Summary

Histamine intolerance is a condition characterized by the inability to properly break down histamine, a compound naturally occurring in the body and many foods.

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Overview

Histamine is crucial for various bodily functions, including immune responses, digestion, and brain function. Histamine intolerance is often caused by reduced activity of the DAO enzyme, responsible for breaking down histamine from ingested foods.

This condition affects approximately 1% of the population and can result from genetic factors, allergies, gastrointestinal issues, medications, and dietary choices. Symptoms can vary widely and affect different body systems, including the digestive, skin, respiratory, cardiovascular, neurological, and musculoskeletal systems.

Diagnosing histamine intolerance is challenging and involves ruling out other conditions with similar symptoms. It may involve maintaining a food diary and trying a low-histamine diet. Treatment typically includes dietary modifications, such as avoiding high-histamine foods and taking DAO enzyme supplements. Prevention involves avoiding histamine-rich foods and substances that trigger histamine release.

With proper management, many individuals with histamine intolerance can significantly reduce their symptoms and lead normal lives, although it is considered a chronic condition.

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What is histamine? 

Histamine is a biogenic amine, an organic compound derived from the amino acid histidine. It is a vital molecule in the human body, participating in several physiological processes. Histamine functions as a neurotransmitter, modulating various brain functions, including wakefulness and appetite regulation. Additionally, it plays a crucial role in the immune response, acting as a chemical messenger during allergic reactions and defending the body against foreign invaders. Histamine also regulates stomach acid production, aiding in digestion.^[1]

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Pathophysiology

Histamine intolerance occurs when the body's histamine metabolism is compromised. The primary reason for this is often the reduced activity of the DAO enzyme. 

The body has two primary enzymes responsible for breaking down histamine:^[2]

• Diamine Oxidase (DAO). DAO is found in the digestive tract, particularly in the small intestine. Its main job is to break down histamine that comes from ingested food. In individuals with low DAO activity, histamine can accumulate, leading to symptoms of histamine intolerance.
• Histamine N-Methyltransferase (HNMT). HNMT is primarily active in the central nervous system and helps degrade histamine within the brain.

When histamine-containing foods are ingested, or histamine-releasing substances are encountered, individuals with DAO deficiencies struggle to break down histamine efficiently. As a result, excess histamine accumulates in the body, leading to a wide range of symptoms. 

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Prevalence & Risk factors

Histamine intolerance is a condition that affects a significant portion of the population. While prevalence estimates may vary, studies suggest that approximately 1% of people may experience histamine intolerance.^[2]

Several things can contribute to histamine intolerance by either affecting the histamine levels or the activity of the DAO enzyme. These include:^[3]

• Genetics. Genetic factors can contribute to histamine intolerance. Variations in genes responsible for encoding enzymes like diamine oxidase (DAO) or histamine receptors may influence how the body metabolizes histamine.
• Allergies. People with existing allergies, particularly food allergies, may be at an increased risk of developing histamine intolerance. Allergic reactions trigger the release of histamine, further burdening the body's histamine processing mechanisms.
• Gastrointestinal problem. Certain GIT conditions can contribute to the development. These include colon polyps, malabsorption, food allergies, celiac disease, inflammatory bowel diseases (such as Crohn’s disease or ulcerative colitis), irritable bowel syndrome, functional dyspepsia, and small intestinal bacterial overgrowth (SIBO).
• Medications. Certain medications can inhibit the activity of DAO or promote histamine release. These include non-steroidal anti-inflammatory drugs (NSAIDs), certain antidepressants, antiarrhythmics, antibiotics, and some antihypertensive drugs.
• Diet. Some foods can also contribute to histamine intolerance through several mechanisms. 

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Genetics

Genetic factors influence how efficiently our bodies process histamine. Histamine intolerance is linked to gene variations involved in its metabolism, such as DAO and HNMT. These genes affect the enzymes responsible for the histamine breakdown. Mutations or polymorphisms in these genes can impair histamine clearance, contributing to intolerance symptoms.^[8]

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Single nucleotide polymorphisms (SNPs) in the DAO gene have been found to significantly affect DAO serum activity. For instance, the minor allele at rs2052129 increases the risk of reducing its activity.^[9]

Environmental factors, like diet and gut microbiota composition, also interact with genetic predispositions, making histamine intolerance a complex interplay between genes and the environment.^[3]

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Signs & Symptoms 

The onset and severity of histamine intolerance symptoms can vary significantly from person to person.  Symptoms often worsen after consuming foods high in histamine or substances that trigger histamine release. 

