How Is MCAS Diagnosed?

How Is MCAS Diagnosed? A Comprehensive Guide to Mast Cell Activation Syndrome

Mast Cell Activation Syndrome (MCAS) has become increasingly recognised over the past two decades, yet it remains challenging to diagnose because its symptoms can look like many other conditions. Understanding how MCAS is diagnosed requires knowing what this syndrome is, how it affects the body, and the specific criteria doctors use to identify it accurately.

What Is MCAS?

Mast Cell Activation Syndrome is a condition where certain immune cells called mast cells become overactive and release chemicals that cause severe, recurring symptoms throughout the body. To understand MCAS, it helps to first understand what mast cells do normally.

Mast cells are immune cells that live in tissues throughout your body—in your skin, digestive tract, lungs, and other organs. They act as part of your body’s defence system and play an important role in allergic reactions. When mast cells detect a threat (like an allergen you’re allergic to), they release stored chemical messengers called mediators. These include histamine (the chemical that antihistamines block), along with other substances like tryptase, prostaglandins, and leukotrienes. This is one of the thing that differentiates it from histamine intolerance. MCAS is not just about histamine, but dozens of other substances.

In a normal allergic reaction, this release is controlled and proportionate to the threat. In MCAS, however, mast cells release these chemicals too easily, too often, or in excessive amounts, causing severe symptoms that can affect multiple body systems at once.

The severity of MCAS depends on several factors: how many mast cells are involved, how easily they’re triggered (called “releasability”), which organs are affected, and whether you have other health conditions that make you more sensitive to these reactions.

It’s important to understand that not all mast cell activation means you have MCAS. The syndrome specifically refers to severe, recurring, body-wide episodes that meet established medical criteria. To be diagnosed with MCAS, you need all three of these things: typical severe symptoms affecting at least two body systems, laboratory proof that mast cells are involved (usually through a blood test for tryptase), and improvement when taking medications that block mast cell activity or the chemicals they release.

Types of MCAS

Doctors classify MCAS into three main categories based on what’s causing it:

Primary (Clonal) MCAS happens when you have abnormal mast cells that carry genetic mutations—most commonly a mutation called KIT D816V. Think of these as “faulty” mast cells that behave differently than normal ones. Some people with this type have an underlying condition called mastocytosis, where too many mast cells build up in the body. Others have these abnormal mast cells without quite meeting the criteria for mastocytosis. These abnormal cells can be identified because they display a protein marker called CD25 on their surface.

Secondary MCAS occurs when an underlying condition triggers excessive mast cell activation, but the mast cells themselves are normal—they’re just responding too strongly to triggers. The most common cause is severe IgE-mediated allergies (the type of allergy that involves IgE antibodies and can cause anaphylaxis). Other inflammatory conditions or repeated exposures to allergens can also cause secondary MCAS. In this type, the mast cells are working as designed, but external factors are causing them to overreact.

Idiopathic MCAS is diagnosed when you meet all the criteria for MCAS but doctors can’t find an underlying cause—no abnormal mast cells and no obvious triggers. “Idiopathic” is a medical term meaning “of unknown cause.” These patients need ongoing evaluation because sometimes an underlying cause becomes clear over time.

Some patients have overlapping forms. For example, someone with mastocytosis (abnormal mast cells) who also has severe bee sting allergies faces particularly high risks of life-threatening reactions and needs specialised treatment tailored to both conditions.

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Conditions Associated with MCAS

Several conditions increase your risk of developing MCAS or commonly occur alongside it:

Mastocytosis is a disorder where too many mast cells accumulate in your tissues. People with systemic mastocytosis (where mast cells build up throughout the body, not just the skin) are at increased risk for severe mast cell activation events, especially if they also have severe allergies like bee or wasp venom allergy.

Hereditary Alpha Tryptasemia (HAT) is a genetic condition you can inherit from your parents. People with HAT have extra copies of the gene that makes alpha-tryptase (one of the chemicals mast cells release), so their baseline tryptase levels are naturally elevated. They may experience symptoms involving multiple body systems and are at higher risk for more severe reactions when they have anaphylaxis, allergies, or mastocytosis. HAT is more common in people with systemic mastocytosis than in the general population.

Severe IgE-mediated allergies are the most common condition associated with secondary MCAS. These are classic allergies—to insect stings, foods, or medications—that can trigger body-wide (systemic) anaphylactic reactions severe enough to meet MCAS criteria.

Clinical Symptoms of MCAS

The symptoms of MCAS can affect nearly every part of your body and range from uncomfortable to life-threatening. Understanding the typical patterns helps doctors suspect MCAS, though symptoms alone can never confirm the diagnosis—lab tests are essential.

Typical Acute Symptoms During Flares

When mast cells suddenly release their chemical mediators, you might experience: sudden hives, flushing (red, warm skin), intense itching, headaches, abdominal cramping, diarrhoea, breathing difficulties, and dangerously low blood pressure. When multiple symptoms occur together—particularly affecting two or more body systems—and improve with medications that block mast cell chemicals, mast cell activation becomes more likely.

