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A range of acute and chronic clinical conditions have been described in which mast cells may be increased in numbers or display hyperreactivity. While a specific and consistent definition of mast cell activation syndrome (MCAS) has yet to be established, the condition is described as a chronic, multisystem disorder of inappropriate mast cell activation triggered by various stimuli.^1-3 Clinical features may include inflammation, allergic-type responses, and non-specific symptoms ranging across cardiovascular, gastrointestinal, dermatologic, and respiratory systems.^2,4,5 MCAS may be further classified as primary, secondary, or idiopathic based on the etiology, and the condition overlaps with various chronic diseases, disorders, and infections.^2,3,5 The connection between MCAS and chronic illness is an intricate clinical topic, and confirming an MCAS diagnosis may be difficult;^4,6 however, functional medicine is uniquely positioned to effectively investigate, treat, and support this complicated condition, as well as general mast cell regulation, through a systems biology approach to health.

Mast Cell Mediators & Chronic Conditions

The hyperreactivity described in MCAS triggers unregulated mast cell degranulation and release of mediators including histamine, heparin, proteases, hydrolases, and proinflammatory cytokines through which systemic manifestations may surface, from compromised intestinal and neurologic barrier function to hyperinflammation.^3,7,8 Recently, researchers analyzed data from a large US database that included information from over 53 million patients and found the strongest specific association between irritable bowel syndrome (IBS) and MCAS: those with IBS were at least four times more likely to have a mast cell disorder compared to the general population.⁹ Other recent human-based research on mast cells and IBS suggests the involvement of both enteric glial cells and mast cells in the colon’s barrier function, with their altered communication during IBS contributing to colonic permeability.¹⁰

Mast cell mediators are also present in other gastrointestinal disorders such as functional dyspepsia (FD) and neurological manifestations such as migraine and headache.^2,8,11 A pediatric cross-sectional study assessed both headache prevalence in 235 patients with FD and the association between the reported headaches and mast cell amounts.¹¹ Results indicated that headache was reported by 73.8% of the patients with FD and that headache was associated with significant increases in duodenal mast cell densities and non-gastrointestinal symptoms such as fatigue, dizziness, and muscle, joint, and chest pain.¹¹

Researchers continue to explore the relationship between MCAS and a range of other conditions such as acute COVID-19 infection and chronic post-COVID-19 illness.^3,12,13 A 2021 online assessment-based study investigated the prevalence and severity of mast cell activation symptoms in those individuals experiencing long-COVID-19 illness (n=136).¹² For comparison, general population controls (n=136) and MCAS patients who never had COVID-19 symptoms (n=80) were recruited. Based upon symptom evaluation between groups and controls, results indicated that mast cell activation symptoms were increased in those experiencing long-COVID-19 illness and were reflective of symptoms and severity reported by patients with MCAS.¹² As research reveals additional overlaps between mast cell activation and chronic disease, infection, and illness, potential underlying causes and approaches for effective treatment will become clearer.

Clinical Applications

As reported in a variety of research studies, hypersensitive mast cell activation and the unregulated degranulation and subsequent release of mediators may span multiple body systems and be a cause of impaired health. Chronic diseases and lifestyle choices may influence mast cell dysregulation and overall immunity. Identifying the triggers and perpetuators of mast cell activation and establishing any potential antecedents is an important assessment approach to determine the mast cell impact on a patient’s medical condition and to develop a treatment path that supports both structural integrity and a healthy immune response.

As noted with MCAS, patients may have non-specific symptoms; therefore, a systems biology perspective may be most effective for addressing this complex condition. Evaluating what activates mast cells for an individual patient in different conditions is an important first step. Identifying and avoiding dietary triggers, then using an anti-inflammatory diet and foods (e.g., nettles, quercetin, turmeric, ginger, omega-3s, etc.) to help stabilize hyperreactive mast cells is a two-pronged nutritional approach to MCAS that may be an appropriate intervention. Additional MCAS therapies may include reducing psychological stress and engagement in stress transformation practices such as yoga, meditation, and exercise.¹⁴ For a more comprehensive food and nutrient list and to read in depth about the impact of histamine-reduced diets and the enzyme diamine oxidase, please read IFM’s article Fight Inflammation and Stabilize Mast Cells Naturally. Learn more about the functional medicine approach to immune health and clinical tools that help to enhance resilience at IFM’s upcoming Immune Advanced Practice Module (APM).

