Idiopathic Mast Cell Activation Syndrome

Idiopathic mast cell activation syndrome is mast cell activation with documented mediator release, but no clonal mast cell disease and no identified allergic or other trigger. It is a diagnosis of exclusion.

Pathophysiology. Mast cells release mediators in an unregulated manner without a clonal KIT variant or an allergic trigger. Some patients have hereditary alpha tryptasaemia (extra TPSAB1 copies), which raises baseline tryptase and the risk of reactions.

It is less common than often assumed, and overdiagnosis is frequent because symptoms are non-specific.

Episodes may be intermittent over years, with no end organ damage.

• Episodic flushing, itching, urticaria and angio oedema
• Abdominal pain, diarrhoea, nausea
• Palpitations, presyncope and hypotension
• Wheeze and nasal congestion
• Headache and fatigue between episodes
• No anaphylaxis triggered by a clear allergen

• Diagnostic criteria (all 3): typical episodic symptoms in 2 or more organ systems, a documented rise in tryptase of more than 20% over baseline plus 2 microgram/L, and response to mediator targeted treatment.
• Exclusion of allergy: skin prick tests or specific IgE to foods, venoms and drugs as indicated, and alpha gal IgE.
• Exclusion of clonal disease: KIT D816V testing in blood, bone marrow biopsy when the REMA score is 2 or more or baseline tryptase is over 20 microgram/L.
• Baseline tryptase, with TPSAB1 copy number testing when over 8 microgram/L.
• Exclusion of mimics: carcinoid (urinary 5-hydroxyindoleacetic acid), phaeochromocytoma (plasma metanephrines), hereditary angio oedema (C4, C1 inhibitor), endocrine disease, postural tachycardia syndrome.
• Urine mediators: N-methylhistamine, 11-beta-prostaglandin F2-alpha and leukotriene E4 collected after an episode.

Differential diagnosis.

• Monoclonal mast cell activation syndrome and mastocytosis
• Hereditary alpha tryptasaemia
• Chronic spontaneous urticaria
• Carcinoid syndrome and phaeochromocytoma
• Postural tachycardia syndrome and panic attacks
• Functional gastrointestinal disorders and menopause

• Stepwise treatment: begin with an H1 antihistamine and add drugs as needed, judging response over 4 to 8 weeks.
  • Cetirizine 10 mg orally once daily, which may be increased to twice daily (children 1 to 5 years 2.5 mg twice daily; 6 to 11 years 5 mg twice daily).
  • Famotidine 20 mg orally twice daily (reduce at creatinine clearance under 50 mL/min).
  • Sodium cromoglicate 200 mg orally four times daily before meals for gastrointestinal symptoms.
  • Montelukast 10 mg orally at night.
  • Omalizumab 150 to 300 mg subcutaneously every 4 weeks for refractory disease in specialist care.
• Trigger avoidance: heat, alcohol, NSAIDs and opioids where relevant, and treat infection.
• Emergency plan: adrenaline 0.5 mg intramuscularly (children 0.01 mg/kg, maximum 0.5 mg) into the anterolateral thigh for anaphylaxis, with auto injector: 150 microgram for 7.5 to 25 kg, 300 microgram for 25 to 50 kg, 500 microgram for over 50 kg.
• Avoid unnecessary restrictive diets, and use a low histamine diet only for a limited time if symptoms follow food.
• Stop ineffective treatments after 8 weeks with no benefit, to limit drug burden.
• Psychological support and graded activity for fatigue and anxiety.

Special groups.

• Patients with hereditary alpha tryptasaemia: higher risk of severe venom or drug reactions, so review the need for an auto injector and venom immunotherapy.

Monitoring. Episode diary and symptom score every 3 months. Baseline tryptase yearly. Review treatment response and stop ineffective drugs.

Referral and escalation. Refer to allergy or immunology for suspected mast cell activation, to confirm the diagnosis and exclude clonal disease. Emergency for anaphylaxis.