Mast Cell Activation Syndrome (MCAS) is among the most challenging diagnostic entities in contemporary medical practice, with substantial gaps between clinical presentation and accurate diagnosis that have created significant confusion in both patient care and research.
Table of contents
- Clinical presentation and diagnostic criteria challenges
- The Vienna Consensus
- The problem of misdiagnosis and overdiagnosis
- Laboratory biomarker limitations
- Diagnostic overlap and symptom complexity
- Exclusion diagnosis requirements
- Challenges in case recognition and clinical practice
- Access to specialised testing
- The distinction between diagnosis and therapeutic response
- Summary of diagnostic gaps
- References:
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Clinical presentation and diagnostic criteria challenges
The fundamental challenge in diagnosing Mast Cell Activation Syndrome or MCAS stems from its non-specific clinical presentation. The following three criteria conventionally diagnose MCAS:
- typical clinical symptoms,
- a substantial elevation in serum tryptase levels during an attack relative to baseline, and
- a response to mast cell mediator-targeting therapy [1].
However, the clinical picture of MCAS is remarkably non-specific, making it difficult for clinicians to identify and confirm the entity [2]. Symptoms of mast cell activation are observed in many diseases, including allergic conditions with localised or systemic clinical manifestations, and these overlapping presentations create significant diagnostic uncertainty.
International expert groups have established the consensus criteria for MCAS diagnosis. Despite well-described diagnostic criteria, incidence rates have increased with the use of multiple alternative criteria for MCAS diagnosis [3].
The Vienna Consensus
The Vienna Consensus criteria for diagnosing Mast Cell Activation Syndrome are built around three required pillars [3]:
- Clinical criterion (symptoms):
The person has severe, recurrent episodes consistent with an anaphylaxis-type reaction involving two or more organ systems (e.g., skin + gut, or breathing + cardiovascular). - Laboratory criterion (objective marker):
The most specific “gold standard” laboratory evidence is a significant rise in serum tryptase measured within a few hours of the episode (typically up to ~4 hours).
The rise is considered significant if it meets:
Other biomarkers are not currently recommended because they’re less specific and don’t have clear-cut-offs. - Response criterion (treatment effect):
There should be a clear improvement (fewer and/or less severe episodes) when using mast cell–targeting treatments.
However, not all experts agree with these criteria, with some finding them too restrictive, leaving some mast cell-related conditions unaccounted for, while others consider them too permissive and prone to overdiagnosis.
The problem of misdiagnosis and overdiagnosis
A critical gap in MCAS diagnosis is the increasing number of patients who receive misdiagnoses due to the use of nonspecific criteria [1]. The clinical presentation involving multiple organ systems and nonspecific symptoms creates opportunities for patients to receive an MCAS diagnosis when the actual underlying condition may be entirely unrelated to mast cell activation. This is particularly problematic because misdiagnoses of MCAS may lead to missed diagnoses of underlying diseases not associated with mast cell activation, and appropriate treatment will not be administered to the patient [3].
Recent real-world evidence demonstrates this overdiagnosis problem. Among 703 patients with suspected mast cell disorders, the overall prevalence of idiopathic MCAS was only 4.4%, indicating that MCAS is an uncommon condition that is often suspected but rarely confirmed [4].
Laboratory biomarker limitations
One of the most critical gaps in MCAS diagnosis relates to serum tryptase measurement and interpretation. The most specific and widely accepted marker of severe systemic mast cell activation is an event-related, transient increase in serum tryptase above the individual’s baseline [5].
The 2012 consensus group proposed the 120% + 2 ng/mL formula, which covers the great majority of groups, including cases with low, normal, or elevated basal serum tryptase levels [5].
Despite this formula, significant gaps remain. Baseline serum tryptase concentrations vary among donors, depending on genetic background, age, renal function, and underlying disease.
Elevated baseline tryptase levels can occur in various conditions, including chronic kidney disease, obesity, and haematological neoplasms, making baseline tryptase values difficult to interpret [6]. Furthermore, a genetic trait called hereditary alpha-tryptasemia is characterised by increased TPSAB1 copy number and is associated with a baseline tryptase level above 8 ng/mL [6]. The determination of other biomarkers is not currently recommended as standard diagnostic tools due to their lower specificity and the lack of clearly defined cut-off values [3].
The need for accurate timing of blood samples exemplifies the challenge of baseline tryptase. Tryptase must be drawn within four hours of a symptomatic episode for the comparison of acute versus baseline values to be meaningful [7]. Many patients present to clinical evaluation days or weeks after an episode, making baseline tryptase comparison impossible. Additionally, normal tryptase levels do not exclude the possibility of MCAS.
