To understand HIT it is first necessary to have an understanding of histamine. Known as a biogenic amine it was discovered in 1910 by Dale and Laidlaw and is present in nearly every cell in the body. It is synthesised via decarboxylation of the amino acid histidine and is found in mast cells, basophils and eosinophils. When released into the surrounding tissue it contributes to localised inflammation and is best known for its role in allergies which was first recognised in 1932. In addition to this, it plays many lesser known roles in the body which include regulating sleep, the release of gastric acid, memory, sexual function, wound healing, mood and more recently it is thought to play a role in multiple sclerosis due to its ability to support T-cell differentiation.
The role it plays in HIT is due to a rise in histamine levels in the body beyond the body’s capacity to metabolise it and break it down. This results in a build-up of histamine and this imbalance is accompanied by associated symptoms. The main symptoms of HIT therefore include asthma, dysmenorrhea, headache/migraine, tachycardia, urticaria, pruritus, diarrhoea, hypotension, flushing and rhinitis. Conditions and symptoms frequently seen in clinic. Given their similarity to an allergic reaction they are often mistakenly attributed to this and the condition is often underestimated and misinterpreted. Unlike an allergy, however, the symptoms may not always develop straight away as it can take some time for the concentration of histamine to build up as it is gradually released into the system. This rise in histamine occurs due to the body’s inability to remove histamine through its normal pathways: deactivation via the enzymes diamine oxidase (DAO) and histamine N-methyltransferase (HNMT). The reason this break down in the enzymes occurs are multifactorial including both genetic and acquired impairment.
The prevalence of HIT is not clearly defined. Varying references are made ranging from to 1-8% of the population having the condition and 80% of those being middle aged. Since it is not such a recognised condition this confusion is understandable and with more research the true numbers and extent of the condition will hopefully become clear.
What is known is that due to the reduced activity of DAO or HNMT, both endogenous and exogenous sources of histamine are capable of increasing histamine levels in the body and as such finding ways to reduce these sources is one of the main methods of treating HIT.
Since DAO is the main enzyme which metabolises ingested histamine one of the primary exogenous sources is via the diet through increased consumption of histamine and to some extent histidine rich foods. The list of histamine rich foods is long and includes every day foods like cured meats, fish, hard cheeses, beans and pulses and certain vegetables and fruit. This can make following a HIT diet hard to implement and increases the importance of supporting the production of DAO as well as reducing the impact of associated inflammation through supplementation (see below).
A rise in histamine can also occur when foods are consumed that liberate histamine in the body, some examples include oranges and soya sauce. Although they are not high in histamine they contain putrescine, another biogenic amine, which is thought to have the capacity to displace histamine from its mucosal mucine linkage and consequently increases the concentration of circulating histamine. Other foods which are known histamine liberators include chocolate, avocado, strawberries, papaya and walnut, although the mechanism behind how they release histamine is not entirely understood.
Bowel flora balance is an important factor which can affect histamine production. For example, antibiotics and diet can compromise the gut resulting in an increase of bacteria that favour histamine production. Certain bacteria (e.g. Lactobacillus casei, Lactobacillus reuteri and Lactobacillus plantarum) produce histidine carboxylase, an enzyme which can convert the amino acid histidine to histamine. Once converted in the colon it is absorbed into the body contributing to symptoms. This source can be balanced by the concentration of bacteria which degrade histamine (e.g. Bifidobacterium infantis, Lactobacillus rhamnosus and salivarius). The amount of histamine produced will be dependent on the balance of these two groups of bacteria and of course the protein pool available for conversion.
Furthermore, as one of the main sites of DAO expression is in the small bowel and colon, any conditions like Crohn’s disease which can cause damage to these areas, have the potential to reduce the prevalence of DAO production. Subsequently HIT may contribute to some of the symptoms experienced by an individual with compromised digestion.
Aerobic exercise is known to increase the release of histamine and for those with histamine intolerance may result in an increase in associated symptoms like itching and migraine. The mechanism behind this is not entirely understood, but it should be something to note during a case history as a possible marker of HIT.
Medication and alcohol
Acquired impairment of the enzymes can be due to commonly prescribed medication such as cimetidine, amitriptyline and nonsteroidal anti-inflammatory, all known DAO inhibitors. This is easily resolved when under the correct supervision they are gradually withdrawn or changed to ones that don’t have an inhibitory affect. When considering HIT, intake of drugs and the start of symptoms should therefore be evaluated, especially in the case of long-term medication.
