Do Postural Orthostatic Tachycardia Syndrome (POTS) and Mast Cell Activation Syndrome (MCAS) contribute to fatigue?

Do POTS and MCAS Cause Fatigue?

Yes, both Postural Orthostatic Tachycardia Syndrome (POTS) and Mast Cell Activation Syndrome (MCAS) are established causes of fatigue, and managing these conditions is critical because fatigue significantly impairs daily function and quality of life in otherwise healthy individuals.

POTS as a Direct Cause of Fatigue

• Fatigue is one of the most common and disabling symptoms in POTS, occurring alongside orthostatic intolerance, exercise intolerance, and postexertional malaise 1, 2.
• The syndrome predominantly affects young women (approximately 80% of cases) and can severely impair daily activity and quality of life 3.
• POTS is characterized by excessive tachycardia upon standing (heart rate increase ≥30 beats/min within 10 minutes) accompanied by symptoms including weakness, lightheadedness, and profound fatigue 1.
• Fatigue in POTS is multifactorial and requires an individualized assessment to identify the specific mechanisms contributing to each patient's symptoms 4.

MCAS as a Direct Cause of Fatigue

• MCAS causes systemic symptoms affecting at least 2 organ systems through the release of inflammatory mediators including histamine, prostaglandin D2, and leukotriene C4 5.
• These inflammatory mediators produce widespread effects including fatigue, along with flushing, urticaria, wheezing, gastrointestinal symptoms, and cardiovascular manifestations 1, 5.
• The episodic nature of mast cell degranulation leads to recurrent symptomatic flares that include fatigue as a prominent feature 1.

The Critical Overlap Between POTS and MCAS

• 42% of patients initially diagnosed with POTS also exhibit laboratory findings suggesting MCAS, particularly when they present with additional nonorthostatic symptoms such as migraine, allergic complaints, skin rash, or gastrointestinal symptoms 6.
• Among patients with both POTS and hypermobile Ehlers-Danlos syndrome (hEDS), 31% have concurrent MCAS, representing a 32-fold increased odds compared to patients without POTS and EDS 7.
• This overlap is clinically significant because viral infections can trigger both POTS and MCAS, with 42% of POTS cases preceded by viral illness 1.

Why Managing Both Conditions Is Essential

Impact on Morbidity and Quality of Life

• Untreated POTS and MCAS cause substantial functional impairment in young, otherwise healthy individuals who should be at peak productivity 3, 2.
• The constellation of fatigue, exercise intolerance, postexertional malaise, and cognitive impairment (brain fog) severely limits work capacity and daily activities 1, 2.
• Chronic symptoms lasting more than 6 months can lead to profound disability if not properly diagnosed and treated 1.

Diagnostic Imperative

• Failure to diagnose MCAS in POTS patients leads to inadequate treatment because the conditions require different therapeutic approaches 6.
• When patients with POTS present with additional symptoms including gastrointestinal complaints, allergic manifestations, or skin symptoms, testing for MCAS should be performed 1, 6.
• Serum tryptase levels should be collected at baseline and 1-4 hours following symptom flares, with increases of 20% above baseline plus 2 ng/mL considered diagnostic 1.
• Additional biochemical markers including prostaglandins and histamine metabolites should be measured when MCAS is suspected 6.

Treatment Approach

For POTS Management:

• Begin with patient education and non-pharmacologic interventions including increased fluid and salt intake 2.
• Address orthostatic symptoms with postural maneuvers and compression garments 2.
• Consider pharmacologic treatment for specific symptoms, though no FDA-approved medications exist specifically for POTS 2.

For MCAS Management:

• Initiate treatment with H1 and H2 histamine receptor antagonists as first-line therapy 5.
• Add leukotriene receptor antagonists and COX inhibitors for patients with inadequate response 5.
• Consider mast cell stabilizers for refractory cases 1.
• Implement dietary interventions including low-histamine diets with appropriate nutritional counseling to avoid restrictive eating patterns 5, 8.

For Overlapping POTS and MCAS:

• Treat both conditions simultaneously because managing only one will leave significant symptoms unaddressed 6.
• Refer to allergy specialists or mast cell disease research centers when MCAS is confirmed through clinical and laboratory findings 1.
• Consider autonomic function testing including tilt table testing to fully characterize the POTS component 1, 9.

Common Pitfalls to Avoid

• Do not attribute all symptoms to POTS alone when patients present with gastrointestinal, allergic, or dermatologic manifestations that suggest MCAS 6.
• Avoid delaying MCAS testing in POTS patients with nonorthostatic symptoms, as early diagnosis allows for targeted treatment 6.
• Do not implement restrictive diets without nutritional counseling, as patients with both conditions are at risk for inadequate nutrition 8.
• Recognize that opioid medications should be avoided in patients with chronic pain associated with these conditions, as they can worsen gastrointestinal symptoms and fatigue 1.