Mast Cell Activation (MCA), Fibromyalgia, and Ehlers-Danlos Syndrome (EDS): The Overlapping Connection

By SWA

 

Mast Cell Activation (MCA), Fibromyalgia (FM), and Ehlers-Danlos Syndrome (EDS) are three conditions that often co-occur, suggesting an underlying immune and connective tissue dysfunction. Understanding their relationship may help improve diagnosis and treatment for individuals experiencing overlapping symptoms.

Mast Cell Activation (MCA) and Its Role in the Body

Mast cells are immune cells found in tissues like the skin, lungs, gut, and blood vessels. They play a key role in allergic reactions and immune defense. Mast Cell Activation (MCA) occurs when these cells release inflammatory mediators such as histamine, tryptase, prostaglandins, and cytokines in response to triggers.

Types of Mast Cell Activation

  • Normal Activation: Occurs in response to allergens, infections, or injury.
  • Abnormal Activation: Leads to excessive inflammation, as seen in Mast Cell Activation Syndrome (MCAS) or mastocytosis.

Symptoms of MCA and MCAS

  • Flushing, hives, skin rashes
  • Low blood pressure, dizziness
  • Anaphylaxis (severe allergic reactions)
  • Digestive issues (nausea, bloating, diarrhea)
  • Brain fog, fatigue, and headaches
  • Temperature sensitivity
  • Chronic pain and inflammation

Allergy and the Immune System’s Role in MCA

An allergy is an exaggerated immune response to harmless substances (allergens) like pollen, food, or pet dander.

How MCA Contributes to Allergies

  1. Sensitization: The immune system mistakenly identifies an allergen as dangerous.
  2. IgE Production: B cells produce Immunoglobulin E (IgE) antibodies specific to the allergen.
  3. Mast Cell Binding: IgE attaches to mast cells, priming them for future reactions.
  4. Allergic Reaction: On re-exposure, mast cells release histamine, causing symptoms like sneezing, swelling, or anaphylaxis.

Common Allergies Associated with MCA

  • Food allergies
  • Drug allergies
  • Asthma
  • Hay fever
  • Anaphylaxis

Fibromyalgia and Mast Cell Activation: The Connection

Fibromyalgia (FM) is a chronic condition characterized by widespread pain, fatigue, brain fog, and sleep disturbances. Emerging research suggests that mast cell activation may play a significant role in fibromyalgia symptoms.

How Mast Cells Contribute to Fibromyalgia Symptoms

  • Chronic Pain: Histamine and cytokines sensitize nerve endings.
  • Fatigue: Inflammatory mediators disrupt mitochondrial function.
  • Brain Fog: Mast cells in the brain may contribute to neuroinflammation.
  • Sleep Disturbances: Histamine affects the sleep-wake cycle.
  • Digestive Issues (IBS-like symptoms): Mast cells in the gut may drive symptoms of irritable bowel syndrome (IBS), which is common in FM.

MCAS and Fibromyalgia Symptom Overlap

Many fibromyalgia patients exhibit symptoms consistent with Mast Cell Activation Syndrome (MCAS), such as:

  • Flushing, skin rashes, itching
  • Gastrointestinal discomfort (nausea, bloating, diarrhea)
  • Tachycardia and dizziness (linked to POTS – Postural Orthostatic Tachycardia Syndrome)
  • Temperature sensitivity and headaches

Potential Triggers for Mast Cell Activation in Fibromyalgia

  • Chronic stress (cortisol dysregulation can activate mast cells)
  • Infections (e.g., Lyme disease, Epstein-Barr virus)
  • Food intolerances (histamine-rich foods, gluten, dairy, etc.)
  • Environmental toxins (mold, chemicals, fragrances)

Ehlers-Danlos Syndrome (EDS) and MCA: A Common Comorbidity

Ehlers-Danlos Syndrome (EDS) is a group of connective tissue disorders that affect collagen production, leading to joint hypermobility, skin fragility, and chronic pain. The most common subtype associated with MCA is Hypermobile EDS (hEDS).

How MCA and EDS Are Connected

  1. Collagen Weakness in EDS

    • Mast cells reside in connective tissues and can be overactivated in individuals with weak collagen.
    • This may explain why MCAS is frequently seen in EDS patients.

  2. Dysautonomia and POTS

    • Many EDS patients also have Postural Orthostatic Tachycardia Syndrome (POTS), a form of dysautonomia (nervous system dysfunction).
    • POTS is closely linked to MCAS, as mast cells can contribute to blood pressure instability and increased heart rate.

  3. Chronic Pain and Inflammation

    • In both EDS and fibromyalgia, excessive mast cell activation may drive pain and inflammation.

