What are the symptoms and treatment options for mast cell activation?

Mast Cell Activation: Clinical Presentation and Management

Clinical Presentation

Mast cell activation presents with episodic, multi-system symptoms affecting at least 2 organ systems, most commonly manifesting as cutaneous, gastrointestinal, cardiovascular, and neuropsychiatric symptoms. 1

Dermatologic Manifestations

• Flushing of the face, neck, and chest 1
• Pruritus with or without rash 1
• Urticaria (hives) and skin rashes 1
• Angioedema (swelling) 1
• Dermatographism 1

Gastrointestinal Symptoms

• Diarrhea and abdominal cramping 1
• Nausea and vomiting 1
• Abdominal pain and bloating 1
• Gastroesophageal reflux disease (GERD) 1

Cardiovascular Manifestations

• Anaphylaxis (most severe presentation) 1
• Light-headedness, presyncope, and syncope 1
• Tachycardia and chest pain 1
• Blood pressure instability (hypotension or initial hypertension followed by hypotension) 1

Respiratory Symptoms

• Wheezing and shortness of breath 1
• Throat itching and swelling 1
• Nasal itching and congestion 1
• Conjunctival injection 1

Neuropsychiatric Symptoms

• Headache 1
• Brain fog, cognitive dysfunction 1
• Poor concentration and memory 1
• Anxiety and depression 1

Musculoskeletal Manifestations

• Bone and muscle pain 1
• Osteopenia, osteoporosis, and osteosclerosis 1

Other Symptoms

• Fatigue 1

Treatment Algorithm

First-Line Therapy: Antihistamine Blockade

Begin with combined H1 and H2 receptor antagonists at higher-than-standard doses, as these medications work prophylactically rather than acutely. 1

H1 Receptor Antagonists

• Nonsedating H1 antihistamines (fexofenadine, cetirizine) at 2-4 times FDA-approved doses 1, 2
• These control skin symptoms (pruritus, flushing, urticaria, angioedema), gastrointestinal symptoms, neurologic symptoms, cardiovascular symptoms (tachycardia, presyncope), and pulmonary symptoms 1
• Avoid first-generation H1 antihistamines (diphenhydramine, hydroxyzine) in elderly patients due to cognitive decline risk from anticholinergic effects 1

H2 Receptor Antagonists

• Famotidine, ranitidine, or cimetidine 1
• These prevent histamine-mediated acid secretion and blunt vasoactive effects when combined with H1 antagonists 1

Second-Line Therapy: Cromolyn Sodium

Add oral cromolyn sodium 200 mg four times daily for persistent symptoms, particularly gastrointestinal manifestations. 3

• FDA-approved for mastocytosis with documented improvement in diarrhea, flushing, headaches, vomiting, urticaria, abdominal pain, nausea, and itching 3
• Clinical improvement occurs within 2-6 weeks of treatment initiation 3
• Particularly effective for gastrointestinal symptoms (diarrhea, abdominal pain, nausea, vomiting) and cutaneous symptoms 1, 3
• Topical cromolyn cream can be applied 2-4 times daily for localized cutaneous symptoms (urticaria, pruritus, vesicles, bullae), but avoid on denuded lesions 1

Third-Line Therapy: Leukotriene Modifiers and Aspirin

Consider leukotriene receptor antagonists (montelukast) or 5-lipoxygenase inhibitors (zileuton) if urinary leukotriene E4 levels are elevated. 1, 2

• These reduce bronchospasm and gastrointestinal symptoms refractory to antihistamines 1

Consider aspirin therapy if urinary prostaglandin metabolites are elevated, but use with extreme caution. 1

• Effective for symptoms associated with elevated urinary prostaglandin levels 1
• Critical caveat: Aspirin can trigger mast cell activation in some patients, so risks and benefits must be carefully weighed 1

Fourth-Line Therapy: Omalizumab

For symptoms insufficiently controlled by conventional therapy, particularly recurrent anaphylaxis and severe skin symptoms, use omalizumab (anti-IgE monoclonal antibody). 1, 4

• Particularly effective for recurrent anaphylaxis and skin symptoms 1
• Less effective for gastrointestinal, musculoskeletal, and neuropsychiatric symptoms 1
• Clinicians must be prepared to identify and treat potential anaphylaxis when administering omalizumab 4

Additional Adjunctive Therapies

Corticosteroids

• Short-term use for refractory symptoms 1
• For radiologic or invasive procedures when mast cell activation has been problematic, give prednisone 50 mg at 13 hours, 7 hours, and 1 hour before the procedure 1
• Steroid side effects limit enthusiasm for long-term use 1

Cyproheptadine

• Sedating H1 antihistamine with antiserotonergic activity 1
• May help gastrointestinal symptoms, particularly diarrhea and nausea 1

Topical Therapies for Skin

• Skin moisturizers to avoid dryness 1
• Topical corticosteroids 1
• For diffuse lesions, apply bath or sterile gauze with zinc sulfate 1

Management of Osteopenia/Osteoporosis

For bone manifestations, initiate supplemental calcium and vitamin D with bisphosphonates (continued with antihistamines). 1

• Bisphosphonates may resolve bone pain and improve vertebral bone mineral density more than femoral head bone mineral density 1
• For refractory bone pain or worsening bone mineral density on bisphosphonates, consider PEG-interferon-alfa 1
• Denosumab (anti-RANKL monoclonal antibody) is generally used as second-line therapy for patients with bone pain not responding to bisphosphonates 1

Acute Management of Anaphylaxis

For anaphylaxis or severe episodes, immediately assume supine position, administer intramuscular epinephrine, and call emergency services. 1, 2

• All patients with history of systemic anaphylaxis or airway angioedema must be prescribed epinephrine autoinjector with proper training 1
• Supine positioning is critical for hypotensive episodes; use bedpan for diarrhea and emesis basin after rolling to side 1
• Albuterol via nebulizer or metered-dose inhaler for bronchospasm 1

Critical Clinical Pitfalls

Diagnostic Considerations

• Do not diagnose based on chronic symptoms alone—mast cell activation syndrome requires episodic symptoms affecting ≥2 organ systems 5, 2
• Document temporal relationships between triggers (including hormonal changes) and symptom episodes 5
• Measure mast cell mediators at baseline and during acute episodes (serum tryptase 1-4 hours after symptom onset, 24-hour urine for N-methylhistamine, leukotriene E4, 11β-prostaglandin F2α) 2

Treatment Considerations

• Antihistamines work prophylactically, not acutely—once symptoms are apparent, it is too late to block histamine binding to receptors 1
• Avoid anticholinergic H1 antihistamines in elderly patients due to cognitive decline risk 1
• Aspirin can trigger mast cell activation—use only when prostaglandin metabolites are documented and benefits outweigh risks 1

Trigger Identification and Avoidance

• Common triggers include: hot water, alcohol, certain drugs, stress, exercise, infection, physical stimuli, hormonal fluctuations, insect venoms, temperature extremes, and mechanical irritation 1, 5
• Hymenoptera venom allergy is a significant risk factor for severe recurrent anaphylaxis and may be the presenting symptom of mastocytosis 1