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References

1. Giannetti A, Filice E, Caffarelli C, Ricci G, Pession A. Mast cell activation disorders. Medicina (Kaunas). 2021;57(2):124. doi:10.3390/medicina57020124
2. Weinstock LB, Pace LA, Rezaie A, Afrin LB, Molderings GJ. Mast cell activation syndrome: a primer for the gastroenterologist. Dig Dis Sci. 2021;66(4):965-982. doi:10.1007/s10620-020-06264-9
3. Afrin LB, Weinstock LB, Molderings GJ. COVID-19 hyperinflammation and post-COVID-19 illness may be rooted in mast cell activation syndrome. Int J Infect Dis. 2020;100:327-332. doi:10.1016/j.ijid.2020.09.016
4. Matito A, Escribese MM, Longo N, et al. Clinical approach to mast cell activation syndromes: a practical overview. J Investig Allergol Clin Immunol. 2021;31(6). doi:10.18176/jiaci.0675
5. Valent P, Akin C, Nedoszytko B, et al. Diagnosis, classification and management of mast cell activation syndromes (MCAS) in the era of personalized medicine. Int J Mol Sci. 2020;21(23):9030. doi:10.3390/ijms21239030
6. Leru PM, Anton VF, Ureche C, Zurac S, Bratu O, Neagoe CD. Mast cell activation syndromes – evaluation of current diagnostic criteria and laboratory tools in clinical practice (review). Exp Ther Med. 2020;20(3):2348-2351. doi:10.3892/etm.2020.8947
7. Hendriksen E, van Bergeijk D, Oosting RS, Redegeld FA. Mast cells in neuroinflammation and brain disorders. Neurosci Biobehav Rev. 2017;79:119-133. doi:10.1016/j.neubiorev.2017.05.001
8. Conti P, D’Ovidio C, Conti C, et al. Progression in migraine: role of mast cells and pro-inflammatory and anti-inflammatory cytokines. Eur J Pharmacol. 2019;844:87-94. doi:10.1016/j.ejphar.2018.12.004
9. Kurin M, Elangovan A, Alikhan MM, et al. Irritable bowel syndrome is strongly associated with the primary and idiopathic mast cell disorders. Neurogastroenterol Motil. 2022;34(5):e14265. doi:10.1111/nmo.14265
10.  Meira de-Faria F, Casado-Bedmar M, Mårten Lindqvist C, Jones MP, Walter SA, Keita ÅV. Altered interaction between enteric glial cells and mast cells in the colon of women with irritable bowel syndrome. Neurogastroenterol Motil. 2021;33(11):e14130. doi:10.1111/nmo.14130
11.  Friesen C, Singh M, Singh V, Schurman JV. An observational study of headaches in children and adolescents with functional abdominal pain. Medicine (Baltimore). 2018;97(30):E11395. doi:10.1097/MD.0000000000011395
12.  Weinstock LB, Brook JB, Walters AS, Goris A, Afrin LB, Molderings GJ. Mast cell activation symptoms are prevalent in long-COVID. Int J Infect Dis. 2021;112:217-226. doi:10.1016/j.ijid.2021.09.043
13.  Wechsler JB, Butuci M, Wong A, Kamboj AP, Youngblood BA. Mast cell activation is associated with post-acute COVID-19 syndrome. Allergy. 2022;77(4):1288-1291. doi:10.1111/all.15188
14.  Hamilton MJ. Nonclonal mast cell activation syndrome: a growing body of evidence. Immunol Allergy Clin North Am. 2018;38(3):469-481. doi:10.1016/j.iac.2018.04.002