Time to review the role of dietary histamine in the food allergy and intolerance debate
Dr. Rozita Spirovska Vaskoska
(FoodLegal Scientist and Researcher)
© Lawmedia Pty Ltd, April 2021
Histamine is a biogenic amine that serves an important physiological role in the human body. Although histamine can be found naturally in many foods, excessive histamine in one’s diet can also cause severe reactions or intolerance or allergy symptoms for many people. In more extreme cases, under given circumstances, histamine can cause food poisoning (scombroid poisoning). This article reviews the role of histamine in the human body, the symptoms of histamine poisoning and intolerance, the presence of histamine in certain foods, the limited impact of current processes on histamine levels, and other issues. This article invites opportunities by regulators and food companies to review their approach in relation to histamine in foods.
(The author would like to thank FoodLegal founder Joe Lederman for raising several hypothetical scenarios that triggered new avenues for the research on this topic).
Histamine in the human body
Biogenic amines as a group perform many functions in the human body. Because of its unique chemical characteristics, histamine (the most well known biogenic amine) has a major importance in physiological processes such as anaphylaxis, immune response, secretion of acid in the stomach, and widening of the blood vessels important for maintenance of blood pressure [1, 2]. Histamine`s main physiological role is gastric secretion and its main pathological role is in allergy.
There are at least 4 types of histamine receptors in the body . The antagonists of these receptors have been explored for years as therapy for a range of health conditions. The most well-known use of histamine antagonists is the use of anti- histamines for managing allergy symptoms such as hay fever and rhinitis, related to the H1 receptor of histamine. The antagonists of other receptors are explored for treating obesity, memory and learning deficits, epilepsy, asthma and inflammation .
Biogenic amines can be consumed through food. Histamine in food occurs as a product of decarboxylation (removal of the acidic group) of the amino acid histidine . Histamine is the most common and most well-known biogenic amine present in food. FoodLegal Bulletin has previously discussed the presence and regulation of biogenic amines in the context of fermented foods .
At high doses, dietary histamine is considered to cause food poisoning, while at low doses in sensitive individuals it leads to food intolerance reactions.
For histamine poisoning to occur, a medium (100 mg) or large quantity (1000 mg= 1 g) of histamine needs to be ingested . This amount can be ingested by eating spoiled scombroid (tuna, mackerel) or non- scromboid (mahi- mahi, sardines, pilchards, herring) fish. Histamine forms naturally in fish by their gut bacteria converting histidine to histamine, and if fish is stored for longer time or improperly, toxic levels may be yielded.
In Australia, 57 outbreaks of histamine fish poisoning have been recorded in the period between 2001 and 2013. The breakdown per country and months is presented in Figure 1, with no apparent trends related to time of emergence .
Histamine poisoning can be distinguished from food allergy, by the fact that poisoning often occurs as an outbreak affecting more people, and by the levels of serum tryptase enzyme in the gut, which does not increase in a histamine poisoning scenario, whereas it is at an increased level in the case of a food allergy reaction . The symptoms of histamine poisoning are dose dependent. For instance, if histamine is present in the plasma at 1-2 ng/ml it can present with a change in heart rate, while 100 ng/ml in the plasma can even cause a cardiac arrest .
Figure 1. Histamine poisoning outbreaks in Australia in the period 2001- 2013, from 
Histamine intolerance is defined as a state where the body cannot process enzymatically the histamine released inside the body or the histamine ingested from external sources such as food, thus leading to adverse reaction and symptoms . In healthy individuals, histamine ingested through food should not be absorbed by the digestive system as it should be degraded by enzymes . However, in some individuals, there is a possibility of histamine passing the gastrointestinal barrier and entering the bloodstream . Thus, medical practitioners suspect that histamine intolerance is not solely driven by the ingestion of food, but that a prerequisite for symptoms to emerge is a change in the permeability of the intestines . Most experts believe that histamine intolerance is associated with a lack of enzyme called diamine oxide (DAO). The lack of DAO enzyme in the human body can come from insufficient synthesis due to either genetic condition, or inhibition of its secretion by other diseases like inflammatory bowel disease or by the action of drugs (DAO inhibitor drugs have become quite common) .
The symptoms of histamine intolerance include migraine; skin symptoms: redness of the face (flushing), itching and rashes of the body; gastrointestinal symptoms (nausea, vomiting and abdominal pain) and cardiovascular symptoms (low blood pressure, dizziness, tachycardia) . The emergence of symptoms in various sites in the body is related to the multiple receptors mentioned above (see also Figure 2 below).
