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World J Hematol. Feb 6, 2014; 3(1): 1-17
Published online Feb 6, 2014. doi: 10.5315/wjh.v3.i1.1
A concise, practical guide to diagnostic assessment for mast cell activation disease
Lawrence B Afrin, Gerhard J Molderings
Lawrence B Afrin, Division of Hematology/Oncology, Medical University of South Carolina, Charleston, SC 29425-6350, United States
Gerhard J Molderings, Institute of Human Genetics, University Hospital of Bonn, D-53127 Bonn, Germany
Author contributions: Afrin LB wrote the initial draft; Afrin LB and Molderings GJ contributed equally to the final revision processes; and Molderings GJ subsequent edits.
Correspondence to: Lawrence B Afrin, MD, BSB103, MSC635, Division of Hematology/Oncology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425-6350, United States.
Telephone: +1-843-7924271 Fax: +1-843-7920644
Received: September 5, 2013
Revised: October 6, 2013
Accepted: November 15, 2013
Published online: February 6, 2014

As recognition of mast cell (MC) involvement in a range of chronic inflammatory disorders has increased, diagnosticians’ suspicions of MC activation disease (MCAD) in their chronically mysteriously inflamed patients have similarly increased. It is now understood that the various forms of systemic mastocytosis - diseases of inappropriate activation and proliferation of MCs seemingly driven by a small set of rare, usually constitutively activating mutations in assorted MC regulatory elements - comprise merely the tip of the MCAD iceberg, whereas the far larger and far more clinically heterogeneous (and thus more difficult to recognize) bulk of the iceberg consists of assorted forms of MC activation syndrome (MCAS) which manifest little to no abnormal MC proliferation and may originate from a far more heterogeneous set of MC mutations. It is reasonable to suspect MCAD when symptoms and signs of MC activation are present and no other diagnosis better accounting for the full range of findings is present. Initial laboratory assessment should include not only routine blood counts and serum chemistries but also a serum total tryptase level, which helps direct further evaluation for mastocytosis vs MCAS. Appropriate tissue examinations are needed to diagnose mastocytosis, while elevated levels of relatively specific mast cell mediators are sought to support diagnosis of MCAS. Whether assessing for mastocytosis or MCAS, testing is fraught with potential pitfalls which can easily yield false negatives leading to erroneous rejection of diagnostic consideration of MCAD in spite of a clinical history highly consistent with MCAD. Efforts at accurate diagnosis of MCAD are worthwhile, as many patients then respond well to appropriately directed therapeutic efforts.

Keywords: Mast cell activation disease, Mastocytosis, Mast cell activation syndrome, Mast cell mediators, Tryptase, KIT mutations

Core tip: Mast cell activation disease (MCAD) is characterized by accumulation of genetically altered mast cells and/or abnormal release of these cells’ mediators, affecting functions in potentially every organ system, often without causing abnormalities in routine laboratory or radiologic testing. Recent data suggest a high prevalence of MCAD. Thus, MCAD should be considered routinely in the differential diagnosis of patients with chronic multisystem polymorbidity of a generally inflammatory theme or patients in whom established diagnoses do not well account for the patient’s presentation of symptoms consistent with mast cell mediator release. Mediator testing can be challenging but typically is manageable. Diagnostic efforts are worthwhile, as diagnosis often leads to effective therapy.