Mast cell activation syndrome explained

Mast cell activation syndrome should not be confused with Mastocytosis.

Mast cell activation syndrome
Field:Immunology (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 inappropriately and excessively release chemical mediators, 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.[5]

MCAS is an umbrella term that describes a set of symptoms; it is not a specific diagnosis.[1] [6] Multiple diagnostic schemes for MCAS have been proposed. MCAS has been increasingly over-diagnosed or misdiagnosed.[7] [8]

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] [9]

Common symptoms include:

Causes

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 and specifically), 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] [10] [11] It has been found that MCAS patients 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.[12] Mediators include leukotrienes, histamines, prostaglandin, and tryptase.[13]

Pathophysiology

Mast cell activation can be localized or systemic, but a diagnosis of MCAS requires systemic symptoms.[14] 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.[15]

Diagnosis

MCAS is often difficult to identify due to the heterogeneity of symptoms and the "lack of flagrant acute presentation".[16] Many of the numerous symptoms are non-specific in nature. Diagnostic criteria were proposed in 2010 and revised in 2019. Mast cell activation was assigned an ICD-10 code (D89.40, along with subtype codes D89.41-43 and D89.49) in October 2016.[17]

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. 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.[18]

Although different diagnostic criteria are published, a commonly used strategy to diagnose patients is to use all three of the following:

  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

Pharmacological treatments include:

Prognosis

The prognosis of MCAS is uncertain.[22]

History

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.[23] and Akin et al.[24]

