What is Mast Cell Activation Syndrome (MCAS) and how is it diagnosed and treated?

Mast Cell Activation Syndrome (MCAS): Comprehensive Overview

What is MCAS?

MCAS is a clinical disorder characterized by recurrent, episodic symptoms affecting at least two organ systems simultaneously due to inappropriate mast cell mediator release, confirmed by laboratory evidence of elevated mediators during symptomatic episodes, and demonstrating clinical response to mast cell-targeted therapies. 1

Key Distinguishing Features

• MCAS presents with episodic rather than chronic symptoms affecting multiple organ systems concurrently, consistent with systemic anaphylaxis criteria 1
• The disorder differs fundamentally from systemic mastocytosis by the absence of pathologic mast cell burden, no multifocal mast cell infiltrates, no KIT D816V mutation, and no aberrant CD25 expression on mast cells 2
• Symptoms are triggered by identifiable factors including temperature extremes, mechanical irritation, alcohol, certain medications (aspirin, radiocontrast agents, anesthetic agents), stress, exercise, infection, physical stimuli, and hormonal fluctuations 3, 4

Clinical Presentation by Organ System

Dermatologic Manifestations

• Recurrent episodes of flushing, pruritus, urticaria, and angioedema 1, 2
• Secondary skin changes including flaking may develop from chronic scratching 1
• Unlike mastocytosis, MCAS patients typically lack persistent skin lesions such as urticaria pigmentosa 2

Gastrointestinal Symptoms

• Abdominal cramping, bloating, diarrhea (episodic rather than specifically nocturnal), nausea, vomiting, and malabsorption 3, 2
• Symptoms often mimic irritable bowel syndrome and are frequently misdiagnosed as functional gastrointestinal disorders 5, 6
• Gastrointestinal manifestations can be prominent and may be the presenting complaint 6

Cardiovascular Symptoms

• Hypotension, tachycardia, syncope, and in severe cases, cardiovascular collapse 3, 2
• Hypotensive episodes require immediate supine positioning 3

Respiratory Symptoms

• Bronchospasm, wheezing, dyspnea, and rarely laryngeal angioedema 3, 2

Neuropsychiatric Symptoms

• Headaches, brain fog, anxiety, and cognitive difficulties 3, 1
• These symptoms may respond to oral cromolyn sodium 3

Systemic Anaphylaxis

• 20-50% of patients with underlying systemic mastocytosis experience systemic anaphylaxis, typically with hypotension and rarely with laryngeal angioedema 3

Diagnostic Criteria: The Three Essential Requirements

All three criteria must be met for MCAS diagnosis: 1

1. Clinical Criteria: Episodic Multi-System Symptoms

• Recurrent, episodic symptoms affecting at least two organ systems concurrently 1
• Symptoms must be consistent with systemic anaphylaxis criteria 1
• Episodic pattern is critical—persistent chronic symptoms without clear episodes should direct evaluation toward alternative diagnoses 4

2. Laboratory Evidence: Documented Mediator Elevation

Serum Tryptase (Cornerstone Test)

• Baseline serum tryptase: Obtained when patient is completely asymptomatic to establish individual baseline 1
• Acute serum tryptase: Measured within 30-120 minutes (ideally 1-4 hours) of symptom onset during an episode 1, 2
• Diagnostic formula: Acute tryptase should exceed baseline by the formula: (1.2 × baseline) + 2 ng/mL 1
• If baseline tryptase is persistently >20 ng/mL, bone marrow evaluation for systemic mastocytosis is indicated 1, 2

24-Hour Urine Collection for Histamine Metabolites

• N-methylhistamine measurement is preferred over plasma or serum histamine due to superior sensitivity and specificity 1
• Plasma and serum histamine levels are not recommended due to poor diagnostic utility 3

Additional Mediator Testing

• Urinary prostaglandin D2 metabolite (11-β-prostaglandin F2α) provides additional diagnostic support 1
• Urinary leukotriene E4 (LTE4) can guide therapeutic decisions, particularly if elevated 1
• Chromogranin A is not recommended as it resides in neuroendocrine cells, not mast cells 3
• Heparin has not been validated as a marker of mast cell activation in blood 3

Critical Timing Requirement

• Mediator elevation must be documented during symptomatic episodes on at least two separate occasions 1

3. Therapeutic Response Criterion

• Patient must demonstrate clinical improvement with mast cell-targeted therapies including H1 antihistamines, H2 antihistamines, mast cell stabilizers (cromolyn sodium), or leukotriene modifiers 1, 2
• Response to therapy is a required diagnostic criterion, not optional 1

