Diagnosing MCAS (Mast Cells Activation Syndrome)

Why Diagnosis of MCAS can be Tricky

Diagnosis of Mast cell Activation Syndrome (MCAS) can be difficult to achieve as many people with suspected MCAS do not fulfil the diagnosis criteria. Very limited validated test further increases difficulty of diagnosis.

The range of symptoms can be very diverse which further complicates diagnosis as other clinical diagnosis of these different symptoms need to be medically checked to help reduce risk of incorrect diagnosis.

Additionally, access top a Medical Specialist with experience with MCAS is challenging.

Overlap with MCAS Symptoms and Many other Issues

As there is considerable overlap between symptoms occurring in MCAS  and various other clinical issues, then other diagnosis need to be medically considered and ruled out. For example, other conditions with similar symptoms to those in MCAS  include testosterone or estrogen deficiency, inflammatory bowel disease and allergic reactions.

It is therefore essential that tailored workup based on clinical assessment has been appropriately performed to rule out these other potential undiagnosed causes. 

Difficult regarding Objective Laboratory Tests and MCAS Diagnosis

Although various mediators are produced and released by mast cells when activated and can be detected in serum or urine, these markers vary in sensitivity and specificity for MCAS so are not reliable enough to use, reference intervals for normal individuals and those with MCAS have not been established and because errors associated with specimen collection and handling can significantly alter results.  

Unfortunately, non-validated laboratory tests are sometimes used make a diagnosis of MCAS  which can cause confusion for both patients and clinicians, such as urinary metabolites of histamine, blood prostaglandin D₂, metabolite 11-β-prostaglandin F₂α, and urinary leukotriene E4.

Mast cell tryptase remains the marker of choice for laboratory investigation of MCAS as per international consensus.

As tryptase only rises following mast cell activation, peaking within 4 hours and returning to normal levels by 24 hours, tryptase needs to be measured (thus collected from a blood sample) between 30 mins and 2 hours after an event otherwise levels will be normal. Although, tryptase can still be useful if elevated above the baseline up to 6 hours after the event.

Tryptase levels after a triggering event needs to be compared to a baseline level.

Many people suspected of having MCAS do not show any increase or high enough tryptase levels to be considered diagnostic for MCAS.

THE DIAGNOSTIC GUIDELINES FOR MCAS IN AUSTRALIA

Testing guidelines in Australia for mast cell activation syndrome (MCAS) are informed by international consensus criteria, including key updates in 2019 and 2021.

The most widely accepted, and arguably strict, criteria are known as the Consensus-1 (Valent et al.) criteria, which require three elements to be met.

A. Typical signs and symptoms of mast cell mediator release (affecting at least 2 organ systems)

The clinical criterion of MCAS requires the simultaneous involvement of ≥ 2 organ systems, for example:

• Skin: flushing, pruritus, urticaria, angioedema

• Cardiovascular: hypotension

• Respiratory: wheezing, objective upper-airway involvement (e.g. stridor, laryngeal oedema)

• Gut: diarrhea

• Naso-ocular: pruritus.

B. Objective evidence of mediator release: mast cell tryptase

Secondly, the diagnosis of MCAS requires laboratory proof.  Mast cell tryptase (tryptase) remains the marker of choice for laboratory investigation of MCAS. 

Baseline serum tryptase – A blood test that measures tryptase, a chemical released by mast cells. (In MCAS, tryptase may be normal at baseline).

Event (reactive) tryptase – A blood test taken ideally within 1 – 4 hours of a significant episode. MCAS diagnosis requires baseline and reactive tryptase testing; neither test in isolation constitutes a diagnosis.

·       Levels more than 11.4ug/L are considered increased

·       Criteria of at least 20% + 2ng/mL over baseline is considered indicative of mast cell activation^.

C. Response to therapy that blocks mast cell mediator activity

• H1-receptor with or without H2-blockers, ketotifen, sodium cromoglicate, aspirin, and leukotriene receptor antagonists

Diagnostic criteria for mast cell activation syndrome (MCAS). All three criteria must be fulfilled to confirm a diagnosis of MCAS: A clinical criterion, B laboratory criterion and  C response criterion.

BRIEF DISCUSSION OF MCAS DIAGNOSTIC CRITERIA

Whether the diagnostic criteria for Mast Cell Activation Syndrome (MCAS) are "too narrow" is a subject of significant debate, with expert consensus groups generally favouring strict criteria to ensure accuracy, while some clinicians argue this excludes many patients with chronic, lower-intensity symptoms.

Objections with Criteria being too Narrow

Diagnosis criteria focus on acute, severe, anaphylaxis-like events, which may exclude patients who experience chronic, waxing-and-waning symptoms that are not immediately life-threatening but still debilitating.

The requirement to capture a spike in tryptase within a short 1–4 hour window of an episodic event is logistically difficult, as many patients cannot reach a lab in time.

Many symptoms of mast cell activation occur without massive tryptase release, making it hard for patients with "lesser" reactions to meet the strict biochemical thresholds.

Objections with Widening Criteria

Experts argue that a very wide range of symptoms are commonly reported, many of which can be caused by other conditions (e.g., Gut disease, psychiatric issues, other autoimmune diseases).

Alternative, broader definitions have been criticized for lacking specificity, creating the potential for over diagnosis and preventing patients from getting the correct diagnosis for their symptoms.

While some argue for a "chronic" form of MCAS, some consensus groups state there is currently no evidence supporting the existence of chronic MCAS without severe, episodic.

There are alternative definitions—often called "Consensus-2" or alternative proposals—which allow for a wider array of symptoms and less rigid testing, but these have not been as widely accepted or validated as the Vienna/Consensus-1 criteria. 

Currently, for those who fit the clinical picture but do not meet all criteria, the diagnosis is often labeled as "Suspected MCAS". 

MCAS REFERENCES

Gulen, Theo. (2024). Using the Right Criteria for MCAS. Current Allergy and Asthma Reports. 24. 10.1007/s11882-024-01126-0. https://www.allergy.org.au/images/stories/pospapers/ASCIA_HP_Mast_Cell_Disorders_2025.pdf, accessed 16 March 2026.