Diagnosing mast cell activation without shortcuts

A patient describes repeated episodes of flushing, itching, abdominal cramps and palpitations. They have undergone allergy testing, but their skin-prick tests are negative. Between episodes, their blood tests may be entirely normal.

Could this be mast cell activation syndrome (MCAS)?

The difficulty is that the symptoms are real but individually non-specific, and the investigations can be surprisingly difficult to interpret.

Mast cells are tissue-resident immune cells that release mediators including histamine and tryptase. Although many clinicians associate mast cell activation with IgE-mediated allergy, this is only one activation pathway. Temperature changes, pressure, vibration, hormonal changes, medicines and stress may also contribute.

Negative skin-prick testing therefore does not exclude the non-IgE mast cell activation described in the discussion.

The diagnostic assessment starts with the pattern. Recurrent symptoms affecting at least two organ systems are more suggestive than an isolated symptom. Flushing alongside abdominal cramping and palpitations, for example, provides a reason to investigate further.

But a multisystem symptom pattern alone cannot establish MCAS. The assessment also considers evidence of mediator release and response to targeted treatment, although consensus groups differ in their diagnostic requirements.

Interpreting tryptase

Tryptase illustrates why the timing and context of investigations matter.

A single normal baseline tryptase does not exclude MCAS. The more useful comparison is between a sample taken during a symptomatic flare and another obtained when the patient is well.

The calculation discussed is baseline tryptase multiplied by 1.2, plus 2 µg/L. For someone with a baseline of 10 µg/L, a flare value of 14 µg/L meets this calculation.

Persistently raised baseline tryptase raises different possibilities. Hereditary alpha-tryptasaemia involves extra copies of the tryptase gene, whereas systemic mastocytosis involves clonal mast cell expansion. They should not be treated as interchangeable diagnoses.

Other investigations also need caution. Increased mast cell counts on CD117-stained gastrointestinal biopsies may contribute to assessment, but cannot independently diagnose MCAS. Reference populations affect interpretation.

When treatment becomes another problem

Management is not simply a matter of prescribing antihistamines.

H1 and H2 antihistamines and mast cell stabilisers have different roles. Ketotifen acts systemically but can cause sedation, increased appetite and mood changes. Oral sodium cromoglicate mainly targets gastrointestinal symptoms.

Dietary restriction deserves particular attention. Patients may progressively eliminate foods in an attempt to control symptoms, sometimes combining several restrictive approaches.

Without structured re-challenge and nutritional supervision, these diets can become increasingly difficult to sustain and potentially harmful.

There are overlapping diagnostic problems too. Postural orthostatic tachycardia syndrome (POTS), hypermobility disorders and persistent post-viral symptoms may coexist. Proposed mechanisms linking these conditions remain uncertain, and overlapping symptoms do not establish a single cause.

The practical approach is to document the episodes, look for reproducible triggers, compare appropriately timed investigations and assess alternative explanations, including coeliac disease and hypothyroidism.

Avoid dismissing unexplained multisystem symptoms as anxiety. Equally, avoid assigning MCAS on the basis of symptoms or one abnormal test.

For the next patient, a carefully documented symptom history and a plan for interpreting investigations may achieve more than ordering an increasingly broad panel of tests.