Classification of MCAS Subtypes

After confirming MCAS diagnosis, classify into one of three categories: 3, 7

Primary MCAS

• KIT-mutated, clonal mast cells are detected 7
• Peripheral blood testing for KIT D816V mutation should be performed, though sensitivity is limited in peripheral blood 1
• May represent a forme fruste of systemic mastocytosis 7

Secondary MCAS

• Underlying inflammatory disease identified, often IgE-dependent allergy 7
• No KIT-mutated mast cells found 7
• Secondary causes must be excluded: allergies, drugs, infections, and other inflammatory conditions 1, 2

Idiopathic MCAS

• Neither underlying allergy/inflammatory disease nor KIT-mutated mast cells are detectable 7
• Diagnosis of exclusion after thorough evaluation 7

Additional Diagnostic Considerations

When to Pursue Bone Marrow Evaluation

• Baseline serum tryptase persistently >20 ng/mL 1, 2
• Clinical suspicion for clonal disease remains high despite negative peripheral testing 1
• Bone marrow biopsy with immunophenotyping, flow cytometry for aberrant CD25/CD2 expression, and KIT D816V mutation testing 2

Hereditary Alpha-Tryptasemia

• Consider if baseline tryptase is elevated without meeting systemic mastocytosis criteria 2
• Diagnosed via buccal swab rather than bone marrow biopsy 3
• TPSAB1 gene testing may be useful 2

Referral Indications

• Complex or borderline cases should be referred to specialized centers with expertise in mastocytosis 2

Critical Diagnostic Pitfalls

MCAS is Substantially Overdiagnosed

• Do not diagnose based solely on nonspecific symptoms, single organ system involvement, or symptoms without documented mediator elevation 1
• Many patients referred for suspected MCAS are ultimately diagnosed with autoimmune, neoplastic, infectious diseases, or other conditions unrelated to mast cell activation 8
• Misdiagnosis as MCAS can delay appropriate treatment for the actual underlying condition 8

What MCAS is NOT

• Not diagnosed by chronic, persistent symptoms without clear episodic pattern 4
• Not diagnosed by symptoms alone without laboratory confirmation 1
• Not diagnosed by single organ system involvement 1
• Not diagnosed without demonstrating therapeutic response to mast cell-targeted therapy 1

Management and Treatment

Acute Management of Mast Cell Activation Episodes

Acute management corresponds to treatment of systemic anaphylaxis: 3

Hypotension

• Immediate supine positioning 3
• Intramuscular epinephrine administration 3
• Patients should be transported to emergency department by ambulance while remaining supine 3

Laryngeal Angioedema

• Intramuscular epinephrine is required 3

Bronchospasm

• Intramuscular epinephrine or inhaled rapidly acting bronchodilator (albuterol) via nebulizer or metered-dose inhaler 3

Epinephrine Autoinjector

• All patients with history of systemic anaphylaxis or airway angioedema should be prescribed an epinephrine autoinjector and instructed on proper use 3

Preventive Pharmacologic Management

Treatment is highly individualized and targeted to bothersome symptoms, following a stepwise approach: 3

First-Line Therapy: H1 Antihistamines

• Nonsedating H1 antihistamines are generally preferred and can be increased to 2-4 times the standard FDA-approved dose 3, 1
• Reduce dermatologic manifestations (flushing, pruritus, urticaria), tachycardia, and abdominal discomfort 3
• Sedating H1 antihistamines (diphenhydramine, hydroxyzine) may acutely cause drowsiness and impair driving ability, and chronically lead to cognitive decline, particularly in the elderly 3
• Work better as prophylactic than acute treatment because once symptoms are apparent, it is too late to block histamine binding to receptors 3

H2 Antihistamines

• Can be used as first-line therapy for gastrointestinal symptoms 3
• May help H1 antihistamines attenuate cardiovascular symptoms 3
• Examples include ranitidine, famotidine, cimetidine 2

Oral Cromolyn Sodium

• Reduces abdominal bloating, diarrhea, and cramps 3
• Benefit may extend to neuropsychiatric manifestations 3
• Requires at least 1 month trial at 200 mg four times daily for onset of action 1, 2
• Divided dosing and weekly upward titration to reach target dose may improve tolerance and adherence 3

Leukotriene Modifiers

• Cysteinyl leukotriene inhibitors (montelukast) or 5-lipoxygenase inhibitor (zileuton) may reduce bronchospasm or gastrointestinal symptoms 3
• Particularly effective if urinary LTE4 levels are increased 3
• Work synergistically with H1 antihistamines and are particularly efficacious for dermatologic symptoms 1

