Histamine intolerance (HIT) is caused by the imbalance of accumulation and degradation of histamine in the body manifesting in an allergy-like symptom such as hive, gastrointestinal symptoms, asthma, headache, migraine or even a chronic symptom such as fatigue, insomnia, anxiety and depression.
Histamine is known as a mediator of allergic reactions. It is released mainly by mast cells as an immediate inflammatory response to stimuli e.g. infection, insect bites, dust mites and toxic substances. Histamine also plays other roles in the body such as a neurotransmitter (a brain chemical that communicates information throughout our brain and body) and immunomodulator (a chemical affecting the immune function) depending on what receptors it binds to. There are four types of histamine receptors (designated H1-H4). Excess activation of H1 receptors triggers the symptoms of hay fever and other seasonal allergies. H2 receptors are found mainly on gastric parietal cells in the stomach lining and are responsible for stimulating the release of gastric acid. H3 receptors are present in the central nervous system affecting sleep and mood as well as regulating histamine in the body. H4 receptors regulate the levels of white blood cell released from bone marrow and direct mast cells.
Some people with allergies take antihistamines regularly to block histamine receptors however the common antihistamine drugs (e.g. fexofenadine) only target H1 receptor and is less effective for histamine-related symptoms involving other histamine receptors. When histamine excessively accumulates, the development of symptoms can be varied depending on histamine binding to corresponding receptors. These symptoms may include headache, migraine, diffuse pain of stomach, colic, flatulence, diarrhoea, rhinorrhoea (runny nose), nasal obstruction and in extreme cases even attack of bronchial asthma, bronchoconstriction, coughing, wheezing, chronic urticaria, dysmenorrhoea (painful period) and headaches connected with menstrual cycle. Mast cell degranulation and histamine release is the main mechanism for histamine overload, and in some patients with chronic idiopathic urticaria, this may be related to non-IgE food intolerance. Moreover, chemical and physical factors including stress, trauma, alcohol, and medications are responsible for histamine release.
Other chronic symptoms of HIT
Histamine and mast cell activation may play a crucial role in the pathogenesis of fibromyalgia. A study found a significant increase in mast cells (up to 14 times) in the papillary dermis of all fibromyalgia patients compared to healthy controls. The results reflect the mastocyte degranulation-related symptoms (e.g. fatigue, headache, abdominal discomfort) observed in fibromyalgia patients. In addition, mast cells may play a role in a subset of fibromyalgia patients who are highly pain sensitive similar to irritable bowel syndrome (IBS). Increased mast cell degranulation in proximity to the nerves innervating the colonic mucosa may be associated with abdominal pain in patients with IBS. A study demonstrated that the release of histamine was significantly increased by 118% in IBS patients compared to controls and was significantly correlated with the number of infiltrating mast cells.
Estrogen stimulates mast cell degranulation and histamine release. Individuals with high estrogen may have increased histamine responses. Increased concentration of histamine stimulates synthesis and release of stress hormones, which can cause paradoxical increase of blood pressure (even though histamine itself causes its decrease), nervousness, and insomnia.
What causes histamine intolerance?
In healthy individuals, the amount of circulating histamine is regulated and maintains a balance. Histamine is inactivated primarily by enzymes diamine oxidase (DAO), which regulates the amount of histamine entering the body from the digestive tract. Inability to break down histamine efficiently can cause histamine overload or known as histamine intolerance (HIT). As the production of DAO and breakdown of histamine occur mainly in the gut, HIT symptoms may develop due to reduced DAO activity caused by gastrointestinal disorders. Moreover, animal studies show that mast cells are activated during stress through corticotropin-releasing hormones causing the release of histamine and other inflammatory molecules.
Consuming histamine-rich foods can trigger HIT symptoms. A study in 316 middle age subjects with main symptoms of HIT involving skin (83%), gastrointestinal tract (52%), respiratory system (26%) and eyes (9%) reported that serum DAO activity significantly reduced in these patients compared to healthy controls and the symptoms disappeared along with increased serum DAO activity after implementing a histamine-free diet for 6-12 months. In addition, alcohol and some drugs can block DAO activity.
The neurotransmitter activity of histamine in the brain is controlled by histamine-N-methyltransferase (HNMT) affecting sleep cycle and cognitive function. HNMT inactivates histamine via methylation (i.e. the addition of a methyl group). Therefore, undermethylation (i.e. too little methyl) may impair HNMT activity resulting in elevated histamine. Methylation may be compromised due to high toxic load (e.g. cigarette smoking, alcohol, air pollution, amalgam filling, highly processed food). Chronic stress and sleep deprivation can deplete the body’s stores of magnesium, a cofactor for the production of methyl donor.
Some gut bacteria can convert histidine to histamine whereas certain types of gut bacteria can break down histamine. Therefore, imbalanced gut microflora (gut dysbiosis) may lead to histamine overload. Disrupted gut microflora may be caused by infections, overuse of antibiotics, medications, high sugar, processed food and low fibre intake.
Low histamine diet
Being aware of which foods contain high histamine helps identify the foods that can be problematic. Everyone has different sensitivity threshold depending on how much histamine is released intrinsically, and how efficient the body metabolises histamine. It is important that an individual consumes low histamine food in accordance to their threshold, which can be assessed by eliminating high histamine food for a short period (4-6 weeks), followed by reintroducing histamine containing foods one at a time to see how the body can tolerate it. A study evaluating the efficacy of histamine-restricted diet in 44 subjects diagnosed with urticaria, angioedema and pruritus reported that 61.4% of participants had a significant improvement in primary symptoms and 18.2% had some improvement after implementing a histamine restricted diet for 4 weeks.
Histamine levels in foods also vary depending on freshness, ripeness, processing and storage of foods. Aging and fermentation of foods increases the histamine content. In addition, cooked meats that are leftover or are not frozen quickly may be high in histamine. This is because bacteria naturally present in meats can convert histidine to histamine, and histamine is not destroyed by heat. Alcohol, coffee, and teas can block the activity of DAO enzyme.
Vitamin C, vitamin B6 and copper are cofactors in histamine degradation by DAO. Copper deficiency was shown to be correlated with reduced plasma DAO levels. Vitamin C may help break down histamine in the body. Quercetin is an antioxidant found in onion, kale and apples and possesses antihistamine property preventing mast cell activation and mastocytosis (excess of mast cells in the body).
If you have a histamine intolerance, avoiding high histamine foods can be very helpful but is not recommended for a long term. This is because a low histamine diet is highly restricted and may lead to nutrient deficiency. It is recommended you address the underlying cause of your histamine intolerance which could be due to a gut health issue, particularly gut dysbiosis or gluten sensitivity and leaky gut syndrome which can result in DAO insufficiency. In some case, undermethylation may be caused by genetic variations.