Alcohol also has the ability to inhibit DAO and in addition to this, depending on the type of alcohol, can have high a histamine content.
Conditions Where HIT may Play a Role
Estradiol stimulates the production of prostaglandins which when not opposed by progesterone can contribute to the symptoms of dysmenorrhea. Histamine may cause this balance to shift due to its ability to stimulate the synthesis of estradiol compared to progesterone resulting in an imbalance of the two hormones. It is therefore possible that HIT may play a role in dysmenorrhea and other symptoms associated with oestrogen dominance like headaches and breast tenderness. It may also be something to explore in hormonal conditions like endometriosis where one of the most common symptoms is dysmenorrhea. While this pain is often understandably attributed to the condition it is possible that it may not always be related to endometrial tissue and rather simply to pain caused by histamine driven oestrogen dominance.
People who suffer with atopic eczema have been shown to have higher histamine concentrations as well as in increase in histamine after food challenges. In addition to this a subgroup exists which have been found to have reduced DAO activity and they are therefore also more likely to suffer with symptoms of HIT.
Anything that can help to reduce inflammation will play an important part in supporting an individual’s health. By its very nature histamine is associated with an increase in inflammation. Identifying imbalances in the metabolism of histamine and working to reduce these can therefore play a key role in supporting long term health.
Histamine levels are influenced by a person’s ability to methylate as it is de-activated by HNMT to N-methylhistamine on receipt of a methyl group. Those people who under-methylate therefore tend to have a higher level of histamine. This is why elevated histamine can be used as a marker or guide towards looking for the need to include methylation in a protocol.
Before considering HIT it is important to exclude other potential causes of symptoms particularly allergy. Once these have been ruled out a practitioner can test for the presence of DAO and based on test results and a thorough case history recommend that their client follow a histamine free diet.
While it is now possible to supplement with the DAO enzyme this should not detract from looking at ways in which to naturally reduce histamine. One of these includes supporting the synthesis of DAO due to potential deficiencies in its co factors, vitamin B6 and copper. Vitamin C Is also important as it helps to degrade histamine. Increasing foods rich in these nutrients or supplementing may therefore help to increase DAO synthesis and support the degradation of histamine thus reducing symptoms. In addition, balancing the bowel flora and supporting its integrity will play a key role in any protocol. This would include observing for potential leaky gut and reduced digestive ability.
While HIT may well prove to be a game changer, it is only with more research that we will be able to truly understand how the condition negatively impacts the body. In the meantime, the potential for identifying and supporting clients who suffer with HIT is an exciting prospect.
Ahrens F et al. Release and permeation of histamine are affected by diamine oxidase in the pig and large intestine. Inflamm Res 2002 51: S83-4
Bodis J et al. The effect of histamine on progesterone and estradiol secretion of human granulosa cells in serum-free culture. Gynecol Endocrinol 1193 7:235-9.
Bieganski T et al. The importance of human intestinal diamine oxidase in the oxidation of histamine and/or putrescine. Arch Immunol Ther Exp 1980, 28:901-6.
Johnston CS. The antihistamine action of ascorbic acid. Subcell Biochem 1996, 25:189-213.
Maintz L and Novak N. Histamine and histamine intolerance. Am J Clin Nutr 2007, 85:1185-96.
Masterman G. What HIT me? Living with histamine intolerance: A guide to diagnosis and management of HIT – A patient’s point of view. Createspace Independent Publishing Platform, 2ed 2013
Missbichler A. Diagnostischer Nachweis der Activität von Diaminooxidase in serum order Plasma. In: Jarisch R ed. HIstamin-Intoleranz. Histamine und Seekrankheit. Stuttgart, Georg Thieme Verlag KG; 2004. 8-17.
Music E et al. Serum diamine oxidase (DAO) activity as a diagnostic test for histamine intolerance. Clinical and Translational Allergy 2011, 1(Suppl 1): 115.
Sampson HA and Jolie PL. Increased plasma histamine concentrations after food challenges in children atopic dermatitis. N Engl J Med 1984 311: 372-6.
Schmidt WU et al. Human intestinal diamine oxidase (DAO) activity in Chron’s disease: a new marker for disease assessment? Agents Actions 1990, 30:267-70.
www.histaminintoleranz.ch - for a list of foods which affect histamine level in the body
http://thelowhistaminechef.com/ - for information and recipes to share with clients