Spectrum of mast cell activation disorders

Abstract

Mast cell (MC) activation disorders present with multiple symptoms including flushing, pruritus, hypotension, gastrointestinal complaints, irritability, headaches, concentration/memory loss and neuropsychiatric issues. These disorders are classified as: cutaneous and systemic mastocytosis with a c-kit mutation and clonal MC activation disorder, allergies, urticarias and inflammatory disorders and mast cell activation syndrome (MCAS), idiopathic urticaria and angioedema. MCs are activated by IgE, but also by cytokines, environmental, food, infectious, drug and stress triggers, leading to secretion of multiple mediators. The symptom profile and comorbidities associated with these disorders, such as chronic fatigue syndrome and fibromyalgia, are confusing. We propose the use of the term ‘spectrum’ and highlight the main symptoms, useful diagnostic tests and treatment approaches.

Keywords::

• antihistamines
• brain
• c-kit mutation
• IgE
• inflammation
• mast cell
• mastocytosis
• mediators
• tryptase

Financial & competing interests disclosure

Aspects of our work discussed here were supported in part by US National Institutes of Health (NIH) grants NS055681; DK062861; AR47652; NS66205; NS71361, and from Theta Biomedical Consulting and Development Co., Inc. (Brookline, MA, USA) to TC Theoharides. TC Theoharides is on the Scientific Advisory Board of The Mastocytosis Society (TMS, www.tmsforacure.org), and JM Stewart is Regional TMS coordinator for Michigan. TC Theoharides is the Scientific Director of Algonot, LLC, which has developed flavonoid-containing dietary supplements. TC Theoharides is the inventor of US patents No. 6,635,625; 6,641,806; 6,645,482; 6,689,748; 6,984,667 and EPO 1365777 covering the use of proteoglycans and flavonoids for the treatment of MC related and inflammatory diseases. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The term MCAD is used when specific criteria are fulfilled. A careful medical history (including the familial history), physical examination and specific laboratory tests are necessary for proper clinical evaluation.

  • Tryptase is a rather specific mediator for MCs, and it is recommended as the biomarker of choice even though IL-6 may better reflect disease activity in the absence of inflammatory diseases. Urine (24 h) histamine (serum, urine) metabolites and PGD₂ are helpful.

  • MC activation disorders are classified into three categories: primary, secondary and idiopathic.

  • The establishment of SM requires one major and one minor or three minor criteria.

  • Screening tissue sections for MCs should use antibodies against tryptase, CD₁₁₇ or CD_25. Degranulated MC can be assessed with tryptase staining. In certain cases, bilateral BM biopsies might provide higher yield [96].

  • Secondary MCADs are triggered by allergic or nonimmune stimuli, but do not involve MC clonality.

  • Idiopathic MCADs fulfill the criteria of MCADs, but there is no detectable clonal MC, no underlying reactive disease and no allergen-specific IgE.

  • There is no curative treatment for MCADs at the present time. Prevention of the MC triggers and reduction of the effects of MC mediators are main goals. Good control of symptoms with combination of different agents for improved quality of life is the first aim.

Notes

Words in italics are the most common signs and symptoms.

MC: Mast cell; Ra: Receptor antagonists.

Data taken from [33].

AHNMD: Associated with a hematological nonmast cell lineage disease.

Data taken from [33,37].