Mast cell activation syndrome (MCAS), also called mast cell activation disorder (MCAD), is an immunologic condition in which mast cells are aberrantly activated, resulting in inappropriate mediator release.
- MCAS can be responsible for chronic symptoms in multiple organs that cannot be attributed to another cause[vi].
- Patients frequently receive diagnosis for a number of idiopathic conditions prior to correct diagnosis with MCAS[vi].
- Mast cell activation syndrome is overwhelmingly a secondary condition. MCAS can be secondary to a number of conditions, including autoimmune diseases, connective tissue diseases, and atopic conditions[i].
- The term “primary MCAS” refers to mediator release symptoms associated with mastocytosis[xvii] . However, the term “mastocytosis” generally conveys the understanding that both proliferation and mediator release symptoms are possible.
- In idiopathic MCAS, no cause for symptoms can be identified[xvii] .
- The presence of multiple mast cell patients in one family is not uncommon. A heritable gene has not yet been identified. Epigenetic mechanisms are suspected for transmission of mast cell disease to another generation[iv].
- Approximately 75% of mast cell patients have at least one first degree relative with mast cell disease and not always the same subtype[ii]. For example, a mother may have MCAS, while one of her children has SM and the other has CM.
- MCAS is a recently described diagnosis. In the absence of large studies, several groups have developed their own, sometimes conflicting, diagnostic criteria.
- Differential diagnoses with potential to cause similar symptoms should be considered and excluded[iii].
- The criteria most frequently used include those by a 2010 paper by Akin, Valent and Metcalfe[iii]; a 2011 paper by Molderings, Afrin and colleagues[iv]; and a 2013 paper by Castells and colleagues[v].
- The criteria described in the 2011 paper by Molderings, Afrin and colleagues have been updated to include response to medication[vi].
- Of note, a 2012 consensus proposal[x] was authored by a number of mast cell experts including Valent, Escribano, Castells, Akin and Metcalfe. It sees little practical use and is not generally accepted in the community.
- The major sets of criteria listed above all include the following features:
- Recurrent or chronic symptoms of mast cell activation
- Objective evidence of excessive mast cell mediator release
- Positive response to medications that inhibit action of mast cell mediators
- Valent warns that in some cases, patients may not fulfill all criteria but still warrant treatment: “In many cases, only two or even one of these three criteria can be documented. In the case of typical symptoms, the provisional diagnosis of ‘possibly MCA/MCAS’ can be established, and in acute cases, immediate treatment should be introduced.”[vii]
Evidence of mediator release
- Mast cells produce a multitude of mediators including tryptase, histamine, prostaglandin D2, leukotrienes C4, D4 and E4, heparin and chromogranin A[viii].
- Serum tryptase and 24 hour urine testing for n-methylhistamine, prostaglandin D2, prostaglandin 9a,11b-F2 are frequently included in testing guidelines in literature (Castells 2013)[ix], (Akin 2010)[x], (Valent 2012)[xi].
- It can be helpful to test for other mast cell mediators including 24 hour urine testing for leukotriene E4[xii]; plasma heparin[xiii]; and serum chromogranin A[xiv].
- In most instances, elevation of a mediator must be present on two occasions[ix]. This helps to exclude situations of appropriate mast cell activation, such as infection or wound healing.
- For patients with baseline tryptase level >15 ng/mL, elevation of tryptase above this baseline is only required on one occasion[viii].
Symptoms associated with mast cell activation
- Mediator release causes a wide array of symptoms, including hypertension[xv], hypotension, hypertension, wheezing, itching, flushing, tachycardia, nausea, vomiting, diarrhea, constipation, headache, angioedema, fatigue, and neurologic symptoms[iv].
- In a small MCAS cohort (18 patients), 17% had a history of anaphylaxis[xvii] . A larger data set is desirable.
- Patients with history of anaphylaxis should be prescribed epinephrine autoinjectors[v]. If patient must be on a beta blocker, they should be prescribed a glucagon injector for use in the event of anaphylaxis[v].
Response to medications that inhibit action of mast cell mediators
- Treatment of MCAS is complex and may require a number of medications. Second generation H1 antihistamines; H2 antihistamines; and mast cell stabilizers are mainstays of treatment[xvi].
- Additional options include aspirin; anti-IgE; leukotriene blocker; and corticosteroids[xiii] .
- First generation H1 antihistamines may be used for breakthrough symptoms[xiii] .
- “An important point is that many different mediators may be involved in MCA-related symptoms so that the final conclusion the patient is not responding to antimediator therapy should only be drawn after having applied several different antimediator-type drugs[xiii] .
- Inactive ingredients are often to blame for reaction to mast cell mediator focused medications. Many mast cell patients see benefit from having medications compounded[xvii].
- In one MCAS cohort of 18 patients, 33% had a complete (no unmanaged symptoms) response and 33% had a major (only one serious symptom) response after one year of mast cell treatment[xviii].
- In another MCAS cohort of 135 patients, 51% demonstrated significant improvement, 11% had no obvious change in symptom severity and 38% experienced worsening symptoms[v]. (Author’s note: While described in an Afrin 2016[v] paper, the data from this cohort has not yet been published. Molderings is the principle investigator.
[i] Frieri M, et al. (2013). Mast cell activation syndrome: a review. Current Allergy and Asthma Reports, 13(1), 27-32.
[ii] Molderings GJ, et al. (2013). Familial occurrence of systemic mast cell activation disease. PLoS One, 8, e76241-24098785
[iii] Akin C, et al. (2010). Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol, 126(6), 1099-1104.e4
[iv] Molderings GJ, et al. (2011). Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology, 4(10), 10.1186/1756-8722-4-10
[v] Castells M, et al. (2013). Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clin Ther, 35(5), 548-562.
[vi] Afrin LB, et al. (2016). Often seen, rarely recognized: mast cell activation disease – a guide to diagnosis and therapeutic options. Annals of Medicine, 48(3).
[vii] Valent P. (2013). Mast cell activation syndromes: definition and classification. European Journal of Allergy and Clinical Immunology, 68(4), 417-424.
[viii] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.
[ix] Picard M, et al. (2013). Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clinical Therapeutics, 35(5), 548-562.
[x] Akin C, et al. (2010). Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol, 126(6), 1099-1104.e4
[xi] Valent P, et al. (2012). Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol, 157(3), 215-225.
[xii] Lueke AJ, et al. (2016). Analytical and clinical validation of an LC-MS/MS method for urine leukotriene E4: a marker of systemic mastocytosis. Clin Biochem, 49(13-14), 979-982.
[xiii] Vysniauskaite M, et al. (2015). Determination of plasma heparin level improves identification of systemic mast cell activation disease. PLoS One, 10(4), e0124912
[xiv] Zenker N, Afrin LB. (2015). Utilities of various mast cell mediators in diagnosing mast cell activation syndrome. Blood, 126(5174).
[xv] Shibao C, et al. (2005). Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension, 45(3), 385-390.
[xvi] Cardet JC, et al. (2013). Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep, 13(1), 10-18.
[xvii] Afrin LB. “Presentation, diagnosis and management of mast cell activation syndrome.” In: Mast Cells. Edited by David B. Murray, Nova cience Publishers, Inc., 2013, 155-232.
[xviii] Hamilton MJ, et al. (2011). Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations. Journal of Allergy and Clinical Immunology, 128(1), 147-152.e2