Mast cell activation syndrome (MCAS) can present with a wide range of symptoms, which is one reason it is frequently overlooked or incorrectly labelled. Patients may experience sudden, recurrent episodes affecting multiple organ systems, including flushing, urticaria, angioedema, abdominal pain, diarrhoea, wheeze, dizziness, hypotension, and syncope.
Importantly, symptoms alone do not confirm MCAS. The most reliable approach is to apply strict, evidence-based diagnostic criteria and focus on event-related changes in mast cell mediators, rather than relying on a single baseline result. In this guide, Mast Cell Activation Syndrome: Latest diagnostic and testing advances, we outline the Vienna Consensus framework, explain how to use serum tryptase correctly (including the 20% + 2 rule), clarify where urinary mediator testing may be helpful, and highlight when to consider clonal mast cell disease.
Table of contents
- Five key takeaways
- Overview of MCAS and clinical presentation
- Current diagnostic criteria and classification
- Serum tryptase: The gold standard biomarker
- Urinary mast cell mediators: Emerging diagnostic tools
- Additional biomarkers and mediator testing
- Genetic testing and clonal mast cell disorders
- Histopathological assessment
- Diagnostic challenges and overdiagnosis concerns
- Therapeutic response as a diagnostic criterion
- Recommendations for clinical practice
- References:
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Five key takeaways
- MCAS is defined by episodes, not background symptoms. True MCAS typically involves severe, recurrent flares affecting two or more organ systems.
- Use the Vienna Consensus 3-part framework. Diagnosis requires (1) typical clinical episodes, (2) objective lab evidence of mediator rise, and (3) improvement with mast cell-directed treatment.
- Serum tryptase is still the most accepted biomarker but timing is everything. Aim to take the sample within 14 hours of symptom onset, then compare it to a baseline when well.
- The 20% + 2 (120% + 2 ng/mL) rule matters for tryptase analysis.
- Urinary mediators can help, but theyre not a stand-alone diagnosis. Tests like N-methylhistamine, LTE4, and prostaglandin metabolites can support the picture, especially when paired baseline vs flare samples are available but assays are technically demanding and cut-offs are less established.
Overview of MCAS and clinical presentation
Mast cell activation syndrome (MCAS) represents a significant diagnostic challenge in contemporary medicine, with an estimated prevalence ranging from 1% to 17% of the general population [1], [2]. The condition is characterised by recurrent episodes of severe systemic symptoms involving at least two organ systems, typically presenting as idiopathic anaphylaxis or similar acute mast cell-related events [1]. MCAS is fundamentally defined by abnormal and inappropriate mast cell activation, with subsequent release of mediators, including both preformed inflammatory substances stored in granules and newly synthesised lipid mediators [3].
The prototypical presentation of MCAS involves episodic symptoms that may include flushing, urticaria, angioedema, abdominal pain, diarrhoea, hypotension, and syncope, though the manifestations are remarkably heterogeneous and multisystemic [4]. Clinical symptoms reflect the diverse array of mediators released by activated mast cells, which include not only the classical histamine and tryptase but also numerous other inflammatory mediators with significant pathophysiological consequences [5].
Current diagnostic criteria and classification
The Vienna Consensus has established the most widely accepted diagnostic framework for mast cell activation syndrome, comprising three essential components: clinical, laboratory, and therapeutic response [6]. The clinical criterion requires severe, recurrent, episodic symptoms characteristic of mast cell activation involving at least two organ systems. The laboratory criterion, which remains the cornerstone of MCAS diagnosis, relies on the demonstration of elevated mast cell mediators. Most importantly, the therapeutic response criterion indicates that appropriate mast cell-directed therapy should result in a reduction of symptom frequency and severity [4].
Classification of MCAS is based on its underlying aetiology and distinguishes between three principal subtypes. Primary MCAS is diagnosed when clonal expansion of mast cells is demonstrated, meeting criteria for systemic mastocytosis or exhibiting minor criteria for mastocytosis. Secondary MCAS develops when normal mast cells are activated by identifiable triggers, most commonly IgE-mediated hypersensitivity reactions or drug-induced anaphylaxis. Idiopathic MCAS is diagnosed when neither clonal expansion nor an identifiable trigger for mast cell activation can be identified [6], [7].
