Millions of people live with debilitating symptoms like chronic fatigue, unexplained allergies, intolerances, and pain that are difficult to trace to a specific condition. For some, the answer lies in Mast Cell Activation Syndrome (MCAS)—a complex and often overlooked disorder. But despite growing awareness, MCAS is widely misdiagnosed, or worse, dismissed altogether. Why?

This post explores the reasons behind frequent misdiagnosis of MCAS, its connections to conditions like Ehlers-Danlos Syndrome (EDS) and Postural Orthostatic Tachycardia Syndrome (POTS), and why understanding histamine’s role is crucial. We’ll also shed light on how integrative and functional medicine offers new insights to help patients seek accurate diagnoses and effective care.

What is MCAS?

Mast Cell Activation Syndrome (MCAS) occurs when mast cells, a type of immune cell, become overly reactive. Mast cells are responsible for releasing histamine and other chemicals during allergic reactions, but in MCAS, these cells unpredictably release mediators, resulting in widespread inflammation and symptoms (1).

People with MCAS may experience:

  • Chronic fatigue
  • Recurrent rashes or hives
  • Abdominal pain, bloating, or diarrhea
  • Brain fog or difficulty concentrating
  • Headaches or migraines
  • Respiratory symptoms, like wheezing or congestion
  • Heart palpitations or dizziness
  • Sensitivity to food, odors, or medications

The symptoms vary widely, depending on which body systems or organs are affected. That variability, coupled with limited awareness among patients (and many conventional healthcare professionals), makes MCAS challenging to diagnose.

Why is MCAS Often Misdiagnosed?

Overlapping Symptoms with Other Disorders 

One major obstacle in diagnosing MCAS is its similarity to other conditions. The symptoms—digestive issues, skin reactions, fatigue, or heart irregularities—mimic those seen in gastrointestinal disorders, autoimmune diseases, and even anxiety (2,3).

Patients are often misdiagnosed with:

These label treatments only scratch the surface, leaving the root cause unchecked.

Lack of Standardized Diagnostic Criteria 

Unlike conditions like diabetes (where diagnostic tests and markers are widely accepted), MCAS lacks universal diagnostic criteria. Testing for mast cell mediators such as tryptase or histamine levels can be inconsistent, as levels may fluctuate or appear normal outside flare-ups (4). This variability often results in dismissals or inconclusive diagnosis.

Limited Awareness Among Many Conventional Physicians 

MCAS is still underrepresented in Western medical training programs. Mainstream doctors often miss the complexity of mast cell disorders, and many are not trained to recognize their full spectrum of symptoms, despite research showing that nearly 17% of the general population experiences MCAS symptoms (5). 

While allergists and immunologists may lead the charge, MCAS is better understood through a multidisciplinary approach involving gastroenterologists, neurologists, and functional medicine practitioners especially.

Histamine Intolerance Muddles the Picture 

The connection between histamine and MCAS adds another layer to the confusion. Histamine intolerance, where the body accumulates excess histamine due to enzyme deficiencies, shares many symptoms with MCAS. However, the two conditions require different treatments, and failure to differentiate them may lead to mismanagement (3).

Related: When Everyday Scents Become Overwhelming—Understanding Multiple Chemical Sensitivity

One of the most intriguing discoveries in functional medicine is the growing connection between MCAS and hypermobility disorders, such as Ehlers-Danlos Syndrome (EDS). Research suggests a higher prevalence of MCAS in patients with joint hypermobility, and many who have EDS endure unexplained symptoms, such as allergic-like reactions or nervous system dysregulation (6).

Similarly, Postural Orthostatic Tachycardia Syndrome (POTS)—characterized by dizziness, fainting, and heart rate irregularities upon standing—is another condition frequently co-existing with MCAS. Up to 30% of POTS patients exhibit mast cell involvement (7). 

