Mast Cell Activation Syndrome (MCAS) is a complex and multifaceted condition that challenges both patients and healthcare professionals with its vast array of comorbidities. This enigmatic disorder, characterized by the excessive release of mast cell mediators, manifests in a myriad of symptoms that can affect nearly every system in the body. The interplay between MCAS and its numerous comorbid conditions not only complicates diagnosis and treatment but also significantly impacts the quality of life of those affected. This article aims to explore the intricate web of comorbidities associated with MCAS, shedding light on the challenges and considerations in managing such a multifarious condition. From gastrointestinal disorders to cardiovascular issues, and from neurologic symptoms to skin manifestations, understanding the diverse comorbidities of MCAS is crucial for developing comprehensive and personalized care plans for patients navigating this perplexing syndrome.

Common MCAS Comorbidities: 

Neurological and Mental Health Conditions

• Attention Deficit Hyperactivity Disorder (ADHD): ADHD and other types of neurodiversity seem to be linked to MCAS as well as EDS. This link may be related to the role of histamine in brain function, affecting attention and activity levels.
• Alzheimer’s Disease: Emerging research suggests a link between inflammation, including mast cell activation, and the pathogenesis of Alzheimer’s Disease.
• Autism Spectrum Disorder (ASD): ASD and MCAS share common features, such as immune dysregulation and gastrointestinal symptoms, suggesting a potential connection.
• Anxiety/Depression: Mast cells can influence neuroinflammatory processes, potentially contributing to the development or exacerbation of anxiety and depression.
• Post Traumatic Stress Disorder (PTSD): PTSD and MCAS may be related through the stress response, which can trigger mast cell activation.

Dermatological

• Alopecia: Autoimmunity and inflammation, including mast cell activation, are implicated in some forms of hair loss.
• Eczema (Atopic dermatitis): a condition that causes dry, itchy and inflamed skin

Musculoskeletal Conditions and Chronic Pain

• Ehlers-Danlos Syndrome (EDS): The co-occurrence of MCAS and EDS points to a complex interplay between connective tissue and immune system dysregulation.
• Fibromyalgia: This condition, characterized by widespread pain, may have links to MCAS through shared pathways of chronic inflammation and pain.
• Multiple Sclerosis: The link between MS and MCAS has not yet been widely researched, but it appears there is a link between MS and Ehlers-Danlos Syndrome.
• Arthritis (osteoarthritis and rheumatoid arthritis): Inflammatory processes play a central role in both forms of arthritis, with mast cells contributing to the inflammatory milieu.

Respiratory and Cardiovascular Conditions

• Asthma: Mast cells are key players in the inflammatory response in asthma, making MCAS a relevant factor in asthma exacerbation.
• Cardiovascular Symptoms: Mast cell mediators can affect cardiovascular health, contributing to symptoms such as palpitations and hypertension.
• Pulmonary Fibrosis: Inflammation and fibrosis in the lungs may be exacerbated by mast cell activation.

Gastrointestinal and Genitourinary Conditions

• Irritable Bowel Syndrome (IBS): The link between IBS and MCAS highlights the role of mast cells in gastrointestinal symptoms and dysmotility.
• Interstitial Cystitis: Often co-occurring with MCAS, this painful bladder syndrome may involve mast cell-mediated inflammation.
• Endometriosis: Mast cell activation is implicated in the inflammatory processes associated with endometriosis, suggesting a connection between these conditions.

Endocrine and Metabolic Conditions

• Diabetes (Type 1 and Type 2): The inflammatory response, including mast cell activation, plays a role in insulin resistance and autoimmune attacks on pancreatic cells.
• Obesity: Inflammation, including that mediated by mast cells, is a recognized component of obesity and its metabolic consequences.

Other Significant Co-occurring Conditions

• Postural Orthostatic Tachycardia Syndrome (POTS): MCAS and POTS share a likely the role of mast cells and the immune system more broadly in the function of the autonomic nervous system including cardiovascular regulation. There is also evidence suggesting the link is driven by the excessive stretchiness of blood vessels seen in hypermobile EDS.
• COVID-19 Hyperinflammation & Post-Covid-19 Illness: The hyperinflammatory state induced by COVID-19 can trigger or exacerbate MCAS, contributing to long-term symptoms.

Additional Co-occurring Conditions

• Food Protein-Induced Enterocolitis Syndrome (FPIES): FPIES is a severe gastrointestinal reaction to specific foods, potentially linked to MCAS through shared inflammatory pathways.
• Eosinophilic Colitis: A condition characterized by the accumulation of eosinophils in the colon, suggesting an immune-mediated mechanism that may overlap with MCAS.
• Eosinophilic Esophagitis: Similar to eosinophilic colitis but affecting the esophagus, indicating a potential connection to MCAS through eosinophil and mast cell interaction.
• Lyme Disease: Chronic symptoms of Lyme disease may intersect with MCAS, potentially due to immune dysregulation and inflammation.
• Urticaria (Hives): Chronic urticaria has been associated with MCAS, as mast cells play a central role in the development of hives.
• Angioedema: Often occurring alongside urticaria, angioedema involves deeper swelling, possibly related to mast cell activation.
• Gastroparesis: Delayed gastric emptying can be a manifestation of MCAS and EDS, given the role of mast cells and connective tissue in gastrointestinal motility.
• Dysautonomia: Including Postural Orthostatic Tachycardia Syndrome, dysautonomia may be linked to MCAS through autonomic and immune system interactions.
• ME/CFS: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome shares several symptoms with MCAS, suggesting an underlying connection possibly related to immune dysfunction and inflammation.

