Mast cells and mast cell activation disorders

What is a mast cell?

Mast cells are a normal part of the immune system found throughout the body’s connective tissues, particularly under the skin, near blood and lymph vessels, along nerves, and within the lungs and intestines.^1,2,3 They normally have a protective role, responding to bacteria and parasites, and helping to regulate allergic and inflammatory reactions.^2,3

Mast cells contain numerous granules filled with preformed chemical compounds known as mast cell mediators, including histamine, tryptase and heparin.^⁴ Following activation, mast cells can also produce and release other mediators, including cytokines, prostaglandins and leukotrienes.^⁴ While research continues to characterise the full range of mast cell mediators, these substances contribute to normal immune function, influencing blood flow, immune responses, inflammation and tissue repair.^⁴˒⁵

Provided by Mariana Castells, MD, PhD

What are mast cell activation disorders (MCADs)?

Mast cell activation disorders (MCADs) refer to conditions resulting from mast cell dysfunction. Also known as ‘mast cell diseases’, these disorders may involve increased mast cell numbers due to abnormal proliferation and accumulation, abnormal mast cell activation (MCA), or both.^1,2,3 Excessive MCA triggers the release of mediators, leading to diverse symptoms across multiple organ systems.^2,5

Broadly, these conditions can occur in childhood or adulthood, although paediatric forms can exhibit characteristic age patterns. Generally, there is no recognised external trigger or defining health event that explains the onset of MCADs, and the underlying mechanisms vary between conditions, with some well characterised and others not yet fully understood.⁵

Some patients with MCADs experience acute reactions, while others have chronic symptoms ranging from mild to severe.² In some cases, MCADs can lead to life-threatening reactions such as anaphylaxis.^2,3 However, most MCADs are not considered life-limiting, and life expectancy is similar to that of the general population.^6,7,8

In MCADs, a range of treatments and management strategies may be used, but there is no one-size-fits-all approach. Identifying relevant triggers, finding the most effective medications to reduce MCA or block the effects of released mediators, and managing symptoms in a way that balances immediate medical needs with quality of life may require careful adjustment over time under the guidance of the treating specialist.²

The two main categories of MCAD are:

• Mastocytosis – A group of diseases involving the clonal proliferation and abnormal accumulation of mast cells in one or more organs. There are several variants of mastocytosis.^1,2,3
• Mast cell activation syndrome (MCAS) – A group of conditions where mast cells are typically present in normal numbers but activate and release mediators inappropriately, leading to widespread symptoms.² There are several subtypes of MCAS, including the rare clonal form, primary/monoclonal MCAS (MMAS).^1,3,9

MCADs can also occur in a combined form in which a clonal MCAD, such as systemic mastocytosis or primary/monoclonal MCAS (MMAS), coexists with a secondary condition that contributes to MCA, most often an allergy or other hypersensitivity disorder.^1,3 More recent literature has defined this as a combined MCAD; however, this term is not a new diagnosis and does not replace a person’s MCAD diagnoses. Regardless of the terminology used, recognised secondary contributors are generally documented alongside the clonal MCAD, as they may influence treatment considerations and ongoing patient management.

Hereditary alpha tryptasemia (HαT) may also coexist with an MCAD. HαT is an inherited genetic trait sometimes referred to as a disorder-modifying factor.^{1, 2, 10} The descriptive term HαT-associated MCAD may sometimes be used when both are present, but it does not replace the person’s MCAD diagnosis. Regardless of terminology, confirmed HαT is generally documented in clinical notes and referrals, as it can affect interpretation of basal serum tryptase and may be relevant to monitoring and awareness of anaphylaxis risk in some patients.^{1, 2, 10}

NB: TAMS has developed the above classification diagram to provide a concise representation of conditions and clinical groupings encompassed within the MCAD umbrella.

*Telangiectasia macularis eruptiva perstans (TMEP) is now encompassed within maculopapular cutaneous mastocytosis (MPCM). Patients previously diagnosed with TMEP have been encouraged by the European Competence Network on Mastocytosis to have their classification updated at their next scheduled clinical review.

†Combined MCAD and HαT-associated MCAD are marked with an asterisk in the diagram as newer classification or descriptive refinements. These terms do not replace a person’s underlying diagnosis, and patients with a clonal MCAD and recognised secondary contributors, or an MCAD alongside HαT, should not seek an updated diagnosis solely to adopt this terminology. If you are unsure whether you have a relevant secondary condition, such as Hymenoptera venom allergy, or HαT, please discuss this with your doctor.