Diagnostic overlap and symptom complexity
A significant gap in MCAS diagnosis exists in the overlap with other conditions affecting multiple organ systems. MCAS, postural orthostatic tachycardia syndrome (POTS), and hypermobility spectrum disorders frequently co-occur in young patients [8]. However, the prevalence of each entity relative to the others is not well established and is strongly influenced by the definitions used for the syndrome [8].
The use of overly restrictive diagnostic criteria can be problematic in clinical settings, as it underestimates disease prevalence, thereby preventing clinicians from considering potentially beneficial therapeutic options [8]. Conversely, using overly permissive criteria leads to overdiagnosis.
Additionally, the clinical heterogeneity of MCAS is substantial, with at least three distinct subtypes identified by physical triggers [9]. Relationships between triggers and clinical complaints reveal that abdominal discomfort is primarily triggered by histamine consumption, dermatological discomfort by exercise, and neurological symptoms by physical exertion and periods of starvation; however, the causes of cardiological complaints are multifactorial, and triggers for respiratory complaints remain poorly identified [9].
Exclusion diagnosis requirements
Perhaps one of the most significant gaps is that MCAS diagnosis is established after exclusion of other possible clinical entities in most cases [2]. This places a significant diagnostic burden on clinicians to first rule out other conditions with similar presentations. The diagnosis requires a comprehensive evaluation, including a detailed clinical history, assessment for secondary causes of mast cell activation, and evaluation for clonal mast cell disorders. For patients with idiopathic anaphylaxis, assessment for a clonal mast cell disorder is recommended, including measuring baseline serum tryptase, testing for the KIT p.D816V mutation in peripheral blood using high-sensitivity assays, and calculating a mast cell clonality prediction score [7]. Notably, a bone marrow biopsy should be considered for those with a high probability of mast cell clonality, yet not all clinicians have ready access to these specialised diagnostic resources.
Challenges in case recognition and clinical practice
The practical challenges of MCAS diagnosis in real clinical settings are substantial. A case report highlighted that mastocytosis and MCAS can be diagnosed only when specific criteria are met; when these criteria are not met, establishing an accurate diagnosis becomes extremely challenging [10]. In that case, a 37-year-old man presented with anaphylaxis after a bee sting and elevated serum tryptase levels, yet could not be diagnosed with either mastocytosis or MCAS based on the established diagnostic criteria because symptoms were not recurrent and tryptase release was not event-related [10].
Access to specialised testing
A further gap in MCAS diagnosis is the lack of key diagnostic tools in many clinical settings. Access to urinary mediator assays, sensitive KIT mutation testing, and tryptase genotyping would facilitate diagnosis and improve care for patients with suspected MCAS; however, these tools are not uniformly available [7]. This creates geographic and institutional disparities in diagnostic accuracy.
The distinction between diagnosis and therapeutic response
The requirement that patients show a response to mast cell mediator-targeting therapy as part of the diagnostic criteria creates a temporal gap in diagnosis. Patients cannot be definitively diagnosed until they have been treated and shown clinical improvement, yet treatment often begins based on clinical suspicion. This creates a circular diagnostic dilemma in which diagnosis is partially dependent on treatment response, making it difficult to establish a diagnosis in newly presented cases before therapy has been initiated and evaluated.
Summary of diagnostic gaps
The gaps in diagnosing MCAS are multifaceted and interconnected. The non-specific clinical presentation, combined with variable baseline serum tryptase levels, the need to exclude multiple other conditions, the requirement for event-related tryptase elevation, the temporal lag between symptom onset and diagnostic testing, and the substantial overlap with other multisystem disorders all contribute to widespread misdiagnosis and underdiagnosis of true MCAS while simultaneously leading to overdiagnosis in patients with other underlying conditions. These gaps have led to a state in which MCAS is simultaneously underrecognized among affected individuals and overdiagnosed in patients with non-MCAS pathology, representing a significant clinical challenge that requires further standardisation, improved access to specialised diagnostic testing, and enhanced clinician education.
References:
[6] M. Beyens, A. Toscano, D. G. Ebo, T. Glen, and V. Sabato, “Diagnostic Significance of Tryptase for Suspected Mast Cell Disorders,” Multidisciplinary Digital Publishing Institute, Dec. 2023, doi: https://doi.org/10.3390/diagnostics13243662.
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