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Mast cell activation syndrome

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Not to be confused with Mastocytosis or Maneuvering Characteristics Augmentation System.
Mast cell activation syndrome
SpecialtyImmunology (Allergy)

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],

  1. 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.
  2. 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.
  3. 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

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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]

Common symptoms include:[8]

  • Dermatologic
    • flushing
    • hives
    • easy bruising
    • either a reddish or a pale complexion
    • itchiness
    • burning feeling
    • dermatographism
  • Cardiovascular
  • Gastrointestinal
    • diarrhea and/or constipation, cramping, intestinal discomfort
    • nausea, vomiting, acid reflux
    • swallowing difficulty, throat tightness
  • Neuropsychiatric
    • brain fog
    • headache
    • fatigue/lethargy
    • lack of concentration
    • mild cognitive problems
    • sleep disturbances
  • Respiratory
    • congestion, coughing, wheezing
  • Systemic

Causes

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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

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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

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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]

  1. 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)
  2. Laboratory evidence of mast cell mediator (elevated serum tryptase, N-methyl histamine, prostaglandin D2 or 11-beta- prostaglandin F2 alpha, leukotriene E4 and others)
  3. Improvement in symptoms with the use of medications that block or treat elevations in these mediators

The World Health Organization has not published diagnostic criteria.

Treatment

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Pharmacological treatments include:

Prognosis

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The prognosis of MCAS is uncertain.[17]

History

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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]

