Mediator Tests for MCAS

• 24-hour urine samples are recommended for assessing MCAS as mast cell mediators with short half lives may show normal results in spot urine samples.

• Samples must be kept chilled throughout collection, storage and transport as many mast cell mediators are thermolabile. 

• Multiple tests are often conducted; ideally two abnormal biochemical values are required to diagnose MCAS.

• MCAS patients may not have raised mast cell mediator levels unless they are symptomatic.

• A positive result does not confirm MCAS, and a negative result is insufficient to rule out MCAS. Alongside test results, other diagnostic evidence should always be considered.

Treatment Options

[A table showing the treatments used in mast cell activation diseases (including MCAS) and their mechanisms of action. Sources: Molderings GJ, Haenisch B, Brettner S, et al. Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebergs Arch Pharmacol. 2016;389(7):671-694. doi:10.1007/s00210-016-1247-1; Afrin LB, Butterfield JH, Raithel M, Molderings GJ. Often seen, rarely recognized: mast cell activation disease--a guide to diagnosis and therapeutic options. Ann Med. 2016;48(3):190-201. doi:10.3109/07853890.2016.1161231; Yip KH, Kolesnikoff N, Yu C, et al. Mechanisms of vitamin D₃ metabolite repression of IgE-dependent mast cell activation. J Allergy Clin Immunol. 2014;133(5):1356-136514. doi:10.1016/j.jaci.2013.11.030.]

Mast Cell Related Disorders

The three major forms of mast cell diseases are mastocytosis, mast cell activation syndrome (MCAS), and hereditary alpha tryptasemia syndrome (HαTs).

MCAS can be categorised as primary, secondary or idiopathic. Primary MCAS (known as monoclonal mast cell activation disorder) falls under the primary mast cell disorders category alongside systemic and cutaneous mastocytosis. These disorders are characterised by hyperproliferative mast cells. On the other hand, secondary and idiopathic MCAS are non-clonal. Secondary MCAS occurs due to IgE-mediated or non-IgE mediated allergic reactions while idiopathic MCAS refers to MCAS in which no allergic or autoimmune cause can be found. 

HαTs is a recently recognised condition. It commonly leads to elevated serum tryptase levels due to an increased copy number of the TPSAB1 gene. 

Mediators

Mediators and Symptoms 

Pathways of mast cell mediator release

References

• Castells M. Mast cell mediators in allergic inflammation and mastocytosis. Immunol Allergy Clin North Am. 2006;26(3):465-485. doi:10.1016/j.iac.2006.05.005
• Dahlin, Joakim & Maurer, Marcus & Metcalfe, Dean & Pejler, Gunnar & Sagi-Eisenberg, Ronit & Nilsson, Gunnar. (2021). The Ingenious Mast Cell: Contemporary insights into mast cell behavior and function. Allergy. 10.1111/all.14881. 

• Theoharides TC, Valent P, Akin C. Mast Cells, Mastocytosis, and Related Disorders. N Engl J Med. 2015;373(2):163-72.

• Theoharides TC, Tsilioni I, Ren H. Recent advances in our understanding of mast cell activation - or should it be mast cell mediator disorders?. Expert Rev Clin Immunol. 2019;15(6):639-656. doi:10.1080/1744666X.2019.1596800

[A table of mast cell-derived mediators. While some mediators are preformed and stored in granules, others are synthesised de novo. Source: Castells 2006, Theoharides et al. 2019.]

[A diagram showing the different symptoms associated with MCAS and the mast cell-derived mediators driving these symptoms. Figure adapted from Theoharides et al. 2015.]

[A diagram showing the pathways by which mast cell-derived mediators are released. Upon recognition of endogenous and exogenous products by receptors, mast cells release mediators through one of several pathways: (1) degranulation and release of granules containing mediators such as histamine; (2) release of newly synthesized lipid mediators such as PGD2; (3) release of de novo-synthesized mediators such as cytokines; (4) release of extracellular vesicles, for example, exosomes. Figure taken from Dahlin et al. 2021.]