Mast cell activation syndrome

Overview

Mast Cell Activation Syndrome (MCAS) is a chronic multisystem disorder characterized by the inappropriate and excessive activation of mast cells, a type of white blood cell involved in immune responses. Unlike mastocytosis, which involves an overproduction of mast cells, MCAS is defined by abnormal activation of typically normal quantities of mast cells, leading to the release of various chemical mediators that affect multiple organs and systems.

These mediators include histamine, prostaglandins, leukotrienes, and cytokines, which can cause widespread symptoms ranging from mild allergic-type reactions to severe, potentially life-threatening anaphylaxis. MCAS has gained increased attention in recent years as a possible contributor to unexplained chronic inflammation, allergic-like reactions, and idiopathic multisystem symptoms. It often overlaps with other chronic conditions such as Ehlers-Danlos syndrome, postural orthostatic tachycardia syndrome (POTS), and irritable bowel syndrome (IBS).

Causes

The exact cause of MCAS is not fully understood, and it is likely multifactorial. In many patients, a clear trigger or underlying mechanism cannot be identified. However, known or suspected causes and contributing factors include:

• Genetic predisposition: Some individuals may have inherited mutations or variations in genes that regulate mast cell behavior.

• Immune dysregulation: Disruption of normal immune signaling may lead to inappropriate mast cell activation.

• Environmental triggers: Certain foods, medications, stress, infections, and changes in temperature or pressure may provoke mast cell degranulation.

• Idiopathic: In many cases, no specific underlying cause can be found, leading to a diagnosis of idiopathic MCAS.

MCAS is often distinguished from systemic mastocytosis, a condition in which mast cells proliferate abnormally due to mutations such as KIT D816V. In MCAS, the number of mast cells is normal or only slightly elevated, but their activity is dysregulated.

Symptoms

MCAS can produce a wide range of symptoms due to the widespread distribution of mast cells throughout the body, particularly in the skin, gastrointestinal tract, respiratory system, and cardiovascular system. Symptoms often wax and wane and may be triggered by specific exposures. Common symptoms include:

• Skin symptoms:

  • Flushing

  • Hives (urticaria)

  • Itching (pruritus)

  • Dermatographism (raised skin lines after scratching)

• Gastrointestinal symptoms:

  • Abdominal pain

  • Nausea and vomiting

  • Diarrhea

  • Bloating

• Respiratory symptoms:

  • Shortness of breath

  • Wheezing or asthma-like symptoms

  • Nasal congestion or sneezing

• Cardiovascular symptoms:

  • Palpitations

  • Low blood pressure

  • Dizziness or fainting (especially postural-related)

• Neurological and systemic symptoms:

  • Brain fog

  • Fatigue

  • Headaches

  • Temperature instability

• Anaphylaxis: In rare cases, patients may experience full-body allergic reactions, which can be life-threatening if untreated.

Due to the multisystem nature of the disease, MCAS is often misdiagnosed or mistaken for allergies, anxiety, IBS, or other functional disorders.

Diagnosis

Diagnosing Mast Cell Activation Syndrome can be challenging due to symptom variability, overlap with other conditions, and lack of widely accepted diagnostic criteria. However, most experts agree on three primary criteria:

1. Recurrent symptoms consistent with mast cell mediator release affecting two or more systems (e.g., skin and gastrointestinal symptoms).

2. Objective evidence of mast cell activation through laboratory testing, including:

   • Elevated serum tryptase during or shortly after a symptomatic episode

   • Elevated 24-hour urinary markers such as histamine, prostaglandin D2, or N-methylhistamine

3. Symptom improvement with medications that block mast cell activation or mediators, such as antihistamines or mast cell stabilizers.

Additional diagnostic tools may include:

• Allergy testing to rule out IgE-mediated allergies

• Bone marrow biopsy (to exclude systemic mastocytosis)

• Genetic testing if familial or syndromic features are present

Due to its complexity, diagnosis is often made by allergists, immunologists, or mast cell specialists.

Treatment

There is no cure for MCAS, but symptom management and trigger avoidance can significantly improve quality of life. A comprehensive treatment plan typically includes:

• Trigger avoidance: Identification and elimination of food, environmental, or chemical triggers that provoke symptoms.

• Medications:

  • H1 antihistamines (e.g., cetirizine, loratadine)

  • H2 antihistamines (e.g., famotidine, ranitidine)

  • Mast cell stabilizers (e.g., cromolyn sodium, ketotifen)

  • Leukotriene receptor antagonists (e.g., montelukast)

  • Prostaglandin inhibitors (e.g., aspirin, if tolerated)

  • Epinephrine autoinjector (e.g., EpiPen) for emergency use during anaphylaxis

• Supportive therapies:

  • Low-histamine or anti-inflammatory diet

  • Stress reduction and management of coexisting conditions such as POTS or Ehlers-Danlos syndrome

Treatment must be personalized and often involves trial-and-error to identify the most effective combination of interventions.

Prognosis

The prognosis for individuals with Mast Cell Activation Syndrome varies widely. While it is a chronic condition, many patients experience significant symptom relief with proper diagnosis, treatment, and lifestyle modifications. In some cases, symptoms may stabilize or improve over time.

However, due to the potential for severe reactions and the complexity of managing multisystem symptoms, MCAS can have a substantial impact on daily life and functional ability. Early recognition and a dedicated care team are essential for optimal management.

Ongoing research is improving understanding of MCAS, and future therapies may offer more targeted treatment options as the underlying biology of mast cell disorders becomes clearer.