The Spectrum of Mast Cell Activation Syndromes

The criteria for mast cell activation and mast cell activation syndromes were  developed by an international consensus group of varied subspecialists (allergists,  hematologists, pathologists, dermatologists), have been validated, and have evolved over  the last two decades [7, 9-13]. In order to have MCAS, all three consensus criteria must  be met: 1) patient must have typical signs of severe, recurrent, systemic mast cell activation, 2) there must be confirmed mast cell activation documented by biochemical studies, and 3) response of symptoms to mast cell directed therapy [9]. Regarding the  second MCAS criteria noted above, serum tryptase is relatively mast cell-specific and the preferred marker of mast cell activation; basophils are the only other cell type to secrete tryptase, albeit at < 1% of that which mast cells produce [9]. Tryptase measurements can vary, and defining a relevant increase in serum tryptase is imperative. A commonly used method is the patient’s baseline to plus 20% + 2 ng/mL during acute event (sAT ≥  1.2sBT + 2) [14]; others have proposed an increase of 1.685 (sAT ≥ 1.685 x sBT) to improve specific amongst individuals with hereditary alpha-tryptasemia (HaT) and  indolent systemic mastocytosis (ISM) [15, 16]. While tryptase is the most often measured mediator, other biochemical studies can be performed to quantify transient increases in plasma histamine, urine histamine metabolites (n-methylhistamine, nMH), urine leukotrienes (LTE4) and urine prostaglandin D2 metabolites (2,3 dinor-11β-PGF2α) during an acute event [1, 2, 10, 17]. Urine studies are preferred, as plasma histamine, while being more reliable than serum, still demonstrates circadian variation, susceptibility to false positives, and detection limitations due to a very short half-life (< 15 minutes)  [18, 19]. 

Pathologically speaking, the main causes of abnormal mast cell activation and/or mast cell-related symptoms include: 1) high mast cell burden, 2) hyperactivated mast cells, and 3) comorbid conditions that can modify mast cell activation [7]. For diagnostic and management purposes, MCAS are classified based on the driving process underlying their

mast cell activation: primary (clonal), secondary (non-clonal), and idiopathic. Many of the clinical signs and symptoms of each MCAS variant overlap, given shared convergence at mast cell activation, thus specific criteria for each mast cell activation syndrome variant has been proposed (Figure 1) [7, 9-13]. Depending on the disorder, other symptoms may be

present as a direct result of organ infiltration rather than being a manifestation of mediator release [10, 13, 20-22].