Priority Focus - Mast Cell Activation Disease


Mast cell disease has long been thought to be just the rare disease of systemic mastocytosis with aberrant mast cell mediator release due to neoplastic mast cell proliferation primarily driven by the constitutively activating mutations in codon 816 of transmembrane tyrosine kinase KIT and demonstrating the classic mastocytosis features such as mast cell spindling, aggregation, tryptase overexpression, and CD25 expression. The prevalence of the rare disease variant systemic mastocytosis is on average 5 to 13 out of 100.000 resulting in globally approximately 750.000 patients.

The past decade of sciences show that a new view of mast cell disease is in order, with systemic mastocytosis only being the tip of the disease iceberg now termed Mast Cell Activation Disease (MCAD) and with the bulk of the iceberg being comprised of the more and more recognized mast cell activation syndrome (MCAS), featuring inappropriate mast cell activation leading to widespread systemic symptoms [3, 4, 5]. Most MCAD patients present with often years of decades of chronic multisystem polymorbidity generally of an inflammatory or allergic theme, which most likely is due to the wide underlying mutational heterogeneity in assorted mast cell regulatory elements. Recent science has revealed that MCAD is an epi-genetic driven disease [6, 7, 8] which is confirmed by frequent familial occurrence.

The general prevalence in the population for MCAS is estimated at 5 to 10% (~ 525 million people globally) and leaves it unsurprising that chronic mast cell activation underlies common idiopathic inflammatory and allergic diseases such as fibromyalgia, chronic fatigue syndrome (CFS) / myalgic encephalomyelitis (ME), chronic urticaria, allergy, migraine, chronic lyme disease, POTS, EDS, gulf war illness, endometriosis etc. [1, 2].

Several patients with Mast Cell Activation Disease remain with unclear diagnosis and multiple individually varying symptoms and co-morbities. Mast cell activation disease related clinical symptoms and conditions can be:

Constitutional: asthenia, fatigue, hyperthermia, fevers, easy infections, environmental sensitivities (physical, chemical)

Gastrointestinal: aphthae, burning pain, abdominal pain, helicobacter-pylori-negative gastritis, malabsorption, diarrhoe and/or obstipation, intestinal cramping and bloating (often within minutes), gastroesophageal reflux disease, nausea, multiple food allergies and intolerances, angioedema in any segment of the luminal tract.

Hepatic: hepatomegalie, hypercholesterolemia, hyperbilirubinemia, elevation of liver transaminases, splenomegaly

Respiratory: rhinitis, sinusitis, cough, asthma-like symptoms, dyspnea, pneumonitis, bronchitis
Cardiovascular: tachycardia, POTS, hypertension, hypotension, palpitations, dysrhythmias, presyncope, syncope, flushing

Musculoskeletal: osteoporosis, osteopenia, fibromyalgia, migratory arthritis, bone pain, muscle pain, joint hyperrmobility (Ehlers-Danlos Type III)

Cutaneous: hives, urticaria pigmentosa, telangiectasia, pruritus, angioedema

Neuropsychiatric: migraine / headache, lightneadedness, vertigo, difficulty in concentration, depression, mood disturbances, anxiety, panic, tinnitus, sleep disorders

Neurologic: neuropathic pain, polyneuropathy, dysautonomia
Ophthalmologic: conjunctivitis, episodic difficulty focusing, lid tremor, irritated eyes

Hematologic: “easy” bruising/ bleeding, polycythemia or anemia, thrombocytosis or thrombocytopenia

Scientific Sources
  1. Afrin, B. Lawrence, Mast cell activation disease and the modern epidemic of chronic inflammatory disease, translational research, volume 174, August 2016, Pages 33-59
  2. Afrin, B. Lawrence, Never bet against occam: Mast cell activation disease and the modern epidemics of chronic illness and medical complexity, 2016, Sisters Media, LLC
  3. Lawrence B. Afrin, Joseph H. Butterfield, Martin Raithel, and Gerhard J. Molderings, Often seen, rarely recognized: mast cell activation disease – a guide to diagnosis and therapeutic options, Annals of Medicine, 2016
  4. Lawrence B Afrin, Gerhard J. Molderings, A concise, practical guide to diagnostic assessment for mast cell activation disease, World J Hematol 2014 February 6; 3(1): 1-17
  5. Gerhard J. Molderings, Stefan Brettner, Jürgen Homann, Lawrence B Afrin, Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options, Molderings et al. Journal of Hematology & Oncology 2011, 4:10
  6. Janine Altmüller, Britta Haenisch, Amit Kawalia, Markus Menzen, Markus M. Nöthen, Heide Fier, Gerhard J. Molderings, Mutational profiling in the peripheral blood leukocytes of patients with systemic mast cell activation syndrome using next-generation sequencing, Immunogenetics (2017) 69:359–369
  7. Britta Haenisch, Holger Fröhlich, Stefan Herms, Gerhard J. Molderings, Evidence for contribution of epigenetic mechanisms in the pathogenesis of systemic mast cell activation disease, Immunogenetics (2014) 66:287–297
  8. Gerhard J. Molderings, Transgenerational transmission of systemic mast cell activation disease – genetic and epigenetic features, Translational Research 2016;174:86–97