Figure 2. Symptoms of histamine intolerance in relation to histamine receptors 
The diagnosis of histamine intolerance is very complex, as its symptoms overlap with many other conditions. Histamine intolerance diagnosis can be done via various methods. Enzyme testing for DAO is advertised as a way of diagnosing histamine intolerance in many countries including Australia. As high as 1% of the population might have histamine intolerance with DAO deficit . Other diagnostic methods include a skin prick test, intestinal enzyme activity, histamine in stool samples, histamine in plasma and methyl histamine in urine .
Management of histamine intolerance includes dietary avoidance, but other treatments have also been developed. German medical practitioners in 2017 recommended three phase dietary adjustment for management of histamine intolerance: avoidance (10 days), expansion of choice (6 weeks) and long term diet intervention .
Histamine content of food
Apart from the enzymatic conversion of histidine to histamine in fish, histamine can also appear in food by other means including:
-Naturally occurring (cocoa, spinach, tomatoes, eggplant)
-Formed by fermentation (beer, wine, cheese, soy, fermented meat such as a hung-dried sausage)
-Formed by bacterial growth during improper storage of both Gram positive and Gram negative microorganisms
Normally, intolerance symptoms occur at lower levels of ingestion compared to intoxication. Exact dose response is not well established. The European Food Safety Authority recommended a safe level of 50 mg histamine/meal per healthy person, and below detectable level for any intolerant individual . This zero limit for intolerant individuals relates to the fact that provocation tests have found that levels as low as 50 µg will trigger symptoms in these people .
Figure 3 shows the content of histamine in common food categories. P95 shows the level of histamine that is not exceeded by 95 % of the samples; ‘max’ shows the maximum amount found; while ‘n’ is the number of tested samples. Evidently fermented products as soybean products, cheese and sausages can contain high amounts of histamine (Figure 3). Foods such as asparagus, pumpkin and avocado can have low levels of histamine, while cereals, milk, and eggs normally have insignificant content of histamine . A more extensive table on histamine content in foods is given in Appendix I .
Figure 3. Histamine content of common food categories, from 
Consumption with other foods might also enhance the reaction to histamine. For instance, alcohol undergoes metabolic processes related to histamine, and therefore might exacerbate the reaction of dietary histamine .
Histamine content of food is measured by using enzymatic assays as enzyme- linked immunosorbent assay (ELISA), colorimetric assays, analytical methods as high- performance liquid chromatography, mass spectrometry and Raman spectroscopy. Recent technological developments have led to innovations in the histamine measurement and an example of such methods is the use of aptamers (DNA or RNA oligonucleotides) which can recognize histamine and give a fluorescent signal that can be quantified .
Histamine changes during food processing
Histamine is very heat stable and almost indestructible by cooking. There is some evidence of a minor effect of boiling on histamine stability; however it has not been consistent for all tested foods .
Regulatory approaches in Australia and globally
Histamine can be a reason for food recall in Australia. For example a recent recall relating to histamine included anchovies from Vietnam contaminated with histamine . FSANZ has conducted risk assessments on histamine in fish and fish products in relation to import and found histamine to be of risk for three orders of fish: Perciformes, Clupeiformes and Beloniformes .
Thus, histamine is regulated for fish and fish products in Australia and New Zeeland, and there is an established limit of 200 mg/kg in Schedule 19. A limit of 200 mg/kg applies in many countries and it relates to the calculation based on 250 g portion of fish which would contain maximum 50 mg histamine . Other countries have the same or similar limits for fish and fish products. In addition, some countries also establish limits for fish sauce produced by fermentation of fish products for instance the EU in Regulation 1019/2013.
Considering the high levels of histamine that can occur in fermented foods, it is reasonable to consider regulating histamine in foods other than fish. A study in Austria proposed limits of 500 and 400 mg/kg fermented sausage and cheese, as well as 100-200 mg/kg tolerable levels for fish species other than regulated ones . However, testing is mainly a verification measure and prevention of histamine occurrence by proper fermentation and storage processes is probably just as vital. Alternatively, since histamine intolerance affects mainly sensitive individuals, warning or advisory statements can be used in relation to foods that are prone to have high levels of histamine. Either of these regulatory measures would need to be justified with a risk assessment and cost benefit analysis.
Histamine has physiological and pathological functions in the human body. It can also be ingested through the diet due to natural presence, or contamination of foods with microorganisms that produce histamine from the amino acid histidine. At high doses histamine causes toxicity for the consumer, while at low doses in sensitive individuals it causes symptoms of intolerance. Fish and fermented foods are most prone to high histamine levels. Regulation by establishing legal limits or using advisory statements could favour the widespread multitudes of consumers who appear to be suffering the consequences of histamine intolerance.
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Appendix I. Histamine content of food, from