Serum tryptase: The gold standard biomarker
Serum tryptase measurement has become the most widely accepted and specific biomarker of mast cell activation syndrome [3]. However, interpretation of tryptase levels requires a sophisticated understanding of baseline variation among individuals, as baseline tryptase concentrations vary significantly with genetic background, age, kidney function, and underlying disease [8]. A crucial development in MCAS diagnosis was the establishment of the 120% plus 2 ng/mL formula (also referred to as the 20% plus 2 formula in some literature), which was proposed by consensus groups to define the diagnostic increase in tryptase that qualifies as a criterion for MCAS [8], [9].
This formula has been validated in multiple subsequent studies and has proven to be a robust and consistent diagnostic criterion that accounts for natural variation in baseline tryptase levels across populations [9]. The formula is particularly valuable because approximately 35% of healthy individuals exhibit duplications or multiple copies of the TPSAB1 gene encoding alpha-tryptase, and over 30% of patients with myeloid neoplasms have elevated basal tryptase levels, making relative changes more diagnostically meaningful than absolute values [9]. Blood samples must be drawn within four hours of symptom onset for accurate event-related tryptase elevation assessment [1].
It should be noted that elevated baseline serum tryptase or urinary metabolite levels are not diagnostic of MCAS, nor do normal values exclude the diagnosis, as the key diagnostic finding is the acute, event-related increase relative to individual baseline [1].
Urinary mast cell mediators: Emerging diagnostic tools
Recent advances have highlighted the clinical utility of urinary mast cell mediators as emerging biomarkers in MCAS diagnosis [3]. These non-invasive markers are more readily obtained than serum tryptase levels and include N-methylhistamine, leukotriene E4, and 2,3-dinor-11beta-prostaglandin F2 alpha [3]. Measuring urinary metabolites provides a practical alternative for assessing mast cell activation, with baseline and post-event comparisons being particularly valuable. Urinary metabolites obtained at baseline and during symptom exacerbation represent an important advance in diagnostic methodology [3].
However, these markers present specific challenges in clinical practice. Many of these mediators, such as histamine, are highly unstable and undergo rapid degradation, making their assay technically demanding [10]. In contrast, serum tryptase, being a stable molecule, remains easier to measure reliably. Additionally, although urinary mediators show promise, their specificity and sensitivity require further validation, and they are not currently recommended as the sole diagnostic criterion due to lower specificity and the absence of clearly established cutoff values compared with serum tryptase [6].
Additional biomarkers and mediator testing
Beyond tryptase and urinary metabolites, numerous other mast cell mediators have been investigated as potential diagnostic markers. Histamine, a classic mast cell mediator, poses significant analytical challenges due to its rapid degradation and complex metabolism. Plasma histamine and its metabolites, including methylhistamine, have been evaluated in research settings [11]. In a study examining mast cell activation in patients with postural orthostatic tachycardia syndrome, elevated plasma histamine markers and prostaglandins were among the most frequently detected abnormalities [11].
Heparin, another preformed mast cell mediator, has been shown to be a more sensitive indicator of mast cell activity than other currently established biomarkers, with plasma heparin levels demonstrating greater sensitivity in detecting MCAS activity than serum tryptase or chromogranin A in certain contexts [12]. Chromogranin A, although widely used as a general neuroendocrine marker, has demonstrated relatively low sensitivity for MCAS diagnosis [12].
Prostaglandin D2 (PGD2) and leukotrienes represent important categories of newly synthesised mediators released upon mast cell activation. Functional eicosanoid testing and typing assays have demonstrated that the balance between prostaglandin E2 and peptido-leukotrienes release from peripheral blood leukocytes can differentiate MCAS patients from healthy individuals, with mean prostaglandin D2 release being 6.6-fold higher in MCAS patients compared to controls [13]. Additionally, substance P-triggered prostaglandin D2 release was markedly elevated in MCAS patients compared to healthy individuals, suggesting specific patterns of mediator release in response to different stimuli [13].
Genetic testing and clonal mast cell disorders
For patients with idiopathic anaphylaxis presenting with MCAS, evaluation for underlying clonal mast cell disorders is essential [1]. This includes measuring baseline serum tryptase and testing for the KIT p.D816V mutation in peripheral blood using high-sensitivity assays, when available [1]. The presence of KIT D816V mutations, detected by advanced molecular techniques such as droplet digital PCR or next-generation sequencing, is highly predictive of systemic mastocytosis [14].
Notably, hereditary alpha-tryptasemia represents another important consideration in the genetic landscape of mast cell disorders. The prevalence of hereditary alpha-tryptasemia, caused by TPSAB1 copy number variants, is estimated at 3-6% in general Western populations but may be as high as 17% among patients with mastocytosis [15]. This condition, distinct from MCAS, is characterised by persistently elevated baseline tryptase levels and may predispose individuals to more severe anaphylactic reactions [9].