Sources:

1. Afrin, L. B., & Molderings, G. J. (2016). A concise, practical guide to diagnostic assessment for mast cell activation disease. World Journal of Hematology, 5(1), 1-17. Link
2. Afrin, L. B., Self, S., Menk, J., & Lazarchick, J. (2018). Characterization of mast cell activation syndrome. American Journal of the Medical Sciences, 355(3), 299-304. Link
3. Afrin, L. B., Weinstock, L. B., & Molderings, G. J. (2020). Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome. International Journal of Infectious Diseases, 100, 327-332. Link
4. Cardet, J. C., Castells, M. C., & Hamilton, M. J. (2013). Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Current Allergy and Asthma Reports, 13(1), 10-18. Link
5. Hamilton, M. J., Hornick, J. L., Akin, C., Castells, M. C., & Greenberger, N. J. (2011). Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. Journal of Allergy and Clinical Immunology, 128(1), 147-152.e2. Link
6. Molderings, G. J. (2015). The genetic basis of mast cell activation disease—Looking through a glass darkly. Critical Reviews in Oncology/Hematology, 93(1), 75-89. Link
7. Molderings, G. J., Brettner, S., Homann, J., & Afrin, L. B. (2017). Mast cell activation disease: A concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology, 10(1), 45. Link
8. Theoharides, T. C., Stewart, J. M., Hatziagelaki, E., & Kolaitis, G. (2015). Brain "fog," inflammation and obesity: Key aspects of neuropsychiatric disorders improved by luteolin. Frontiers in Neuroscience, 9, 225. Link
9. Nickel, J. C., et al. (2015). Interstitial cystitis/bladder pain syndrome: A urologic mystery. Translational Andrology and Urology, 4(6), 668-676. Link
10. Caplin, M. E., et al. (2016). Carcinoid syndrome and serotonin: Therapeutic effects of inhibiting its synthesis with telotristat ethyl. Therapeutic Advances in Gastroenterology, 9(6), 889-902. Link
11. Hornig, M., Montoya, J. G., Klimas, N. G., & Peterson, D. (2015). Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Science Advances, 1(1), e1400121. Link
12. Anaf, V., et al. (2020). Targeting mast cells: A viable therapeutic option in endometriosis? EMJ Reviews. Link
13. Afrin, L. B., & Pöhlau, D. (2018). Is it really fibromyalgia? Recognizing mast cell activation syndrome. ResearchGate. Link
14. Weinstock, L. B., Brook, J. B., Myers, T. L., Goodman, B., & Afrin, L. B. (2020). Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulins, and antibiotic treatment. Medical Sciences, 8(1), 8. Link
15. Theoharides, T. C., Donelan, J., Kandere-Grzybowska, K., & Konstantinidou, A. (2005). The role of mast cells in migraine pathophysiology. Brain Research Reviews, 49(1), 65-76. Link
16. Afrin, L. B., & Pöhlau, D. (2021). Should mast cells be considered therapeutic targets in multiple sclerosis? MCAS Ireland. Link
17. Xanthos, D. N., Gaderer, S., Drdla, R., Nuro, E., Abramova, A., Ellmeier, W., & Sandkühler, J. (2018). Central nervous system mast cells in peripheral inflammation. Molecular Pain, 14, 174480691876364. Link
18. Liu, S., Gan, L., Chen, Y., & Ma, D. (2012). The amygdala is a critical neural substrate for Chinese abdominal acupuncture to treat experimental obesity. Evidence-Based Complementary and Alternative Medicine, 2012, 628434. Link
19. Karsenty, G., & Oury, F. (2006). Regulation of male fertility by the bone-derived hormone osteocalcin. Molecular and Cellular Endocrinology, 310(1-2), 31-36. Link
20. Hirsch, E. C., & Hunot, S. (2019). Neuroinflammation in Parkinson's disease: A target for neuroprotection? The Lancet Neurology, 18(4), 382-397. Link
21. Afrin, L. B., Self, S., Menk, J., & Lazarchick, J. (2018). Characterization of mast cell activation syndrome. American Journal of the Medical Sciences, 355(3), 299-304. Link
22. Spagnolo, P., Sverzellati, N., Rossi, G., Cavazza, A., Tzouvelekis, A., Crestani, B., & Vancheri, C. (2013). Idiopathic pulmonary fibrosis: An update. Annals of Medicine, 45(2), 15-27. Link
23. Earley, C. J., Uhl, G. R., Clemens, S., & Ferré, S. (2020). Restless legs syndrome: From pathophysiology to clinical diagnosis and management. Frontiers in Neuroscience, 14, 208. Link
24. Molderings, G. J. (2017). The genetic basis and pathophysiology of mast cell activation disease. Pharmacology & Therapeutics, 174, 116-133. Link
25. Afrin, L. B., & Holinstat, M. (2020). Tinnitus in mast cell activation syndrome: A prospective survey of 114 patients. SciTech Central. Link
26. Nickel, J. C., et al. (2015). Interstitial cystitis/bladder pain syndrome: A urologic mystery. Translational Andrology and Urology, 4(6), 668-676. Link

‍