Mast cell activation syndrome (MCAS) is a term referring to one of two types of mast cell activation disorder (MCAD); the other type is idiopathic MCAD.[1] MCAS is an immunological condition in which mast cells, a type of white blood cell, inappropriately and excessively release chemical mediators, such as histamine, resulting in a range of chronic symptoms, sometimes including anaphylaxis or near-anaphylaxis attacks.[2][3][4] Primary symptoms include cardiovascular, dermatological, gastrointestinal, neurological, and respiratory problems.[3][5]
Based on the 2022 criteria, the following three diagnostic criteria needs to be met in order to be diagnosed with Mast Cell Activation Syndrome (MCAS)[6],
Symptoms: You have severe, recurring symptoms involving at least two organ systems (e.g., skin, stomach, lungs, or heart). These symptoms must be linked to mast cell chemicals such histamine being released such as itching, throat tightening, and wheezing. Other symptoms can be found below.
Lab tests: During a flare-up of symptoms, your body shows an increase in mast cell chemicals beyond normal levels. These chemicals can include tryptase, histamine, etc.
Treatment response: Your symptoms improve significantly when you take medications that either block the effects of mast cell chemicals such as antihistamines or they must suppress mast cell activation directly such as anti-IgE treatments.
Signs and symptoms
Because degranulation events can be triggered in various locations within the body, MCAS can present with a wide range of symptoms in multiple body systems. These symptoms may range from digestive discomfort to chronic pain, mental issues, or full-scale anaphylactic reactions. Symptoms typically wax and wane over time, varying in severity and duration. Many signs and symptoms are the same as those for mastocytosis, because both conditions result in too many mediators released by mast cells.[5][7]
There are many causes of mast cell activation, including allergy. Genetics may play a role. In particular, mutations of the KIT gene (which codes for the KIT protein that regulates cell growth), specifically around codon 816 with the common one being asp816val, have been suspected to be associated with MCAS and is also associated to most systemic mastocytosis patients.[5][9][10] It has been found that people with MCAS tend to have a wider range of KIT mutations around all domains of the protein and multiple at the same time rather than a single one, which could be a potential cause of the heterogeneity of the presenting symptoms of MCAS. Symptoms of MCAS are caused by excessive chemical mediators released by mast cells.[11] Mediators include leukotrienes, histamines, prostaglandin, and tryptase.[12]
Pathophysiology
Mast cell activation syndrome can be categorized into three subclasses depending on the trigger which "activates" the degranulation of cells. In Primary MCAS, researchers theorize that the threshold for chemical mediator release, also called degranulation, is lower, meaning it takes less outside stimulation to cause a reaction.[13] Other research has demonstrated that some patients, specifically those with Monoclonal Mast Cell Activation Disorder and those with Mastocytosis have something of an 'overpopulation' of mast cells in the bone marrow, which leads to stronger response when triggered.[14]Secondary MCAS is far more common, and involve an unclear etiology, though not directly related to monoclonal cells. In these cases, reactions occur as a result of IgE-mediated (an environmental allergen, such as food or medication and non-IgE-mediated (such as exercise) mechanisms.[15]Idiopathic MCAS occurs in patients who have an unremarkable workup, including a benign bone marrow biopsy, which suggests that there are no allergic causes or clonal mast cell diseases[15]
Mast cell activation can be localized or systemic, but a diagnosis of MCAS requires systemic symptoms.[16][17] Some examples of tissue specific consequences of mast cell activation include urticaria, allergic rhinitis, and wheezing. Systemic mast cell activation presents with symptoms involving two or more organ systems (skin: urticaria, angioedema, and flushing; gastrointestinal: nausea, vomiting, diarrhea, and abdominal cramping; cardiovascular: hypotensive syncope or near syncope and tachycardia; respiratory: wheezing; naso-ocular: conjunctival injection, pruritus, and nasal stuffiness). This can result from the release of mediators from a specific site, such as the skin or mucosal tissue, or activation of mast cells around the vasculature.[18]
