Diagnosing MCAS

There is no universal agreement on how MCAS should be diagnosed. Two main approaches, commonly referred to as Consensus-1 and Consensus-2, differ in the evidence required for diagnosis. Consensus-1, developed by Valent and colleagues, uses more restrictive criteria and emphasises objective evidence of mast-cell activation alongside clinical presentation and treatment response. It recognises tryptase as the preferred biochemical marker while also considering other mast-cell mediators. Consensus-2, developed by Molderings, Afrin and colleagues, recognises a broader range of clinical presentations and laboratory evidence.

There is ongoing scientific debate about which approach best identifies people with MCAS, and research directly comparing the diagnostic frameworks remains limited. These differences can affect whether an individual meets diagnostic criteria and may contribute to variation in access to diagnosis and treatment. When assessing suspected MCAS, clinicians should therefore consider the published frameworks alongside the individual clinical picture, appropriate investigations and differential diagnoses. Diagnosing MCAS requires a stepwise approach and can take considerable time. Published approaches consider combinations of characteristic multisystem symptoms, evidence of mast-cell mediator release, response to mast-cell-directed treatment and exclusion of alternative explanations. The precise requirements differ between frameworks.

Key steps include recognising characteristic clinical symptoms, assessing response to treatment, undertaking appropriate mediator testing and ruling out other diagnoses. In practice, not all of these steps are always completed or possible. Where there is clinical suspicion of MCAS but the evidence required for a formal diagnosis has not yet been established, terms such as ‘suspected MCAS’ are commonly used while further assessment is considered. Reaching a diagnosis may require assessment over time, including investigation of symptoms, test results and response to treatment. This uncertainty can be difficult for people who suspect they have MCAS but have not yet received a formal diagnosis. For further information about MCAS diagnosis, see the Diagnostic Support section of our Resources for Medical Professionals page and the MCAS Bibliography.

Useful papers

For more detail on the different diagnostic approaches:

Mast cell activation syndrome: Current understanding and research needs – this 2024 expert review examines current understanding of MCAS and identifies important gaps in diagnosis and research. It acknowledges that serum tryptase is the preferred biochemical marker within current consensus criteria, while also recognising other mast-cell mediators including urinary histamine metabolites, leukotriene E4 and prostaglandin metabolites. The authors state that absence of a tryptase rise does not exclude mast-cell involvement, MCAS or anaphylaxis, and highlight the need for more reliable and sensitive biomarkers. They also identify unresolved questions around patients with suggestive symptoms and treatment response but negative mediator testing.

Diagnosis and Management of Patients With Mast Cell Activation Syndromes: Status 2026 – this 2026 review by Akin, Gülen, Castells, Oude Elberink and Valent provides an updated overview of MCAS and the wider spectrum of mast-cell activation disorders. It supports the continued use of stringent diagnostic criteria for formal MCAS diagnosis, while recognising that mast-cell activation can occur across a broader range of conditions and presentations.

The 2026 review Understanding Tryptase Physiology, Clinical Significance, and Diagnostic Applications: Where Do We Stand? examines current understanding of serum tryptase, including event-related changes, the 20% + 2 formula and factors that can influence baseline levels. It also discusses the limitations of tryptase testing and the potential role of other mast-cell mediators where tryptase results are normal or inconclusive.

This paper reviews the use of urinary mast-cell mediator metabolites in systemic mastocytosis and mast-cell activation disorders.

For further research relating to MCAS diagnosis, see our MCAS Bibliography.

Expand the sections below to learn more about the different elements considered in MCAS diagnosis.

Clinical symptoms

The first step is recognising the presence of typical clinical symptoms across multiple body systems.

MCAS symptoms are often episodic or wax and wane and their severity can fluctuate over time.

