The link between Eosinophilic Esophagitis and Mast Cell Activation

Understanding EoE and MCAS

Eosinophilic Esophagitis (EoE) is a chronic immune-mediated condition that affects the esophagus, characterized by an accumulation of eosinophils (a type of white blood cell) in the esophageal lining. This infiltration leads to inflammation, which can cause a range of symptoms like difficulty swallowing, food impaction, and heartburn. On the other hand, Mast Cell Activation Syndrome (MCAS) is a condition where mast cells, part of the immune system, inappropriately release various inflammatory mediators such as histamine, causing widespread symptoms across different organ systems.

Increasing evidence highlights a significant overlap between EoE and MCAS. In fact, some patients with EoE also exhibit high mast cell counts in the esophagus, suggesting that mast cells may play a critical role in the development and progression of EoE, potentially complicating the diagnosis and treatment​​.

The Role of Mast Cells in EoE

While eosinophils have long been considered the primary immune cells responsible for EoE, recent research has uncovered that mast cells also have a substantial presence in EoE-affected tissue​​. Mast cells, traditionally associated with allergic reactions, can amplify inflammation in the esophagus by releasing mediators such as histamine, tryptase, and cytokines. These substances not only contribute to inflammation but also interact with eosinophils, sustaining and potentially exacerbating the immune response​​.

For instance, tryptase—a mast cell-specific enzyme—has been found to modulate eosinophil activation and limit their ability to die, effectively prolonging the inflammatory state​. This could potentially increase the risk of EoE in people who have Hereditary alpha Tryptasemia (HaT). Additionally, mast cells can stimulate smooth muscle contraction in the esophagus, leading to motility issues that are often seen in EoE patients​. Research also indicates that mast cell degranulation is prevalent in EoE patients, contributing to esophageal remodeling and fibrosis, which worsens the symptoms over time​​.

The Link Between EoE and MCAS

MCAS and EoE share several overlapping mechanisms. In both conditions, mast cells release large quantities of histamine, tryptase, and other mediators that promote inflammation​​. In patients with MCAS, mast cells are hyperactive, releasing these substances in response to a wide range of triggers, including food allergens and environmental toxins. Since EoE is often triggered by food allergens, this suggests a possible link between mast cell hyperactivity in MCAS and the development or exacerbation of EoE​​.

MCAS may also explain why some patients with EoE continue to experience symptoms even after the eosinophils have been controlled with treatments like steroids or dietary changes​. Persistent symptoms in EoE, such as esophageal dysfunction and pain, may be attributed to lingering mast cell activity, which continues to drive inflammation and disrupt normal esophageal function​.

Mast Cell-Eosinophil Interactions in EoE

Mast cells and eosinophils often work together to perpetuate inflammation in allergic diseases like EoE. Both cell types are recruited to sites of inflammation by chemokines like eotaxin, and once they arrive, they further stimulate each other​. Mast cells produce interleukins like IL-3 and IL-5, which extend the lifespan of eosinophils in tissue. This interaction creates a cycle of inflammation that is difficult to break, making both mast cells and eosinophils crucial in the pathology of EoE​.

Moreover, mast cell-derived factors such as stem cell factor (SCF) can attract even more mast cells to the site of inflammation, compounding the problem​. This relationship between mast cells and eosinophils underscores the need to consider both cell types when diagnosing and treating EoE, especially in patients who also have MCAS​​.

Diagnostic and Therapeutic Considerations

Given the strong link between EoE and MCAS, patients exhibiting symptoms of one condition should be evaluated for the other. For example, EoE patients who continue to experience symptoms after eosinophils are reduced should be assessed for elevated mast cell counts and signs of MCAS​. This might include testing for mast cell mediators like tryptase or performing tissue biopsies with special staining to detect mast cells​.

