What is the pathophysiology of Mast Cell Activation Syndrome (MCAS)?

Pathophysiology of Mast Cell Activation Syndrome (MCAS)

Mast Cell Activation Syndrome (MCAS) is characterized by abnormal mast cell activation with episodic release of mediators affecting multiple organ systems, resulting from dysregulated mast cell activation pathways without the presence of mast cell proliferation or clonality seen in mastocytosis. 1

Fundamental Mechanisms of MCAS

Mast Cell Development and Activation

• Mast cells develop from progenitors in the bone marrow that mature either there or after recruitment to tissue sites
• Development occurs under the influence of stem cell factor interacting with the Kit tyrosine kinase receptor on mast cell surfaces
• The capacity for activation and mediator release varies among different types of mature and immature mast cells 1

Activation Pathways

Mast cell activation in MCAS can occur through several mechanisms:

1. Receptor-mediated activation:

   • FcεRI and FcγRI/IIa receptors (antibody-mediated)
   • G protein-coupled receptors
   • Complement anaphylatoxin receptors
   • Mas-related G protein receptors
   • Toll-like receptors 1

2. Mediator release profile:

   • Different activation pathways lead to differential secretion of:
     • Preformed granule mediators (tryptase, histamine)
     • Newly generated mediators (prostaglandins, leukotrienes) 1

Classification of MCAS

MCAS can be categorized into three main types based on etiology:

1. Primary MCAS:

   • Associated with KIT-mutated, clonal mast cells
   • Includes systemic mastocytosis with MCAS features
   • Clonal MCAS with KIT mutations and/or aberrant CD25 expression 1, 2

2. Secondary MCAS:

   • Normal mast cells activated by external triggers
   • Often IgE-dependent allergies
   • Other inflammatory or reactive conditions 1, 2, 3

3. Idiopathic MCAS:

   • Neither a trigger nor genetic trait/mutation identified
   • Diagnosis of exclusion after ruling out primary and secondary causes 1, 2, 3

Pathophysiologic Features

Mediator Release and Effects

• Key mediators involved:

  • Tryptase
  • Histamine
  • Prostaglandin D2 (PGD2)
  • Leukotriene C4 (LTC4)
  • Metabolites: N-methylhistamine, 11β-PGF2α, LTD4/LTE4 1

• Organ system effects:

  • Cardiovascular: hypotension, tachycardia, syncope
  • Dermatologic: urticaria, pruritus, flushing, angioedema
  • Respiratory: wheezing, shortness of breath, stridor
  • Gastrointestinal: abdominal pain, diarrhea, nausea, vomiting 1

Triggers and Potentiating Factors

Common triggers that may precipitate mast cell activation include:

• Hot water
• Alcohol
• Medications
• Psychological stress
• Exercise
• Hormonal fluctuations
• Infections
• Physical stimuli (pressure, friction) 1

Genetic and Molecular Aspects

• Hereditary α-tryptasemia: Associated with increased copy numbers of the TPSAB1 gene encoding α-tryptase, which can contribute to MCAS symptoms 1, 2

• KIT mutations: Present in primary MCAS but absent in idiopathic MCAS 2, 3

• Mast cell releasability: Varies between individuals and may be influenced by genetic factors affecting mast cell stability and activation thresholds 2, 3

Pathophysiologic Distinction from Other Conditions

It's important to distinguish MCAS from:

• Systemic mastocytosis: Features clonal proliferation of mast cells with KIT D816V mutation and consistently elevated baseline tryptase (>20 ng/mL in 75% of cases) 1

• Allergic reactions: Typically have identifiable triggers and IgE-mediated mechanisms 1, 4

• Other inflammatory conditions: May have overlapping symptoms but different underlying mechanisms 4

Clinical Implications of Pathophysiology

The understanding of MCAS pathophysiology guides management:

• Targeting specific mediator pathways based on which mediators are elevated during reactions
• Using mast cell stabilizers to prevent degranulation
• Avoiding identified triggers that initiate the pathophysiologic cascade 1, 5

The complex pathophysiology of MCAS often involves multiple factors acting together, which explains why many patients require combination therapy approaches targeting different aspects of mast cell activation and mediator release 2, 3.