Symptoms can include:

  • dermatologic symptoms: such as flushing/redness, hives or wheals, itching with or without a rash, swelling
  • gastrointestinal symptoms: such as bloating, stomach pain/cramps, reflux, nausea, feeling or being sick, diarrhoea, constipation, dumping syndrome
  • respiratory symptoms: such as sore throat, hoarseness, wheezing, shortness of breath, throat swelling, stridor
  • cardiovascular symptoms: such as chest pain, low blood pressure, fast heart rate, fainting or light headedness
  • naso-ocular symptoms: such as nose congestion, eye watering and itching 
  • neurological problems: such as headache, brain fog (memory or concentration difficulties), numbness, pain or tingling skin, anxiety, behavioural issues, rages
  • musculoskeletal issues: such as joint and muscle pain, osteoporosis (brittle bones), loss of bone mass
  • genital and urinary issues: such as genital pain or swelling, pain when urinating, vaginal pain, discharge or itching, bladder urgency or loss of control
  • extreme tiredness
  • food allergies or intolerances 
  • anaphylaxis

Response to treatment

Response to treatment that reduces mast-cell mediator effects or mast-cell activation can provide supportive evidence when assessing suspected MCAS.

However, treatment response alone does not confirm a diagnosis and should be considered alongside symptoms, biochemical evidence and exclusion of alternative explanations.

People may respond differently to treatment, and more than one approach may need to be considered under the guidance of an appropriate healthcare professional.

The choice of treatment depends on the individual clinical picture and should take account of potential contraindications and adverse reactions.

 Common medications that can be used for MCAS include:

  • H1 antihistamines, such as loratadine, cetirizine and fexofenadine

  • H2 antihistamines, such as famotidine

  • mast-cell stabilisers, such as sodium cromoglicate and ketotifen

  • leukotriene-modifying medicines, such as montelukast

  • medicines targeting prostaglandin pathways, such as aspirin, where clinically appropriate

  • Vit C, Vit D, quercetin, luteolin 

Mediator tests

Ideally, the previous steps are combined with a biochemical assessment to show evidence of elevated mediator release from mast cells.

  • This can be challenging because mast cell mediators may only be elevated during an MCAS episode and then return to normal levels. Therefore, the test needs to be done when the symptoms of MCAS are present.
  • These tests also need to be conducted by an experienced healthcare provider, using an accredited laboratory to ensure that the test samples are handled appropriately.
  • The specific mediators of interest, and the thresholds required to attribute MCAS, are the subject of ongoing research and debate among the medical community.

No single mediator test is definitive; a positive result is not to say that a person certainly has MCAS and, similarly, no single mediator test captures every presentation and so a negative test is not sufficient to rule out an MCAS diagnosis. However, when considered alongside other diagnostic evidence, these mediator tests can provide reasonable confidence in a diagnosis.

Tryptase is often one of the first mediators which is tested for in people with a suspected mast cell disorder (using a blood test), and it remains the only mediator test with a specified increase in levels for diagnosis. However, a tryptase test must be conducted within a short time period (less than 4 hours) after an MCAS ‘flare’ and compared to baseline levels collected 24–48 hours later. Other mediator tests carried out in the UK include tests for urinary N-methylhistamine and prostaglandins D2, DM and F2α. Mediator tests are becoming increasingly available on the NHS.

Rule out other diagnoses

An important part of assessing suspected MCAS is considering other conditions that could explain some or all of the symptoms, as well as recognising that more than one condition may be present.

The differential diagnosis is broad because many symptoms associated with mast-cell activation are not specific to MCAS. Depending on the clinical presentation, clinicians may need to consider allergic, cardiovascular, gastrointestinal, endocrine, infectious, inflammatory, autoimmune, neurological and other conditions.

Some people being assessed for MCAS also have conditions such as Postural Orthostatic Tachycardia Syndrome (PoTS) or connective-tissue disorders including Ehlers-Danlos syndromes. These conditions can produce overlapping symptoms and may coexist, although the nature of their relationship with mast-cell activation remains an area of ongoing research.

Careful assessment of alternative and coexisting diagnoses is therefore important before attributing symptoms to MCAS.

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