Diagnosis
MCAS is often difficult to identify due to the heterogeneity of symptoms and the "lack of flagrant acute presentation".[8] Many of the numerous symptoms are non-specific in nature. Diagnostic criteria were proposed in 2010[3] and revised in 2019.[17] Mast cell activation was assigned an ICD-10 code (D89.40, along with subtype codes D89.41-43 and D89.49) in October 2016.[19]
According to the American Academy of Allergy, Asthma, and Immunology (AAAI), the most precise method of diagnosing MCAS is through a bone marrow biopsy and aspirate.[17] This method is commonly used to diagnose systemic mastocytosis, and the presence of SM increases the possibility of subsequently having MCAS. In addition, other common laboratory tests including KIT-D816X mutational analysis and flow cytometry analysis seeking co-expression of CD117 and CD25 are also commended for diagnosing clonal MCAS.[20]
Although different diagnostic criteria are published, a commonly used strategy to diagnose patients is to use all three of the following:[citation needed]
Symptoms consistent with chronic/recurrent mast cell release: Recurrent abdominal pain, diarrhea, flushing, itching, nasal congestion, coughing, chest tightness, wheezing, lightheadedness (usually a combination of some of these symptoms is present)
Laboratory evidence of mast cell mediator (elevated serum tryptase, N-methyl histamine, prostaglandin D2 or 11-beta- prostaglandin F2 alpha, leukotriene E4 and others)
Improvement in symptoms with the use of medications that block or treat elevations in these mediators
The condition was hypothesized by the pharmacologists Oates and Roberts of Vanderbilt University in 1991, and named in 2007, following a build-up of evidence featured in papers by Sonneck et al.[24] and Akin et al.[25][7]
^Akin C (May 2015). "Mast cell activation syndromes presenting as anaphylaxis". Immunology and Allergy Clinics of North America. 35 (2): 277–85. doi:10.1016/j.iac.2015.01.010. PMID25841551.
^ abcConway AE, Verdi M, Shaker MS, Bernstein JA, Beamish CC, Morse R, Madan J, Lee MW, Sussman G, Al-Nimr A, Hand M, Albert DA (March 2024). "Beyond Confirmed Mast Cell Activation Syndrome: Approaching Patients With Dysautonomia and Related Conditions". J Allergy Clin Immunol Pract. 12 (7): 1738–1750. doi:10.1016/j.jaip.2024.03.019. PMID38499084.
^Afrin L (2013). "Prevention, diagnosis, and management of mast cell activation syndrome.". In Murray D (ed.). Mast cells: Phenotypic features, biological functions and role in immunity. Nova Sciences Publishers. pp. 155–231. ISBN978-1-62618-166-3.
^Akin C (August 2017). "Mast cell activation syndromes". The Journal of Allergy and Clinical Immunology. 140 (2): 349–355. doi:10.1016/j.jaci.2017.06.007. PMID28780942.
^ abcdefCastells M, Butterfield J (April 2019). "Mast Cell Activation Syndrome and Mastocytosis: Initial Treatment Options and Long-Term Management". The Journal of Allergy and Clinical Immunology: In Practice. 7 (4): 1097–1106. doi:10.1016/j.jaip.2019.02.002. PMID30961835.
^Finn DF, Walsh JJ (September 2013). "Twenty-first century mast cell stabilizers". British Journal of Pharmacology. 170 (1): 23–37. doi:10.1111/bph.12138. PMC3764846. PMID23441583. A diverse range of mast cell stabilizing compounds have been identified in the last decade from; natural, biological and synthetic sources to drugs already in clinical uses for other indications. Although in many cases, the precise mode of action of these molecules is unclear, all of these substances have demonstrated mast cell stabilization activity and therefore may have potential therapeutic use in the treatment of allergic and related diseases where mast cells are intrinsically involved.Table 1: Naturally occurring mast cell stabilizersArchived 2020-11-02 at the Wayback Machine
^Sonneck K, Florian S, Müllauer L, Wimazal F, Födinger M, Sperr WR, Valent P (2007). "Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: Monoclonal mast cell activation syndrome". International Archives of Allergy and Immunology. 142 (2): 158–64. doi:10.1159/000096442. PMID17057414. S2CID25058981.[non-primary source needed]