See also

Notes and References

  1. Valent . Peter . Hartmann . Karin . Bonadonna . Patrizia . Gülen . Theo . Brockow . Knut . Alvarez-Twose . Ivan . Hermine . Olivier . Niedoszytko . Marek . Carter . Melody C. . Hoermann . Gregor . Butterfield . Joseph H. . Lyons . Jonathan J. . Sperr . Wolfgang R. . Greiner . Georg . Sotlar . Karl . 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 . 2022-05-24 . 10 . 8 . 1941–1950 . 10.1016/j.jaip.2022.05.007 . 2213-2201 . 35623575 . 10261/296655 . 249073293 . free . 2023-02-10 . 2023-02-11 . https://web.archive.org/web/20230211021934/https://pubmed.ncbi.nlm.nih.gov/35623575/ . live .
  2. Valent P . Mast cell activation syndromes: definition and classification . Allergy . 68 . 4 . 417–24 . April 2013 . 23409940 . 10.1111/all.12126 . 43636053 . free .
  3. Akin C, Valent P, Metcalfe DD . Mast cell activation syndrome: Proposed diagnostic criteria . The Journal of Allergy and Clinical Immunology . 126 . 6 . 1099–104.e4 . December 2010 . 21035176 . 3753019 . 10.1016/j.jaci.2010.08.035 .
  4. Akin C . Mast cell activation syndromes presenting as anaphylaxis . Immunology and Allergy Clinics of North America . 35 . 2 . 277–85 . May 2015 . 25841551 . 10.1016/j.iac.2015.01.010 .
  5. 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 . Beyond Confirmed Mast Cell Activation Syndrome: Approaching Patients With Dysautonomia and Related Conditions . J Allergy Clin Immunol Pract . 12. 7. 1738–1750. March 2024 . 38499084 . 10.1016/j.jaip.2024.03.019.
  6. Gülen . Theo . Akin . Cem . Bonadonna . Patrizia . Siebenhaar . Frank . Broesby-Olsen . Sigurd . Brockow . Knut . Niedoszytko . Marek . Nedoszytko . Boguslaw . Oude Elberink . Hanneke N. G. . Butterfield . Joseph H. . Sperr . Wolfgang R. . Alvarez-Twose . Ivan . Horny . Hans-Peter . Sotlar . Karl . Schwaab . Juliana . 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 . November 2021 . 9 . 11 . 3918–3928 . 10.1016/j.jaip.2021.06.011 . 2213-2201 . 34166845 . 10261/268013 . 235634993 . free . 2023-02-10 . 2023-02-10 . https://web.archive.org/web/20230210150818/https://pubmed.ncbi.nlm.nih.gov/34166845/ . live .
  7. Gülen T, Akin C, Bonadonna P, et al . Selecting the Right Criteria and Proper Classification to Diagnose Mast Cell Activation Syndromes: A Critical Review . J Allergy Clin Immunol Pract . 9 . 11 . 3918–3928 . November 2021 . 34166845 . 10.1016/j.jaip.2021.06.011 . 10261/268013 . 235634993 . free .
  8. Weiler CR . Mast Cell Activation Syndrome: Tools for Diagnosis and Differential Diagnosis . J Allergy Clin Immunol Pract . 8 . 2 . 498–506 . February 2020 . 31470118 . 10.1016/j.jaip.2019.08.022 . 203814795 .
  9. Afrin LB, Molderings GJ . A concise, practical guide to diagnostic assessment for mast cell activation disease. . World Journal of Hematology . February 2014 . 3 . 1 . 1–7 . 10.5315/wjh.v3.i1 . free .
  10. Book: Afrin, Lawrence . Mast cells: Phenotypic features, biological functions and role in immunity. . Nova Sciences Publishers . 2013 . 978-1-62618-166-3 . Murray . David . 155–231 . Prevention, diagnosis, and management of mast cell activation syndrome..
  11. Molderings . Gerhard J. . Kolck . Ulrich W. . Scheurlen . Christian . Brüss . Michael . Homann . Jürgen . Von Kügelgen . Ivar . January 2007 . Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder . Scandinavian Journal of Gastroenterology . en . 42 . 9 . 1045–1053 . 10.1080/00365520701245744 . 17710669 . 0036-5521 . 2023-11-18 . 2023-03-27 . https://web.archive.org/web/20230327215541/https://www.tandfonline.com/doi/full/10.1080/00365520701245744 . live . subscription .
  12. Molderings . Gerhard J. . Meis . Kirsten . Kolck . Ulrich W. . Homann . Jürgen . Frieling . Thomas . 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 . en . 62 . 11 . 721–727 . 10.1007/s00251-010-0474-8 . 20838788 . 1432-1211. subscription .
  13. Akin . Cem . August 2017 . Mast cell activation syndromes . The Journal of Allergy and Clinical Immunology . August 2017 . 140 . 2 . 349–355 . 10.1016/j.jaci.2017.06.007 . 1097-6825 . 28780942 . 2023-02-10 . 2023-01-30 . https://web.archive.org/web/20230130002406/https://pubmed.ncbi.nlm.nih.gov/28780942/ . live .
  14. Hartmann . Karin . Escribano . Luis . Grattan . Clive . Brockow . Knut . Carter . Melody C. . Alvarez-Twose . Ivan . Matito . Almudena . Broesby-Olsen . Sigurd . Siebenhaar . Frank . Lange . Magdalena . Niedoszytko . Marek . Castells . Mariana . Oude Elberink . Joanna N. G. . Bonadonna . Patrizia . Zanotti . Roberta . 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 . January 2016 . 137 . 1 . 35–45 . 10.1016/j.jaci.2015.08.034 . 1097-6825 . 26476479. free .
  15. Akin C . Mast cell activation syndromes . The Journal of Allergy and Clinical Immunology . 140 . 2 . 349–355 . August 2017 . 28780942 . 10.1016/j.jaci.2017.06.007 .
  16. Book: Mast Cells: Phenotypic Features, Biological Functions and Role in Immunity. . Afrin L . Presentation, Diagnosis, and Management of Mast Cell Activation Syndrome. . Nova Science . 2013 . 155–232 . 2015-10-13 . https://web.archive.org/web/20180818065608/https://www.novapublishers.com/catalog/product_info.php?products_id=42603 . 2018-08-18 . dead .
  17. Web site: Mast Cell Disease ICD-10 Codes . 2024-03-21 . TMS - The Mast Cell Disease Society, Inc . en-US . 2024-03-21 . https://web.archive.org/web/20240321105531/https://tmsforacure.org/icd-10-codes/ . live .
  18. Afrin . Lawrence B. . Ackerley . Mary B. . Bluestein . Linda S. . Brewer . Joseph H. . Brook . Jill B. . Buchanan . Ariana D. . Cuni . Jill R. . Davey . William P. . Dempsey . Tania T. . Dorff . Shanda R. . Dubravec . Martin S. . Guggenheim . Alena G. . Hindman . Kimberly J. . Hoffman . Bruce . Kaufman . David L. . 2021-05-01 . Diagnosis of mast cell activation syndrome: a global "consensus-2" . Diagnosis . en . 8 . 2 . 137–152 . 10.1515/dx-2020-0005 . 2194-802X. free . 32324159 .
  19. Frieri M . Mast Cell Activation Syndrome . Clinical Reviews in Allergy & Immunology . 54 . 3 . 353–365 . June 2018 . 25944644 . 10.1007/s12016-015-8487-6 . 5723622 .
  20. Castells M, Butterfield J . 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 . April 2019 . 30961835 . 10.1016/j.jaip.2019.02.002.
  21. Finn DF, Walsh JJ . Twenty-first century mast cell stabilizers . British Journal of Pharmacology . 170 . 1 . 23–37 . September 2013 . 23441583 . 3764846 . 10.1111/bph.12138 . 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
  22. Weiler CR, Austen KF, Akin C, et al . 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 . October 2019 . 31476322 . 10.1016/j.jaci.2019.08.023 . free .
  23. Sonneck K, Florian S, Müllauer L, Wimazal F, Födinger M, Sperr WR, Valent P . 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 . 2007 . 17057414 . 10.1159/000096442 . 25058981 .
  24. Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E, Noel P, Metcalfe DD . Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with 'idiopathic' anaphylaxis . Blood . 110 . 7 . 2331–3 . October 2007 . 17638853 . 1988935 . 10.1182/blood-2006-06-028100 .

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