Mast cell activation syndrome (MCAS) is a rare condition defined by a severe systemic reaction to mast cell derived mediators. Mast cells are effector cells of the immune system. These cells produce a variety of proinflammatory mediators and participate in a number of different pathological conditions. In patients the risk of developing severe anaphylactic (hypersensitivity) events is high.
Mast cell activation is found in many pathological conditions, from drug reactions, food allergies and those who suffer from systemic mastocytosis. When the symptoms are severe and recurrent and meet criteria confirming mast cell involvement, the diagnosis of mast cell activation syndrome (MCAS) can be established.
Common symptoms seen are itching, headache, flushing, abdominal pain, fast heart rate, but they are not specific for mast cell activation. An increasing number of patients are referred because they believe or had been informed that they are suffering from mast cell activation syndrome. Many of these patients do not fulfill the criteria of MCAS. This in turn leads to more frustration in both patients and caregivers as well as the inappropriate use of health care resources.
There are consensus criteria that are widely accepted for the diagnosis of mast cell activation syndrome.
- the episodic (recurrent) occurrence of typical, systemic symptoms that are produced by mast cell mediators and involves at least 2 organ systems.
- an increase in mast cell mediators, preferably serum tryptase by at least 20% over the individual tryptase level plus 2ng/ml, within 3-4 hours after the reaction.
- a substantial (documented) response to drugs that block histamine or suppress mast cell activation.
There may be a number of different clinical conditions and disorders that can mimic MCAS. Here is a list of them:
- Cardiovascular (myocardial infarction, endocarditis, endomyocarditis, aortic stenosis with syncope, acute pericardial effusion, pulmonary embolism)
- Endocrinologic (hypo/hyperthyroidism, hypoglycemia, adrenal insufficiency, hypopituitarism, estrogen or testosterone deficiency, carcinoid, pheochromocytoma, medullarythyroid tumor).
- Gastrointestinal disorders (inflammatory bowel disease, VIP secreting tumor, Crohn’s disease, Ulcerative Colitis, food intoxication, irritable bowel syndrome, mesenteric ischemia, eosinophilic esophagitis or gastroenteritis, gastroparesis).
- Rheumatologic and immunologic disorders (erythema nodosum, acute lupus erythematosus, vasculitis, systemic capillary leak syndrome, allergic episodes involving basophils but not mast cells).
- Infectious Diseases (severe bacterial or viral infections, acute gastrointestinal infection with dehydration, acute encephalitis/meningitis, acute parasitic diseases).
- Neurologic/central nervous system disorders (epilepsy, central nervous bleeding, intoxication, multiple sclerosis, dysautonomia, psychiatric conditions).
- Skin diseases (hereditary angioedema, acquired angioedema, pemphigus vulgaris, lupus erythematodes, acute toxic dermatoses, rosecea, idiopathic flushing, chronic urticaria, drug exanthema).
- Hematologic-acute anemia, acute gastrointestinal bleeding, massive hypermenorrhea, peripheral T-cell lymphoma.
Mast cell activation syndrome can be further classified into primary (clonal), secondary and idiopathic.
Most patients with mast cell activation syndrome suffer from recurrent episodes of severe hypotension (anaphylaxis). If this is not the case, MCAS is a less likely diagnosis. Patients with multiple chemical and environmental intolerances or multiple food intolerances should not be diagnosed as MCAS. 2 or more organs systems need to be involved. When the tryptase level increases substantially during an attack, the reaction can be regarded as mast cell related. Patients with MCAS may suffer from an IgE-dependent allergy and/or underlying mastocytosis.
Advice for affected individuals-many patients are being told that their symptoms are due to mast cell activation or MCAS. Others believe that they could suffer from MCAS when they undergo self-evaluation from questionnaires on the internet, however many do not fulfill the criteria. An answer of “yes” to the majority of following questions make the likelihood of MCAS high.
- Did my symptoms repeatedly occur in the form of severe attacks requiring immediate intervention or hospitalization?
- Did my symptoms lead to an anaphylactic shock?
- Was my serum tryptase level measured before, during and after an attack?
- Is my serum tryptase increased during an attack?
- Did my symptoms improve with antihistamines?
- Did the attacks less with steroids or antihistamines?
- Do I have an IgE-dependent allergy?
- Did my attacks resolve/decrease with Xolair (omalizumab)?
In conclusion, diagnostic criteria has been established and should be used for mast cell activation syndrome. A key diagnostic marker is the event-related increase in mast cell tryptase over the individual’s baseline. When it exceeds 20% from baseline plus 2 ng/ml the diagnosis of MCAS is very likely. Other conditions need to be considered when MCAS criteria are not met. This is important because some are serious and life threatening instead of misdiagnosing mast cell activation syndrome.
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Glossary of Terms:
Mast cell disorder (MCD): Any disorder associated with mast cell proliferation or localized or systemic MCA. A broad term including a variety of common and rare diagnoses such as chronic urticaria, allergic diseases and mastocytosis.
Mast cell activation syndrome (MCAS): A severe episodic multisystem disorder of MCA characterized by involvement of 2 or more systems (skin, respiratory, gastrointestinal, nasoocular and/or cardiovascular) response to to mast cell-targeting drugs and elevation of the level of a validated marker of MCA (such as serum tryptase) during or within a few hours of a symptomatic period.
Idiopathic anaphylaxis: Recurrent clinically diagnosed anaphylaxis of unknown etiology. Those with documented elevations of tryptase level meet the criteria for MCAS.
Mastocytosis: A clonal disorder of mast cell expansion and activation involving skin and/or internal organs that is generally associated with activating KIT mutations.