From a therapeutic standpoint, addressing both eosinophil and mast cell activity is crucial. Treatments like mast cell stabilizers (e.g., Ketotifen) and H1/H2 antihistamines (e.g., Zyrtec and Pepcid) have been used in MCAS and may provide relief for patients with overlapping EoE and MCAS​. Additionally, swallowed steroids, commonly used for EoE, have been shown to reduce both eosinophils and mast cells in the esophagus, potentially offering dual benefits​.

Conclusion

The relationship between EoE and MCAS is complex but significant. Mast cells, traditionally overlooked in the study of EoE, are increasingly recognized as key players in the disease process. Their interactions with eosinophils create a vicious cycle of inflammation that is difficult to control, especially in patients with MCAS. For these patients, a comprehensive approach targeting both mast cells and eosinophils may be necessary to achieve symptom relief and prevent long-term damage to the esophagus. Further research into the shared mechanisms of these conditions will help improve diagnosis and treatment options, offering better outcomes for those affected by both EoE and MCAS.

‍

FAQ

Can EoE cause Mast Cell Activation?

While eosinophilic esophagitis (EoE) and mast cell activation are related, EoE itself does not directly cause Mast Cell Activation Syndrome (MCAS). However, the inflammatory environment created by EoE can activate mast cells in the esophagus, contributing to the overall inflammation and symptoms.

Mast cells are naturally present in the gastrointestinal tract, including the esophagus, and they play a role in immune responses. In EoE, food allergens trigger an immune reaction that leads to eosinophil accumulation. Mast cells, in response to this inflammation, can become activated and release various mediators, such as histamine and tryptase, which further aggravate the inflammation​​.

In some patients with both conditions, EoE may exacerbate symptoms of MCAS by maintaining chronic inflammation, leading to ongoing mast cell activation. This relationship highlights the need to address both eosinophil and mast cell activity in treatment strategies.

Is eosinophilic esophagitis a mast cell disorder?‍

Eosinophilic esophagitis (EoE) is primarily an allergic inflammatory disease driven by food antigens. While it is not classified as a mast cell disorder, mast cells do accumulate in the esophagus of EoE patients, and recent studies suggest that mast cells play a significant role in the inflammation and tissue remodeling seen in EoE.

Can MCAS cause eosinophilia?‍

Yes, MCAS (Mast Cell Activation Syndrome) can contribute to eosinophilia in some cases. In certain patients, eosinophilic esophagitis (EoE) may develop as a consequence of underlying MCAS, driven by the inappropriate activation of mast cells, which release mediators that attract eosinophils to the esophagus.

What is the most common trigger for eosinophilic esophagitis?‍

The most common trigger for EoE is cow's milk. However, other foods such as wheat, soy, eggs, peanuts, and fish can also trigger the condition in many patients.

Can histamine intolerance cause EoE?‍

Histamine intolerance can exacerbate or complicate eosinophilic esophagitis (EoE) due to the inflammatory effects of histamine released by mast cells. In patients with both EoE and MCAS, elevated histamine levels can worsen symptoms, though histamine intolerance alone is not typically a direct cause of EoE.

What autoimmune disease is associated with eosinophilic esophagitis?‍

EoE has been linked to several autoimmune diseases, with celiac disease being the most well-documented. Other conditions, such as connective tissue diseases, have also been observed in some patients with EoE, though more population-based data is needed.

What are most people with EoE allergic to?‍

Most people with EoE are allergic to certain foods, with the most common being cow's milk, wheat, soy, eggs, and, less frequently, peanuts and fish. EoE is thought to be a delayed allergic response to these food proteins.

What can be mistaken for MCAS?‍

MCAS (Mast Cell Activation Syndrome) can be confused with several chronic symptom disorders, including chronic pain syndromes, fibromyalgia, chronic fatigue syndrome, multiple chemical sensitivity syndrome, and irritable bowel syndrome (IBS). These conditions share overlapping symptoms like pain, fatigue, and gastrointestinal issues.