Aspirin

• May reduce flushing and hypotension in some patients, particularly those with increased urinary 11β-PGF2α levels 3
• Contraindicated in those with allergic or adverse reactions to NSAIDs 3
• Clinical improvement may require dosing increase up to 650 mg twice daily, as tolerated 3
• Use with caution 3

Doxepin

• Potent H1 and H2 antihistamine with tricyclic antidepressant activity 3
• May reduce central nervous system manifestations in patients with MCAS 3
• May cause drowsiness and cognitive decline, particularly in the elderly, and may increase suicidal tendencies in children and young adults with depression 3

Cyproheptadine

• Sedating H1 antihistamine with extended anticholinergic and antiserotonergic activities 3
• May help gastrointestinal symptoms, particularly diarrhea through serotonin receptor antagonism 3, 2

Ketotifen

• Sedating H1 receptor antagonist approved in the United States for allergic eye disease but can be compounded as tablets 3
• Whether it is beneficial beyond other antihistamines is unproved 3

Corticosteroids

• Steroid taper/burst may be useful for refractory signs or symptoms at initial oral dosage of 0.5 mg/kg/day, followed by slow taper over 1-3 months 3
• May be helpful to give 50 mg prednisone at 13 hours, 7 hours, and 1 hour before radiologic or invasive procedures when mast cell activation has been problematic 3
• Steroid side effects dampen enthusiasm for long-term use 3

Omalizumab

• Cases indicate prevention of anaphylactic episodes in some patients with MCAS 3
• May be useful in those who cannot otherwise tolerate needed insect venom immunotherapy 3

Trigger Identification and Avoidance

First step in prevention involves identification and avoidance of triggers: 3

• Insect venoms, temperature extremes, mechanical irritation, alcohol, medications (aspirin, radiocontrast agents, certain anesthetic agents) 3
• Patients with systemic mastocytosis sensitive to insect venom, particularly with history of systemic anaphylaxis to prior insect sting, should undergo lifelong venom immunotherapy 3
• Using omalizumab during immunotherapy appears to reduce risk of anaphylaxis to venom immunotherapy 3

Dietary Considerations

Dietary restriction is NOT a primary treatment modality for MCAS: 1

• Management centers on blocking mediator receptors, inhibiting mediator synthesis, and preventing mediator release, rather than dietary restriction 1
• Guidelines do not mandate specific food eliminations as a diagnostic or treatment criterion 1
• Start with pharmacologic management first, rather than restrictive diets 1
• Food elimination alone without pharmacologic management is insufficient and not guideline-recommended 1
• While histamine can be produced by bacteria in foods and may theoretically trigger symptoms, temperature extremes, stress, anxiety, and specific medications are more consistently documented triggers than specific foods 1

Special Considerations

Hormonal Triggers

• Hormonal fluctuations are explicitly identified as potential triggers that can precipitate mast cell activation episodes 4
• If hormonal fluctuations are identified as a consistent trigger in confirmed MCAS, consider prophylactic escalation of mast cell-targeted therapy during predictable hormonal changes 4
• Document temporal relationships between hormonal changes and MCAS symptom episodes 4

Associated Conditions

• Increased awareness of association between MCAS and autonomic dysfunction, small fiber neuropathy, and connective tissue disorders, all of which impact gastrointestinal symptoms 6
• Comprehensive treatment plan should include treatments for associated conditions including autonomic dysfunction, and management of comorbid psychiatric illness and nutritional deficits 6

Procedures and Anesthesia

• For patients with history of problematic mast cell activation during procedures, consider premedication with 50 mg prednisone at 13 hours, 7 hours, and 1 hour before radiologic or invasive procedures 3
• Eliminating additives in drugs by compounding is not recommended—for 100 patients with chronic urticaria, 43 of whom complained of additive allergies, single- or double-blind challenges ruled this out in all patients 3

Prognosis

• Patients with indolent systemic mastocytosis demonstrate normal life expectancy 3
• MCAS prognosis depends on underlying subtype and severity of symptoms 7
• Treatment should be adjusted based on symptoms and increased levels of mast cell mediators 3

Key Takeaway for Clinical Practice

MCAS diagnosis requires rigorous adherence to all three diagnostic criteria: episodic multi-system symptoms, documented mediator elevation during episodes on at least two occasions, and therapeutic response to mast cell-targeted therapy. 1 The disorder is substantially overdiagnosed when clinicians rely on nonspecific symptoms alone without laboratory confirmation or therapeutic response documentation. 1 Management prioritizes pharmacologic mediator blockade with H1/H2 antihistamines, mast cell stabilizers, and leukotriene modifiers, rather than restrictive dietary interventions. 1 Patients with history of anaphylaxis must carry epinephrine autoinjectors and be trained in their use. 3