Mast cells are allergy cells responsible for immediate allergic reactions. They cause allergic symptoms by releasing products called “mediators” stored inside them or made by them. In allergic reactions, this release occurs when the allergy antibody IgE, which is present on the mast cell surfaces, binds to proteins that cause allergies, called allergens. This triggering is called activation, and the release of these mediators is called degranulation.
Some of these mediators are stored in granules in the mast cells and are released quickly and others are made slowly only after the cell has been triggered. Mast cells can also be activated by other substances, such as medications, infections, insect or reptile venoms. These responses, while not desirable, are made by “normal” mast cells. They are called “secondary activation” because they are due to (secondary to) external stimuli.
Sometimes mast cells become defective and release mediators because of abnormal internal signals. Certain mutations in mast cells can produce populations of identical mast cells – called clones – that overproduce and spontaneously release mediators. The spontaneous production of mediators in these clonal mast cell disorders is called “primary activation”. These abnormal cells can grow uncontrollably and are unusually sensitive to activation in a condition called mastocytosis.
Idiopathic Mast Cell Activation Syndrome
MCAS is a condition in which the patient experiences repeated episodes of the symptoms of anaphylaxis – allergic symptoms such as hives, swelling, low blood pressure, difficulty breathing and severe diarrhea. High levels of mast cell mediators are released during those episodes. The episodes respond to treatment with inhibitors or blockers of mast cell mediators. The episodes are called “idiopathic” which means that the mechanism is unknown - that is, not caused by allergic antibody or secondary to other known conditions that activate normal mast cells.
Evaluation for MCAS starts with determining whether the symptoms occur in separate attacks and are typical symptoms of an anaphylactic reaction without a clear cause. Mast cell mediators increase during the episode. Those mediators should be measured during acute episodes and at baseline looking for elevations during symptoms. Finally, the improvement with treatment using inhibitors of mast cell mediators completes the diagnosis.
The symptoms most consistent with anaphylaxis are:
• Heart related symptoms: rapid pulse (tachycardia), low blood pressure (hypotension) and passing out (syncope).
• Skin related symptoms: itching (pruritus), hives (urticaria), swelling (angioedema) and skin turning red (flushing).
• Lung related symptoms: wheezing, shortness of breath and harsh noise when breathing (stridor) that occurs with throat swelling.
• Gastrointestinal tract symptoms: diarrhea, nausea with vomiting and crampy abdominal pain.
Mast cells are known to produce many molecules that cause inflammation, but only a few mediators or their stable breakdown products (metabolites) have been found reliably elevated in episodes of MCAS and measurable in commercial laboratory tests. Increases in serum mast cell tryptase and in urine levels of N-methylhistamine, 11B -Prostaglandin F2α (11B-PGF2α) and/or Leukotriene E4 (LTE4) are the only useful tests in diagnosis of MCAS.
Total serum mast cell tryptase should be drawn between 30 minutes and two hours after the start of an episode, with baseline level obtained many days later. The urine tests are performed on a 24 hour collection of urine that is started immediately.
Since these are not standard laboratory tests, patients should work with their local allergist who can communicate with emergency and lab personnel to assure they are ordered and completed in a timely fashion.
The goals of treatment are both diagnosis and patient relief. The immediate goal is to provide relief for the patient. Lack of response to these treatments suggests that MCAS is not present.
The treatment of acute episodes should follow the recommendations for treatment of anaphylaxis, starting with epinephrine, if indicated by the severity of symptoms.
Antihistamines, such as the first generation histamine type 1 receptor blockers diphenhydramine and hydroxyzine, can be effective for itching, abdominal discomfort and flushing, but their use may be limited by side effects (sleepiness). Second generation antihistamines, including loratadine, cetirizine and fexofenadine, are preferable due to fewer side effects.
Treatment with histamine type 2 receptor blockers, such as ranitidine or famotidine, can be helpful for abdominal pain and nausea.
Aspirin blocks production of prostaglandin D2 and can reduce flushing.
Montelukast and zafirlukast block the effects of leukotriene C4 (LTC4) and zileuton blocks LTC4 production, so these reduce wheezing and abdominal cramping.
Corticosteroids are helpful for edema, hives and wheezing but should only be used as a last resort.
Omalizumab (which blocks binding of IgE to its receptors) has been reported to reduce mast cell reactivity and sensitivity to activation which can reduce anaphylactic episodes.
Since symptoms of anaphylaxis can be similar to symptoms caused by other conditions that do not involve mast cells, diagnostic criteria assure that mast cell activation is responsible for the episode. These criteria require the presence of anaphylactic symptoms, the elevation of mast cell mediators during symptoms and the resolution of symptoms with appropriate treatment(s).
Once these criteria are met, further testing should rule out primary clonal mast cell disorders that can also cause these symptoms. The patient’s blood should be tested for mutation of mast cell growth receptor KIT, called KIT D816V. If positive, it indicates a clonal mast cell disorder. A negative blood test for KIT D816V is helpful but not 100% accurate, so one of several scoring systems should be used, to follow symptoms and lab results to determine if the presentation is consistent with a clonal mast cell disorder. If so, a bone marrow biopsy and aspirate is indicated. The biopsy offers a high level of ability (sensitivity) to find KIT D816V mutation and allows examining bone marrow mast cells for their shape and abnormal cell surface markers. If the bone marrow biopsy is negative for abnormal and clonal mast cells, it establishes the diagnosis of idiopathic mast cell activation syndrome.
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