What disorders are associated with MCAS?‍

MCAS is associated with a wide range of disorders, including allergic conditions (such as asthma, eczema, and anaphylaxis), gastrointestinal conditions (such as EoE and irritable bowel syndrome), and systemic issues like connective tissue disorders, autoimmune diseases, and even POTS (Postural Orthostatic Tachycardia Syndrome).

What mimics eosinophilic esophagitis?‍

Eosinophilic esophagitis can often be mistaken for gastroesophageal reflux disease (GERD), as both conditions share similar symptoms, including chest pain, trouble swallowing, and heartburn. However, while GERD is caused by acid reflux, EoE is an immune response to food antigens.

What are the six foods to avoid with eosinophilic esophagitis?‍

The six foods commonly eliminated in patients with EoE include cow's milk, wheat, soy, eggs, peanuts/tree nuts, and fish/shellfish. These foods are known to trigger allergic reactions in many EoE patients.

Do antihistamines help eosinophilic esophagitis?‍

Antihistamines may help manage some symptoms in EoE, especially in patients who also have MCAS, as they block the effects of histamine released by mast cells. However, antihistamines are not a first-line treatment for EoE, as they do not directly address eosinophil-driven inflammation.

What does it feel like to have eosinophilic esophagitis?‍

Patients with EoE often describe experiencing difficulty swallowing, a sensation of food getting stuck in the esophagus, heartburn, chest pain, and sometimes vomiting. In severe cases, the inflammation can lead to narrowing of the esophagus, causing significant discomfort when eating.

What is the secondary cause of eosinophilic esophagitis?‍

The primary cause of EoE is an allergic response to food antigens, but secondary factors include environmental allergens and conditions that increase susceptibility to inflammation, such as MCAS, which can worsen symptoms by promoting further immune activation in the esophagus.

What kind of doctor treats EoE?‍

Eosinophilic esophagitis is typically treated by gastroenterologists, particularly those with experience in inflammatory and allergic gastrointestinal conditions. In some cases, allergists or immunologists may also be involved, especially if food allergies or mast cell-related disorders like MCAS are suspected.

Do antihistamines lower eosinophils?‍

Antihistamines primarily work by blocking histamine receptors, reducing allergic symptoms, but they do not directly lower eosinophil counts. To reduce eosinophils in conditions like EoE, treatments such as corticosteroids or dietary changes are typically necessary.

‍

References

• Abonia, J. P., Blanchard, C., Butz, B. B., Rainey, H. F., Collins, M. H., Stringer, K., Putnam, P. E., & Rothenberg, M. E. (2010). Involvement of mast cells in eosinophilic esophagitis. Journal of Allergy and Clinical Immunology, 126(1), 140-149. https://doi.org/10.1016/j.jaci.2010.04.009
• Bolton, S. M., Kagalwalla, A. F., Arva, N. C., et al. (2020). Mast Cell Infiltration Is Associated With Persistent Symptoms and Endoscopic Abnormalities Despite Resolution of Eosinophilia in Pediatric Eosinophilic Esophagitis. American Journal of Gastroenterology, 115(2), 224-233. https://doi.org/10.14309/ajg.0000000000000474
• Nelson, M., Zhang, X., Pan, Z., Spechler, S. J., & Souza, R. F. (2021). Mast cell effects on esophageal smooth muscle and their potential role in eosinophilic esophagitis and achalasia. American Journal of Physiology-Gastrointestinal and Liver Physiology, 320(3), G319-G327. https://doi.org/10.1152/ajpgi.00290.2020
• Zimmermann, N., Abonia, J. P., Dreskin, S. C., Akin, C., & Wechsler, J. B. (2021). Developing a standardized approach for assessing mast cells and eosinophils on tissue biopsies: A Work Group Report of the AAAAI Allergic Skin Diseases Committee. Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2021.06.030
• Klimas, L. (2014). Mast cells, eosinophils and the perfect storm of inflammation. Mast Attack. https://www.mastattack.org/2014/05/mast-cells-eosinophils-and-the-perfect-storm-of-inflammation/

‍