment and management strategies. There is significant complexity associated with each of these - paralleled by the ubiquitous physiological and functional nature of this biogenic amine in relation to the many body systems, organs and tissues it influences, as well as the interindividual variability in its clinical manifestation/presentation.2-4

Histaminosis

Histaminosis (HIT) is reported to affect up to 3% of the population, however, with its clinical heterogeneity and diagnostic challenges, its actual prevalence may be higher.5 -7 Histaminosis is defined as the impaired capacity to methylate/deaminate histamine via diamine oxidase  (DAO)  and  histamine  N-methyltransferase  (HNMT) enzymes respectively.  This inability results in the accumulation of endogenous histamine, allowing it to bind to histamine receptors (HR 1-4) producing subsequent effects on tissues and organs2,7,8,10  (See Table 1 and Histamine Basics). 

Histamine Basics

Synthesis

Histamine is synthesised intracellularly in central and peripheral tissues in the Golgi apparatus organelle following decarboxylation of L-histidine by the inducible enzyme histidine decarboxylase.2,11 This occurs in cells that store histamine including mast cells and basophils, and cells that produce histamine in response to stimuli such as enterochromaffin-like, histaminergic neurons, lymphocytes, monocytes, platelets, neutrophils, gastric and dendritic cells.1,4,10 Such stimuli can involve both immunological and non-immunological substances.2

Function

Histamine is necessary in the body for many functional processes including:
• Inflammation
• Innate and adaptive immunity
• Vasodilation and vascular permeability
• Smooth muscle contraction and relaxation
• Gastric acid secretion
• Neuromodulation (including thermoregulation, appetite and cognition).1,3,9,11,12

Metabolism and Inactivation

Endogenous histamine is metabolised intracellularly by histamine N-methyltransferase (HNMT) (expressed in respiratory, small intestinal, liver and kidney cells) via deamination and extracellularly by diamine oxidase (DAO) through methylation.2,4,11,13 DAO, largely expressed by intestinal epithelial villi cells as well as liver, kidney, placental and skin cells, breaks down 15-30% of histamine by removing an amine group, producing imidazole acetaldehyde, ammonia and hydrogen peroxide. This pathway requires vitamins B6, C and copper to function effectively.4,8,11,13 Because HNMT is more widely expression throughout the body it metabolises 50-80% of endogenous histamine by adding a methyl group from S-adenosyl-L-methionine, producing N-methylhistamine and subsequently M-methylimidazole acetic acid.4,8,9

Causes of Histamine Intolerance (HIT)

The many endogenous and exogenous aetiological factors associated with HIT pathophysiology are clinically observed to predominantly involve multiple antecedents rather than an individual trigger.

Endogenous aetiologies of histamine intolerance include:
• Genetic (DAO rs10156191, rs1049742, rs2268999, and rs104979 polymorphisms)
• Acquired (functional) impairment of DAO or HNMT enzymes
• Gastrointestinal dysfunction or pathology (damaged intestinal enterocytes, bleeding, inflammation, dysbiosis and infections)
• Nutrient deficiencies (copper, vitamins C and B6).1-3, 6,8,10,11,13,15,16

Exogenous aetiologies of histamine intolerance include:
• Diet (considered to be a significant exogenous trigger) specifically the ingestion of foods with high levels of histamine (sauerkraut, processed meat, dried anchovies, fish sauce, spinach, tomatoes, cocoa, eggplant, fish, chicken, yoghurt, soy, red wine); those promoting mast cell histamine release (citrus foods, pineapple, bananas, strawberries, papaya, tomatoes, additives); or containing other biogenic amines that interfere with the binding of histamine to mucosal mucine resulting in more histamine in circulation.10,11,13,18
• Other exogenous factors include stress, alcohol, medications and xenobiotics that decrease DAO activity (or interfere with histamine metabolism and distribution).3,8,15,20

Symptoms of Histamine Intolerance

Histamine Intolerance results in the onset of a broad range of symptoms across different body systems. The more commonly observed symptoms in clinical and research settings are:
• Gastrointestinal (abdominal distension, constipation, postprandial fullness, nausea, vomiting, diarrhoea, abdominal pain and constipation)
• Nervous (dizziness, headaches and migraines)
• Respiratory (sneezing, rhinorrhoea, nasal congestion, swelling, phlegm, cough and asthma)

• Integumentary (eczema, dermatitis, urticaria, pruritis, flushing and oedema)
• Muscular (pain)
• Cardiovascular (tachycardia and hypotension)3,5-7,10,13-17

In addition to these more commonly observed clinical presentations of HIT, correlations between the condition and other clinical pathologies are emerging (See Fig. 1 and Table 2).

Clinical Assessment of Histamine Intolerance

The heterogenous nature of the aetiology, pathophysiology and clinical presentation of HIT and the variability of the validity and clinical information provided by commonly utilised assessment strategies are essential considerations in the accurate clinical diagnosis and effective clinical management of HIT. (See Table 3.)

This review emphasises that the basis of effective clinical management of HIT is through the thorough assessment of the systemic clinical presentation and consideration of all potential aetiological and pathophysiological factors in the individual case, as well as the importance of ongoing research to improve the diagnosis and treatment of this condition.


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