Most commonly affected individuals experience gastrointestinal issues, but the condition can affect various systems because histamine receptors are found throughout the body.

The symptoms include:^[4]

• Digestive issues such as abdominal pain, bloating, diarrhea, nausea, acid reflux, and constipation.
• Skin problems like hives, itching, redness, and skin rashes.
• Respiratory symptoms include a runny or stuffy nose, sneezing, nasal congestion, wheezing, and difficulty breathing in severe cases.
• Headaches and migraines.
• Cardiovascular symptoms like a rapid heart rate, low blood pressure, dizziness, or lightheadedness.
• Neurological symptoms such as anxiety, panic attacks, fatigue, difficulty concentrating (brain fog), and sleep disturbances.
• Musculoskeletal symptoms like joint pain, muscle pain, and muscle cramps.
• Menstrual symptoms include menstrual cramps and irregular menstrual cycles.

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Diagnosis

Diagnosing histamine intolerance is challenging and requires the exclusion of other medical conditions that can cause similar symptoms. 

The healthcare professional can begin by excluding conditions such as food allergies and intolerances, celiac disease, inflammatory bowel disease, etc. 

Patients may be asked to maintain a detailed food diary to track symptoms and identify potential triggers. A low-histamine diet may be recommended. If symptoms improve while on the diet and worsen when high-histamine foods are reintroduced, this can suggest histamine intolerance.^[2,4]

In some cases, blood tests measuring DAO enzyme activity may help confirm the diagnosis. 

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Therapy 

Treatment for histamine intolerance typically involves dietary and lifestyle modifications, such as a low-histamine diet. 

It can include foods like:^[5]

• fresh meat and freshly caught fish
• non-citrus fruits
• eggs
• gluten-free grains, such as quinoa and rice
• dairy substitutes, such as coconut milk and almond milk
• fresh vegetables except for tomatoes, avocados, spinach, and eggplant
• cooking oils, such as olive oil

Maintaining a food diary can help you track your symptoms and identify specific triggers. 

Several studies have shown that DAO enzyme supplements can also lead to improvement in symptoms. ^[6]

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Prevention 

Preventing histamine intolerance symptoms involves avoiding triggers and managing your diet. It is recommended to avoid certain foods, including:^[7]

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Foods and drinks that are rich in histamine

• alcohol
• aged cheeses
• canned, pickled, and fermented foods, such as sauerkraut
• smoked products, such as sausage, ham, bacon, or salami
• spinach
• eggplant
• ketchup
• vinegar
• canned fish, such as mackerel and tuna

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Foods that may trigger the release of histamine

• most citrus fruits
• cocoa and chocolate
• tomatoes
• egg whites
• fish
• peanuts

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Drinks that interfere with the activity of DAO enzyme

• alcohol
• energy drinks
• green tea
• black tea
• maté tea

It is also recommended to avoid certain medications that can inhibit the activity of DAO or promote histamine release. These include non-steroidal anti-inflammatory drugs (NSAIDs), certain antidepressants, antiarrhythmics, antibiotics, and some antihypertensive drugs.

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Prognosis

The prognosis for histamine intolerance varies. Histamine intolerance is generally considered a chronic condition, but with proper management, many people can achieve a significant reduction in symptoms and lead a normal life. 

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Recommendations

• Consult a healthcare professional for proper diagnosis and guidance.
• Follow a low-histamine diet with an emphasis on fresh meat, freshly caught fish, non-citrus fruits, eggs, gluten-free grains, dairy substitutes, and certain fresh vegetables. 
• Avoid foods and drinks that are high in histamine, lead to the release of histamine, or block the activity of the DAO enzyme. 
• Maintain a food diary to track symptoms and identify trigger foods.
• Consider DAO enzyme supplements after consulting with a healthcare provider.
• Review medications with your doctor to assess if any are contributing to histamine intolerance.