Mast cells are vital components of our immune system, known for their role in allergic reactions. These cells release substances called “mediators,” which are either pre-stored or newly produced, leading to allergic symptoms. In typical allergic reactions, mast cells are activated when allergy antibodies (IgE) on their surface encounter allergens. This activation triggers the release of mediators, a process termed degranulation.
Mast cells can also be activated by various non-allergen triggers like medications, infections, and venoms. These reactions, while undesirable, are considered normal mast cell responses to external stimuli, known as “secondary activation.”
However, in some cases, mast cells become dysfunctional and release mediators due to abnormal internal signals. Certain genetic mutations can lead to the development of mast cell clones – identical mast cell populations – that overproduce and spontaneously release mediators. This spontaneous mediator release in clonal mast cell disorders is termed “primary activation.” These abnormal cells can proliferate uncontrollably and exhibit heightened sensitivity to activation, a condition known as mastocytosis.
Idiopathic Mast Cell Activation Syndrome (MCAS) and Diagnosis
Idiopathic Mast Cell Activation Syndrome (MCAS) is characterized by recurrent episodes of anaphylaxis-like symptoms. These symptoms mirror severe allergic reactions and can include hives, swelling, low blood pressure, breathing difficulties, and severe diarrhea. Crucially, these episodes are accompanied by elevated levels of mast cell mediators. Patients with MCAS typically find relief from these episodes through treatments that inhibit or block mast cell mediators. The term “idiopathic” signifies that the underlying cause of MCAS is unknown, meaning it’s not triggered by typical allergic antibodies or secondary to other identified conditions that activate normal mast cells.
The diagnostic journey for Mast Cell Activation Syndrome Diagnosis begins by assessing whether a patient experiences distinct, recurring episodes exhibiting classic anaphylactic symptoms without an identifiable trigger. A key step is to confirm the involvement of mast cells by measuring mast cell mediators. These mediator levels should be evaluated both during acute symptomatic episodes and at baseline to detect significant elevations during attacks. Finally, a positive response to treatments targeting mast cell mediators is a crucial element in confirming the diagnosis of MCAS.
Symptoms Indicative of MCAS
The symptoms associated with MCAS often mirror those of anaphylaxis. Key indicators include:
- Cardiovascular Symptoms: Rapid heart rate (tachycardia), low blood pressure (hypotension), and fainting or loss of consciousness (syncope).
- Skin Symptoms: Intense itching (pruritus), hives (urticaria), swelling, particularly angioedema, and skin flushing or redness.
- Respiratory Symptoms: Wheezing, shortness of breath, and a harsh, high-pitched breathing sound (stridor), often indicating throat swelling.
- Gastrointestinal Symptoms: Diarrhea, nausea, vomiting, and crampy abdominal pain.
Mast Cell Mediators and Laboratory Diagnosis
Mast cells produce a wide array of inflammatory molecules. However, only a select few mediators or their stable breakdown products (metabolites) are consistently elevated during MCAS episodes and reliably detectable through commercially available laboratory tests. Currently, the most useful diagnostic tests for mast cell activation syndrome diagnosis involve measuring increases in:
- Serum Mast Cell Tryptase: Blood samples for total serum mast cell tryptase should ideally be drawn between 30 minutes and two hours after the onset of an acute episode, and a baseline level should be obtained several days later when symptoms have subsided.
- Urine N-methylhistamine, 11β-Prostaglandin F2α (11β-PGF2α), and/or Leukotriene E4 (LTE4): These mediators are assessed through a 24-hour urine collection, which should be initiated promptly at the start of a suspected episode.
It’s important to note that these tests are not routine laboratory procedures. Therefore, patients should collaborate closely with their allergist, who can effectively communicate with emergency room and laboratory personnel to ensure these specialized tests are ordered and processed in a timely manner, particularly during acute episodes crucial for mast cell activation syndrome diagnosis.
Treatment Strategies for MCAS
The objectives of MCAS treatment are twofold: to confirm the diagnosis and to provide symptomatic relief to the patient. The immediate focus is on alleviating the patient’s distressing symptoms. A lack of response to treatments targeting mast cell mediators may suggest that MCAS is not the underlying condition.
The management of acute MCAS episodes should align with established anaphylaxis treatment protocols. Epinephrine (adrenaline) is the first-line treatment if symptoms are severe or life-threatening.
For less severe symptoms, various medications can be helpful:
- Antihistamines: First-generation histamine type 1 receptor blockers like diphenhydramine and hydroxyzine can effectively manage itching, abdominal discomfort, and flushing. However, their use may be limited by side effects such as drowsiness. Second-generation antihistamines, including loratadine, cetirizine, and fexofenadine, are often preferred due to their reduced side effect profile.
- Histamine Type 2 Receptor Blockers: Medications like famotidine can be beneficial for abdominal pain and nausea.
- Aspirin: Aspirin can help reduce flushing by blocking the production of prostaglandin D2.
- Leukotriene Modifiers: Montelukast and zafirlukast block the effects of leukotriene C4 (LTC4), while zileuton inhibits LTC4 production. These medications can alleviate wheezing and abdominal cramping.
- Corticosteroids: Corticosteroids can be effective for edema, hives, and wheezing but are generally reserved for more severe cases or as a last resort due to potential long-term side effects.
- Omalizumab: This medication, which blocks IgE binding to its receptors, has shown promise in reducing mast cell reactivity and sensitivity to activation. This can potentially decrease the frequency and severity of anaphylactic episodes in some MCAS patients.
Summary: Reaching a Confirmed MCAS Diagnosis
Because symptoms of anaphylaxis can overlap with those of other conditions not involving mast cells, specific diagnostic criteria are essential to confirm that mast cell activation is indeed responsible for the patient’s episodes. These criteria necessitate:
- The presence of anaphylactic symptoms.
- Evidence of elevated mast cell mediators during symptomatic episodes.
- Symptom resolution with appropriate treatments targeting mast cell mediators.
Once these criteria are met, further investigations are crucial to rule out primary clonal mast cell disorders, which can also present with similar symptoms. Genetic testing for the KIT D816V mutation in blood is a recommended step. A positive result suggests a clonal mast cell disorder. However, a negative blood test for KIT D816V, while helpful, doesn’t entirely exclude a clonal disorder. In such cases, scoring systems considering symptoms and lab results are used to assess the likelihood of a clonal mast cell disorder. If suspicion remains high, a bone marrow biopsy and aspirate are indicated. Bone marrow biopsy offers a higher sensitivity for detecting the KIT D816V mutation and allows for microscopic examination of bone marrow mast cells for abnormalities and clonal markers. A bone marrow biopsy that is negative for abnormal and clonal mast cells, in the context of fulfilled diagnostic criteria, strongly supports the diagnosis of idiopathic mast cell activation syndrome.
Find out more about systemic mastocytosis.
8/23/2024