See also

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References

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  1. ^ Valent P, Hartmann K, Bonadonna P, Gülen T, Brockow K, Alvarez-Twose I, Hermine O, Niedoszytko M, Carter MC, Hoermann G, Butterfield JH, Lyons JJ, Sperr WR, Greiner G, Sotlar K (2022-05-24). "Global Classification of Mast Cell Activation Disorders: An ICD-10-CM-Adjusted Proposal of the ECNM-AIM Consortium". The Journal of Allergy and Clinical Immunology. In Practice. 10 (8): 1941–1950. doi:10.1016/j.jaip.2022.05.007. hdl:10261/296655. ISSN 2213-2201. PMID 35623575. S2CID 249073293. Archived from the original on 2023-02-11. Retrieved 2023-02-10.
  2. ^ Valent P (April 2013). "Mast cell activation syndromes: definition and classification". Allergy. 68 (4): 417–24. doi:10.1111/all.12126. PMID 23409940. S2CID 43636053.
  3. ^ a b c Akin C, Valent P, Metcalfe DD (December 2010). "Mast cell activation syndrome: Proposed diagnostic criteria". The Journal of Allergy and Clinical Immunology. 126 (6): 1099–104.e4. doi:10.1016/j.jaci.2010.08.035. PMC 3753019. PMID 21035176.
  4. ^ 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. PMID 25841551.
  5. ^ a b c Conway 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. PMID 38499084.
  6. ^ Castells M, Giannetti MP, Hamilton MJ, Novak P, Pozdnyakova O, Nicoloro-SantaBarbara J, Jennings SV, Francomano C, Kim B, Glover SC, Galli SJ, Maitland A, White A, Abonia JP, Slee V (August 2024). "Mast cell activation syndrome: Current understanding and research needs". Journal of Allergy and Clinical Immunology. 154 (2): 255–263. doi:10.1016/j.jaci.2024.05.025. ISSN 0091-6749.
  7. ^ a b c [better source needed] Afrin LB, Molderings GJ (February 2014). "A concise, practical guide to diagnostic assessment for mast cell activation disease". World Journal of Hematology. 3 (1): 1–7. doi:10.5315/wjh.v3.i1.
  8. ^ a b [better source needed] Afrin L (2013). "Presentation, Diagnosis, and Management of Mast Cell Activation Syndrome.". Mast Cells: Phenotypic Features, Biological Functions and Role in Immunity. Nova Science. pp. 155–232. Archived from the original on 2018-08-18. Retrieved 2015-10-13.
  9. ^ 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. ISBN 978-1-62618-166-3.
  10. ^ Molderings GJ, Kolck UW, Scheurlen C, Brüss M, Homann J, Von Kügelgen I (January 2007). "Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder". Scandinavian Journal of Gastroenterology. 42 (9): 1045–1053. doi:10.1080/00365520701245744. ISSN 0036-5521. PMID 17710669. Archived from the original on 2023-03-27. Retrieved 2023-11-18.
  11. ^ Molderings GJ, Meis K, Kolck UW, Homann J, Frieling T (2010-12-01). "Comparative analysis of mutation of tyrosine kinase kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects". Immunogenetics. 62 (11): 721–727. doi:10.1007/s00251-010-0474-8. ISSN 1432-1211. PMID 20838788.
  12. ^ 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. ISSN 1097-6825. PMID 28780942. Archived from the original on 2023-01-30. Retrieved 2023-02-10.
  13. ^ Gülen T, Akin C, Bonadonna P, Siebenhaar F, Broesby-Olsen S, Brockow K, Niedoszytko M, Nedoszytko B, Oude Elberink HN, Butterfield JH, Sperr WR, Alvarez-Twose I, Horny HP, Sotlar K, Schwaab J (November 2021). "Selecting the Right Criteria and Proper Classification to Diagnose Mast Cell Activation Syndromes: A Critical Review". The Journal of Allergy and Clinical Immunology. In Practice. 9 (11): 3918–3928. doi:10.1016/j.jaip.2021.06.011. hdl:10261/268013. ISSN 2213-2201. PMID 34166845.
  14. ^ Weiler, Austen, Akin, Barkoff, Bernstein, Bonadonna, Butterfield, Carter, Fox, Maitland, Pongdee, Mustafa, Ravi, Tobin, Vliagoftis, Schwartz (October 2019). "AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management". The Journal of Allergy and Clinical Immunology. 144 (4): 883–896. doi:10.1016/j.jaci.2019.08.023. PMID 31476322 – via JACI.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ a b Gulen T (January 2024). "Using the Right Criteria for MCAS". Current Allergy and Asthma Reports. 24 (2): 39–51. doi:10.1007/s11882-024-01126-0. PMC 10866766. PMID 38243020 – via PubMed.
  16. ^ Hartmann K, Escribano L, Grattan C, Brockow K, Carter MC, Alvarez-Twose I, Matito A, Broesby-Olsen S, Siebenhaar F, Lange M, Niedoszytko M, Castells M, Oude Elberink JN, Bonadonna P, Zanotti R (January 2016). "Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology". The Journal of Allergy and Clinical Immunology. 137 (1): 35–45. doi:10.1016/j.jaci.2015.08.034. ISSN 1097-6825. PMID 26476479.
  17. ^ a b c d Weiler CR, Austen KF, Akin C, et al. (October 2019). "AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management". The Journal of Allergy and Clinical Immunology. 144 (4): 883–896. doi:10.1016/j.jaci.2019.08.023. PMID 31476322.
  18. ^ 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. PMID 28780942.
  19. ^ "Mast Cell Disease ICD-10 Codes". TMS - The Mast Cell Disease Society, Inc. Archived from the original on 2024-03-21. Retrieved 2024-03-21.
  20. ^ Afrin LB, Ackerley MB, Bluestein LS, Brewer JH, Brook JB, Buchanan AD, Cuni JR, Davey WP, Dempsey TT, Dorff SR, Dubravec MS, Guggenheim AG, Hindman KJ, Hoffman B, Kaufman DL (2021-05-01). "Diagnosis of mast cell activation syndrome: a global "consensus-2"". Diagnosis. 8 (2): 137–152. doi:10.1515/dx-2020-0005. ISSN 2194-802X. PMID 32324159.
  21. ^ a b c d e Frieri M (June 2018). "Mast Cell Activation Syndrome". Clinical Reviews in Allergy & Immunology. 54 (3): 353–365. doi:10.1007/s12016-015-8487-6. PMID 25944644. S2CID 5723622.
  22. ^ a b c d e f Castells 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. PMID 30961835.
  23. ^ 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. PMC 3764846. PMID 23441583. 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 stabilizers Archived 2020-11-02 at the Wayback Machine
  24. ^ 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. PMID 17057414. S2CID 25058981.[non-primary source needed]
  25. ^ Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E, Noel P, Metcalfe DD (October 2007). "Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with 'idiopathic' anaphylaxis". Blood. 110 (7): 2331–3. doi:10.1182/blood-2006-06-028100. PMC 1988935. PMID 17638853.[non-primary source needed]
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