  4. Gastrointestinal Issues

    • Many EDS patients experience gut dysmotility, IBS, and food intolerances due to mast cell overactivity in the gastrointestinal tract.

Treatment Approaches for MCA, Fibromyalgia, and EDS

Since mast cell activation plays a significant role in all three conditions, managing MCA symptoms can help improve overall quality of life.

1. Medications

  • Antihistamines (H1 & H2 blockers) – Reduce histamine-related symptoms.
  • Mast cell stabilizers (Cromolyn sodium, Ketotifen, Quercetin) – Prevent excessive mast cell activation.
  • Low-dose naltrexone (LDN) – Reduces chronic pain and inflammation.

2. Diet and Lifestyle Modifications

  • Low-histamine diet – Reduces histamine burden in the body.
  • DAO enzyme supplements – Help break down histamine in the gut.
  • Anti-inflammatory supplements (Curcumin, Omega-3s, Vitamin C) – Help regulate immune responses.

3. Managing Coexisting Conditions

  • POTS treatment (increasing salt and fluid intake, compression garments, beta-blockers)
  • Physical therapy for EDS to strengthen muscles and protect joints

There is no single definitive test for Mast Cell Activation Syndrome (MCAS), but the most effective approach involves a combination of clinical evaluation, lab tests, and symptom response to treatment.

1. Best Lab Tests for MCAS Diagnosis

Since mast cell mediators are released episodically and break down quickly in the body, timing and proper sample handling are crucial for accurate testing. The most useful tests include:

A. Mast Cell Mediator Tests

  • Serum Tryptase (measured during and after a flare)

    • Elevated levels suggest mast cell activation.
    • Baseline tryptase ≥ 11 ng/mL may indicate systemic mastocytosis rather than MCAS.
    • A rise of ≥ 20% + 2 ng/mL from baseline during symptoms supports MCAS.

  • Urinary N-Methylhistamine (24-hour or random sample)

    • A stable histamine metabolite that indicates mast cell activation.

  • Plasma Histamine

    • Must be drawn and processed quickly due to rapid degradation.

  • Prostaglandin D2 (PGD2) or its metabolite (11-β-PGF2α) in urine

    • PGD2 is a key mast cell mediator involved in inflammation and vasodilation.

  • Leukotriene E4 (Urine)

    • Elevated levels suggest excessive mast cell activity.

B. Other Supporting Tests

  • Heparin (Plasma or Urine)
    • Can indicate mast cell activation, but must be carefully handled.
  • Chromogranin A
    • Can be elevated in mast cell disorders but also in other conditions.

2. Other Diagnostic Criteria

  • Symptom History: Symptoms affecting two or more organ systems (skin, GI, cardiovascular, neurological, respiratory).
  • Response to Mast Cell Medications: Improvement with antihistamines (H1/H2 blockers), mast cell stabilizers (Cromolyn, Ketotifen), or leukotriene inhibitors supports MCAS.

3. Best Overall Approach

Since lab tests can be inconsistent, a combination of positive biomarkers, symptom patterns, and treatment response provides the strongest evidence for MCAS. If initial tests are inconclusive, repeating them during a flare increases the chance of detection.

 

Conclusion: The Interconnected Nature of MCA, FM, and EDS

The overlapping symptoms of Mast Cell Activation Syndrome (MCAS), Fibromyalgia (FM), and Ehlers-Danlos Syndrome (EDS) suggest a shared pathophysiology, possibly involving immune dysregulation, connective tissue dysfunction, and nervous system involvement.

By identifying and managing mast cell activation, many individuals with fibromyalgia and EDS can experience symptom relief and an improved quality of life. Research is still ongoing, but the recognition of these conditions as interconnected is an essential step toward better diagnosis and treatment options.

Next Steps

If you suspect you have MCAS, fibromyalgia, or EDS, consider:
✅ Consulting a mast cell specialist, immunologist, or rheumatologist
✅ Keeping a symptom and food diary to track potential triggers
✅ Trying a low-histamine diet to see if symptoms improve
✅ Exploring medications or natural mast cell stabilizers

Dr. Maitland is considered one of the thought leaders in the emerging field of mast cell disorders. She currently serves on the medical and scientific advisory boards of the Ehlers-Danlos Society, the Mastocytosis Society, and the Bobby Jones Chiari & Syringomyelia Foundation. She is the former Past Chair of the Committee for the Underserved and the current Vice Chairperson for the Mast Cell Disorders Committee of the American Academy of Allergy, Asthma, and Immunology. She is also a member of the Allergy and Immunology Faculty of the National Medical Association.
https://www.youtube.com/watch?v=xGZIojcrjbY&t=1231s

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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