Hi Friend
In the landscape of complex chronic illness, few comorbidities are as prevalent—or as clinically challenging—as the intersection of Hypermobile Ehlers-Danlos Syndrome (hEDS) and Mast Cell Activation Syndrome (MCAS).
For years, patients and specialists noted the overlap anecdotally. Now, the scientific literature is beginning to catch up, proposing mechanisms for why a connective tissue disorder would trigger an immunological response.
In this edition, we are removing the conjecture and looking at the current scientific understanding of the hEDS/MCAS interface.
🧬 Pathophysiology: The "Mechanotransduction" Theory
Why do patients with collagen defects often present with systemic inflammation? The prevailing hypothesis focuses on the Extracellular Matrix (ECM) and a process called mechanotransduction.
The Mechanism:
Mast cells are resident immune cells embedded within connective tissue. They adhere to the ECM (the structural scaffold of the body) using cellular anchors called integrins.
In hEDS, the ECM is structurally compromised and lax. Current research suggests that this laxity alters the mechanical forces exerted on the mast cells. When the connective tissue stretches beyond normal physiological limits, it pulls and distorts the mast cells attached to it.
The Reaction:
This physical deformation is interpreted by the mast cell as a "danger signal." Through mechanotransduction (converting physical force into biochemical signals), the mast cell degranulates, releasing mediators like histamine, prostaglandins, and cytokines.
The Takeaway:
In hEDS patients, MCAS may not just be a random co-occurrence; it may be a direct result of the structural instability "agitating" the immune system.
🧪 Clinical Manifestations: The Overlap
Distinguishing between hEDS symptoms and MCAS symptoms can be difficult because the systemic inflammation from MCAS often exacerbates hEDS pain.
Key Areas of Convergence:
Gastrointestinal: hEDS can cause structural dysmotility (gastroparesis), while MCAS can cause functional inflammation (reactions to food compounds). The combination often results in severe visceral hypersensitivity.
Dermatological: Patients often present with "dermatographia" (skin writing). While often attributed to hEDS skin fragility, the raised, red wheal is actually a histamine response driven by mast cells reacting to the pressure.
Neurological: "Brain fog" in this cohort is often attributed to neuroinflammation caused by cytokines crossing the blood-brain barrier, exacerbated by the poor blood flow regulation seen in POTS (a common third comorbidity).
🛡️ Management Strategies: Reducing the Total Load
Because the genetic collagen defect cannot currently be fixed, management of the hEDS/MCAS patient focuses on stabilizing the mast cells to reduce systemic inflammation.
1. Pharmacological Blockade
The standard clinical protocol often involves a multi-step approach:
H1 and H2 Blockers: Blocking histamine receptors (e.g., cetirizine and famotidine) to prevent end-organ reaction.
Mast Cell Stabilizers: Agents like Cromolyn Sodium or Ketotifen that work to strengthen the mast cell membrane, preventing degranulation before it starts.
Leukotriene Inhibitors: Medications like Montelukast that target specific inflammatory pathways often active in MCAS.
2. Environmental & Physical Controls
Vibration and Temperature: Because of the mechanotransduction link, physical vibration (like heavy machinery or rough car rides) and extreme temperature changes can physically trigger mast cells in hEDS patients.
Excipient Awareness: Many hEDS patients react to medications not because of the active drug, but due to fillers (dyes, fillers, binders). Compounded medications are often required to eliminate triggers.
We can help at the mend clinic if you suspect MCAS, appts here
📰 Research Focus: The Tryptase Debate
The Clinical Challenge:
Diagnosing MCAS remains controversial. The "gold standard" has historically been elevated serum tryptase. However, tryptase is a marker of mast cell burden (how many cells you have), not necessarily activation (how active they are).
The Shift:
Recent consensus discussions indicate that many hEDS/MCAS patients present with normal tryptase levels but elevated urinary mediators (such as N-Methylhistamine or Prostaglandin D2).
Note for patients: If you suspect MCAS but have a normal tryptase test, clinical diagnosis based on the "Consensus-2" criteria (symptoms in 2+ systems + response to treatment) is becoming widely accepted among specialists.
🦓 Patient Perspective
"Understanding that my joint instability was physically irritating my immune system was the turning point. It shifted my focus from just 'bracing my joints' to 'calming my system.' Treating the inflammation actually reduced my daily pain levels more than painkillers ever did."
If you suspect MCAS i can see patients privatelyt and hlep diagnmose/treat
Stay Well
Dr Ahmed
