Histamine, a naturally occurring chemical messenger in the body, serves various essential functions, including regulating immune responses, acting as a neurotransmitter, and aiding digestion (10). However, an imbalance between histamine intake and the body's ability to metabolize it can lead to histamine intolerance, a condition characterized by a range of uncomfortable symptoms, like headaches, digestive issues, or skin problems. For those struggling with histamine-related symptoms, diagnosing histamine intolerance is an important first step toward a symptom-free life. In this context, understanding the importance of histamine intolerance testing becomes essential for those seeking effective solutions to their health concerns.

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Understanding Histamine and Its Role

Histamine is a biogenic amine compound present in all bodily tissues, with the highest concentrations in the lungs and basophilic and mast cells of the immune system. Histamine plays many roles in controlling various physiologic functions but is most notorious for its involvement in the body's inflammatory and allergic immune responses. The basic functions of histamine can be explained through its interactions with four distinct receptor types.

The activation of H1 receptors by histamine triggers various responses in different tissues and organs, leading to a diverse range of symptoms associated with allergic reactions: itching, pain, flushing, racing heart, and airway constriction. (13)

H2 receptors play a significant role in regulating gastric acid secretion in the stomach. When histamine molecules bind to H2 receptors, they stimulate gastric acid secretion by parietal cells. H2 receptor activation is the target for medications known as H2 receptor blockers, which block the action of histamine on H2 receptors, thereby reducing gastric acid production. H2 blockers are commonly used to treat conditions associated with excess stomach acid, including ulcers, GERD, and heartburn. (13)

H3 receptors, found predominantly in histaminergic neurons, are key modulators of neurotransmitter release in the central nervous system. In the brain, histamine is involved in processes related to wakefulness, appetite regulation, and cognition. It also modulates the release of other neurotransmitters, including dopamine, serotonin, noradrenaline, and acetylcholine, influencing communication between nerve cells. Modulating H3 receptor activity may have implications for conditions involving neurotransmitter imbalances, such as neurodegenerative disorders, ADHD, and sleep disorders (1). (13)

H4 receptors, found in the bone marrow and on primitive immune cells, play a critical role in regulating immune cell differentiation and inflammatory processes. When H4 receptors are activated, they modulate the migration and activation of immune cells, contributing to the body's protective defense mechanisms. (13)

What Is Histamine Intolerance?

Histamine intolerance refers to a condition where the body experiences difficulty in metabolizing histamine, leading to an accumulation of this neurotransmitter in the bloodstream. This imbalance occurs when the rate of histamine intake surpasses the body's capacity to break it down. Unlike allergies, histamine intolerance does not involve the immune system; instead, it is rooted in a deficiency of the enzymes diamine oxidase (DAO) or histamine-N-methyltransferase (HNMT), which are responsible for the breaking down of histamine. (3, 5)

Individuals with histamine intolerance often experience a range of symptoms due to the excess histamine circulating in their bodies. Common symptoms include headaches, migraines, hives, skin redness, itching, nasal congestion, diarrhea, abdominal pain, irregular menstrual cycles, and dizziness. These symptoms can vary widely in severity and may mimic other conditions, making it challenging to diagnose histamine intolerance. Certain factors can contribute to histamine imbalance, including a diet high in histamine-rich foods, certain medications, alcohol consumption, and underlying gastrointestinal disorders that impair DAO function. (3, 5)

Histamine Intolerance Testing Methods

Histamine intolerance testing methods encompass several approaches, each serving a specific purpose in diagnosing this condition. Before diagnosing histamine intolerance, it is recommended to order skin prick or antibody testing to rule out IgE hypersensitivity caused by dietary and environmental allergens, which can induce high histamine responses and mimic symptoms of histamine intolerance. Serum tryptase should also be ordered to evaluate for mastocytosis or mast cell activation syndrome (MCAS), which are much more serious conditions on the histamine spectrum. (4) 

Once these conditions are ruled out, an elimination diet is a widely accepted method to diagnose histamine intolerance. The patient should be advised to follow a low-histamine diet, which involves removing high-histamine foods from the diet. Improvement in histamine intolerance symptoms during the elimination phase, followed by symptom recurrence upon reintroducing high-histamine foods, can strongly suggest histamine intolerance. (4) 

Functional medicine labs that measure DAO, histamine, and zonulin together can also be used to assess for signs of histamine dysregulation. The Advanced Intestinal Barrier Assessment (IBA) is an example of one such lab panel that measures these biomarkers.