Histopathological assessment
Bone marrow biopsy should be considered for patients with a high probability of mast cell clonality, particularly those with baseline elevated tryptase levels suggesting potential systemic mastocytosis [1]. A novel histopathological approach involves the tryptase depletion index, calculated as the difference between CD117-positive mast cells (representing all mast cells) and tryptase-positive mast cells (representing non-activated, tryptase-containing mast cells) in gastrointestinal biopsies [16]. This index may help discriminate between MCAS patients and controls, though further independent validation is required.
Evaluation of gastrointestinal biopsies for mast cell numbers presents ongoing challenges. While normal mast cell counts in luminal gastrointestinal tissue remain incompletely defined, increased mast cell density has been suggested as a potential marker of MCAS [17]. However, the clinical utility of this finding remains controversial, as there is insufficient evidence to support routine mast cell quantification in gastrointestinal biopsies for diagnosing MCAS outside of research contexts.
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Diagnostic challenges and overdiagnosis concerns
A critical contemporary concern in MCAS diagnosis is overdiagnosis, which has become increasingly prevalent with the use of less stringent diagnostic criteria [6]. Consensus 2 clinical criteria, which use more permissive clinical symptoms, are not considered specific enough to diagnose MCAS and may lead to substantial overdiagnosis of this condition. Indeed, recent studies confirm that true MCAS is quite rare, and false diagnoses may result in missing underlying diseases not associated with mast cell activation while subjecting patients to inappropriate mast cell-targeted therapy [6].
The diagnosis of MCAS requires strict adherence to established consensus criteria. Patients with unspecified or overdiagnosed MCAS exhibit non-specific symptoms without clear pathogenic significance and frequently do not respond to standard mast cell-targeted therapy, thus leading to reduced quality of life and social stigmatisation [6]. The absence of severe systemic attacks with hypotension and shock substantially lowers the likelihood of true MCAS, and baseline symptoms alone cannot be considered diagnostic [4].
Differential diagnosis and associated conditions
MCAS frequently overlaps with other multisystem conditions, creating diagnostic complexity [18]. Particularly notable is the association with postural orthostatic tachycardia syndrome (POTS), hypermobility spectrum disorders, and hypermobile Ehlers-Danlos syndrome. In one study, 42% of patients initially diagnosed with POTS exhibited both additional symptoms and at least one elevated biochemical marker suggesting mast cell activation disorder, with elevated prostaglandins and plasma histamine markers being the most common findings [11].
Therapeutic response as a diagnostic criterion
The third essential diagnostic criterion for MCAS involves a positive therapeutic response to drugs that target mast cells, mast cell mediators, or their effects [6]. First-line pharmacological management typically includes H1-antihistamines, with escalation to H2-antihistamines and mast cell stabilisers as needed. For refractory cases, omalizumab (anti-IgE therapy) has demonstrated significant efficacy, with most patients showing at least partial response [19]. A positive and sustained response to appropriate mast cell-directed therapy actually serves as a retrospective confirmatory criterion for MCAS diagnosis [9].
Recommendations for clinical practice
Current evidence-based guidance emphasises the importance of expanding access to key diagnostic tools in clinical practice to facilitate and improve patient care [1]. These include urinary mediator assays, high-sensitivity KIT mutation testing, and tryptase genotyping. Furthermore, patients with MCAS may require regular monitoring, including annual assessment of serum tryptase levels, to detect potential progression to systemic mastocytosis and related complications [20].
The field of MCAS diagnosis continues to evolve, with ongoing research focused on validating and refining both diagnostic and therapeutic strategies [1]. A personalised medicine approach that considers the aetiology, underlying pathologies, and comorbidities of individual patients is essential for establishing accurate diagnoses and developing optimal management plans [7]. Future research should prioritise the identification of novel biomarkers, the development of more specific diagnostic criteria, and the exploration of targeted therapies that address the root causes of mast cell dysregulation rather than simply addressing symptoms.
Disclaimer: This article is for informational purposes only and does not replace professional medical advice.
References:
Overview of MCAS and clinical presentation
Current diagnostic criteria and classification
Serum tryptase: The gold standard biomarker
Urinary mast cell mediators: Emerging diagnostic tools
Additional biomarkers and mediator testing
Genetic testing and clonal mast cell disorders
Histopathological assessment
Differential diagnosis and associated conditions
Therapeutic response as a diagnostic criterion
Recommendations for clinical practice