Here’s why these disorders are interlinked:

1. Collagen Disorders in EDS 

EDS is characterized by faulty collagen—a protein found in skin, connective tissue, and blood vessels. Insufficient collagen support might make barriers like intestinal and vascular walls more permeable or “leaky,” increasing the chance of mast cell dysfunction.

2. Autonomic Nervous System Dysfunction in POTS 

POTS affects the autonomic nervous system, which regulates involuntary processes like heart rate and digestion. Dysautonomia may trigger mast cell hyperreactivity, causing episodes of inflammation or allergic reactions (5).

3. Immune System Dysregulation Across All Three Conditions 

Both MCAS and linked conditions involve hyperactivation of the immune system. This hyperactivity encourages an overload of immune signals, such as histamine, intensifying systemic inflammation and worsening symptoms.

Recognizing these connections is key for refining diagnostic efforts.

The Role of Histamine in MCAS 

Histamine plays an integral role in both MCAS and associated conditions. Mast cells release histamine as part of the immune defense mechanism, but when its regulation goes awry, it wreaks havoc on the body.

Histamine triggers in MCAS patients may include:

  • High-histamine foods (e.g., aged cheeses, alcohol, or fermented foods)
  • Stress or hormonal changes
  • Extreme temperatures or environmental chemicals

Patients often adopt low-histamine diets to reduce MCAS symptoms, emphasizing fresh, unprocessed foods while avoiding known triggers like tomatoes, cured meats, or certain spices.

Shop: Digest histamine fast with the patented DAO2 enzyme.

The Histamine-Methylation Connection 

Functional medicine has introduced the “histamine bucket” analogy, comparing high histamine levels to an overflowing bucket (8). Genetics play a role—mutations in the DAO enzyme (responsible for breaking down dietary histamine) or methylation-cycle inefficiencies may worsen histamine clearance, amplifying MCAS activity (9).

Individualized histamine regulation strategies can empower patients to regain control.

How Integrative & Functional Medicine is Changing Diagnosis and Care 

Unlike conventional medicine, which often treats individual symptoms, functional medicine adopts a root-cause approach. It considers how genetics, lifestyle, and environmental factors interact to affect overall health, making it an ideal lens for understanding MCAS.

Here’s how functional medicine stands out for MCAS patients:

  • Personalized Testing: Functional practitioners utilize tailored tests (e.g., urinary histamine metabolites, DAO activity) to pinpoint mast cell involvement.
  • Holistic Treatment Plans: Beyond medications like antihistamines, treatment involves low-histamine diets, stress-reduction therapy, gut health repair, and high-quality supplements (e.g., quercetin or vitamin C).
  • Focus on Comorbidities: Functional approaches recognize that treating EDS, POTS, or histamine intolerance alongside MCAS improves outcomes.

Read: The Benefits of Quercetin & Other Natural Antihistamines

Steps Toward an Accurate Diagnosis and Better Management 

If you suspect MCAS but are struggling with misdiagnoses, here are actionable tips:

Document Symptoms: Keep a journal to note potential triggers, foods, or stress levels linked to flare-ups.

Schedule Integrative Appointments: Seek integrative healthcare professionals with experience in mast cell disorders, such as integrative allergists or functional medicine practitioners.

Request Specialized Testing: Advocate for comprehensive histamine metabolite screenings or DAO testing if relevant.

Functional medicine’s capacity to identify and address root causes makes it a beacon of hope for MCAS sufferers—Contact a provider at CentreSpringMD now!

Crafting a Path Forward 

The challenges of living with an underdiagnosed condition like MCAS are immense. Misdiagnoses delay effective treatments and force patients into a cycle of unnecessary medications and frustration. However, emerging research and insights into linked conditions like EDS, POTS, and histamine intolerance are helping more patients find relief.

We encourage you to explore integrative and functional medicine’s potential to clarify your symptoms and improve your quality of life. If your symptoms point toward MCAS, don’t settle for answers that feel incomplete—your health deserves holistic attention. Looking for personalized care? Consider consulting with an integrative practitioner for expert guidance on symptom management and testing. Together, we can reimagine your path toward wellness.