Interpreting Test Results

Interpreting histamine intolerance test results involves considering various factors to ensure accurate diagnosis and differentiation from other conditions. Normal histamine levels in blood typically fall below 1 ng/mL, and results falling within this range are considered normal. High histamine levels, especially when accompanied by clinical symptoms and low DAO levels, can indicate histamine intolerance. (4, 11) 

Several factors can influence test results. Recent allergen exposure and intake of certain medications can skew the results. Therefore, patients should avoid taking antihistamines, oral corticosteroids, H2 receptor blockers, and DAO supplements at least 24 hours before test collection. (7) 

Differentiating histamine intolerance from other conditions is crucial because conditions such as allergies, mastocytosis, and other histamine-related disorders share similar symptoms with histamine intolerance. Increases from the patient's baseline in serum tryptase levels during a symptomatic episode or persistent tryptase elevations greater than 20 ng/mL strongly suggest MCAS and systemic mastocytosis (2). Positive IgE antibodies and skin prick testing are diagnostic for allergies. 

Addressing Histamine Intolerance Post-Diagnosis

Addressing the root causes of histamine intolerance, which may include toxic exposure, intestinal dysbiosis, and hormonal imbalances, is critical to overcoming histamine intolerance and providing long-term solutions for symptom management. Dietary modifications, DAO supplements, and antihistamines are commonly implemented to support histamine degradation and provide fast-acting relief of histamine intolerance symptoms. 

A low-histamine diet has been shown to improve symptoms within one month in 33-100% of patients with histamine intolerance. A low-histamine diet is one in which the consumption of high-histamine and histamine-liberating foods is avoided. Because this diet can be limiting, it should be customized based on each patient's own level of tolerance. Tolerance may vary depending on genetics, hormones, stress levels, and environment. (3) Foods that are generally recommended to limit/avoid on a low-histamine diet include:

• Hard- and semi-hard cheeses
• Fermented foods
• Shellfish
• Processed and smoked meats
• Soy
• Mushrooms
• Avocado
• Nightshade vegetables 
• Olives
• Dried fruits
• Chocolate
• Vinegar
• Alcohol
• Canned foods
• Leftovers (3) 

A comprehensive list that outlines low-histamine diet recommendations can be found here.

Over-the-counter antihistamines and supplements can help support healthy histamine degradation, stabilize histamine-releasing cells, and palliate histamine intolerance-related symptoms. H1-blocking antihistamines (e.g., Claritin, Zyrtec, Allegra) treat systemic allergy symptoms, including hives, itching, and runny nose. H2-blocking antihistamines (e.g., Pepcid) are better suited for addressing gastrointestinal-related symptoms like heartburn. Natural antihistamine agents, such as quercetin, stinging nettle leaf, and vitamin C, can also be considered. (3, 8) 

DAO supplements are often part of a comprehensive approach to managing histamine intolerance. Supplemental DAO is designed to be taken with meals to compensate for DAO enzyme deficiency, aiding in the breakdown of histamine and reducing histamine intolerance symptoms triggered by eating. Several clinical trials have demonstrated the efficacy of DAO supplements in improving histamine intolerance symptoms. (3, 8) 

Monitoring and Reevaluation

Regular monitoring of a patient's symptoms and laboratory biomarkers is an important aspect of reevaluation to manage histamine intolerance effectively. Histamine intolerance is a dynamic condition, with symptoms varying over time and in response to different factors. Therefore, consistent monitoring allows healthcare professionals to assess the progress of the treatment plan and make necessary adjustments to interventions.

Retesting for histamine intolerance, including plasma histamine levels and DAO enzyme activity, helps track changes over time. Periodic assessments enable healthcare providers to gauge the effectiveness of interventions such as dietary changes, supplements, and medications. If symptoms persist or worsen, reevaluation tests can pinpoint whether histamine levels have fluctuated and if other contributing factors must be addressed.

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Summary

Understanding and properly managing histamine intolerance is paramount for individuals struggling with this condition. A personalized approach to histamine intolerance, tailored to an individual's specific needs and symptoms, is key to effective management. By comprehensively addressing factors such as diet, enzyme deficiencies, and other underlying health issues, personalized care can significantly alleviate symptoms and improve overall quality of life. Consistent monitoring, involving regular reevaluation of histamine levels and symptom changes, ensures that interventions remain relevant and adjustments can be made promptly. This proactive and personalized approach enhances treatment efficacy and provides individuals with histamine intolerance the support they need to lead healthier and more comfortable lives.