Cardiovascular (Heart and Blood Vessel) Symptoms

Problems with blood pressure and circulation are particularly significant in MCAS. The chemicals released by mast cells—especially histamine, prostaglandin D2, and leukotrienes—can cause blood vessels to dilate (widen), leading to a dangerous drop in blood pressure. This can cause you to feel dizzy, lightheaded, or even faint (called syncope). Your heart may race (tachycardia) as it tries to compensate. In severe cases, this can lead to anaphylactic shock, a medical emergency.

Skin Symptoms

Skin reactions are common and include urticaria (hives—raised, itchy welts), flushing (sudden redness and warmth), severe itching, and angioedema (swelling of deeper skin layers, often around the eyes and lips). If you have underlying mastocytosis, you might also have characteristic brown skin spots or patches.

Gastrointestinal (Digestive System) Symptoms

Your digestive tract can be significantly affected. Histamine and other mast cell chemicals can cause your stomach to produce too much acid, leading to heartburn or even ulcers. You might experience severe cramping and abdominal pain, diarrhea, nausea, and bloating—all driven by the chemicals mast cells release.

Respiratory (Breathing) Symptoms

In your airways, mast cell mediators can cause nasal congestion, wheezing, throat tightness or swelling, increased mucus production, and bronchoconstriction (tightening of airways that makes it hard to breathe). In severe cases, you might develop pulmonary oedema (fluid in the lungs).

Other Symptoms

You might also experience headaches, nausea, fever and chills, neurological symptoms, and fatigue. However—and this is important—vague symptoms like chronic fatigue, poor sleep, and generalised pain by themselves don’t meet MCAS criteria and could be caused by many other conditions that need proper evaluation.

The Diagnostic Process: A Step-by-Step Approach

Diagnosing MCAS requires a systematic approach following an established algorithm. The goal is to confirm mast cell involvement, determine severity, identify underlying causes, and rule out other conditions with similar symptoms.

Step 1: Assessing Your Symptoms

The diagnostic process begins when you have symptoms suggesting mast cell activation—particularly severe, recurring episodes affecting multiple body systems. Your doctor needs to determine whether your symptoms are severe enough to suggest MCAS. If your reactions aren’t severe, MCAS is less likely, though milder forms of mast cell activation might still be present.

The presence of low blood pressure (hypotension) combined with other typical signs is particularly significant because nearly all MCAS cases involve problems with blood pressure during acute episodes.

Step 2: Laboratory Testing to Confirm Mast Cell Involvement

This is the cornerstone of MCAS diagnosis—you need objective laboratory evidence that mast cells are involved. Simply having symptoms that might be related to mast cell activation isn’t enough.

Serum Tryptase Testing

Tryptase is a protein enzyme that mast cells store and release. It’s considered the most specific marker for mast cell involvement because mast cells contain over 100 times more tryptase than basophils (another type of immune cell that can cause similar symptoms). Here’s how the testing works:

1. Baseline tryptase measurement: This blood test must be done at least 24-48 hours after all your symptoms have completely resolved. This establishes your normal, personal baseline level. Everyone’s baseline is different.
2. Acute tryptase measurement: Blood should be drawn 1-4 hours after symptoms begin, when tryptase levels peak.
3. Applying the diagnostic formula: Doctors use a specific calculation called the “20% + 2 formula” to determine if your increase is significant. The formula is: baseline × 1.2 + 2.

Here’s an example: If your baseline tryptase is 10 ng/mL (the measurement unit), multiply by 1.2 (equals 12) and add 2 (equals 14). Your acute level must be higher than 14 ng/mL to be diagnostic. This formula has been validated in multiple research studies and works for everyone regardless of their baseline level.

Other Markers

When tryptase testing isn’t available or results are unclear, other tests can provide supporting evidence:

• Histamine and its breakdown products: Can be measured in blood plasma or urine, though these are less specific because other cells also produce histamine.
• Prostaglandin D2 breakdown products: Can be measured in a 24-hour urine collection. This test is more specific for mast cells because prostaglandin D2 is primarily made by mast cells, not basophils.
• Leukotriene E4: Can be measured in urine and may also support the diagnosis.

While there aren’t validated thresholds for these alternative markers like there are for tryptase, they can be helpful when tryptase testing isn’t possible.

Step 3: Treatment Response

The third criterion requires that your symptoms improve with medications targeting mast cell activation. This includes:

• Antihistamines (H1 blockers like diphenhydramine or cetirizine, and H2 blockers like famotidine)
• Mast cell stabilisers (like cromolyn sodium, which prevents mast cells from releasing their chemicals)
• Leukotriene inhibitors (like montelukast)
• Medications that block prostaglandin production (like aspirin in some cases)
• Corticosteroids (like prednisone)

A positive response to these medications supports the diagnosis, but this criterion must be combined with the symptom pattern and laboratory evidence—treatment response alone isn’t enough.

Step 4: Finding the Underlying Cause

Once MCAS is confirmed, determining what’s causing it is crucial for proper treatment.

Screening for Primary MCAS (Abnormal Mast Cells)

Warning signs that suggest underlying clonal mast cell disease include:

• Consistently high baseline tryptase (above 20 ng/mL)
• Skin spots or patches characteristic of mastocytosis
• Detection of the KIT D816V genetic mutation in a blood sample
• Unexplained osteoporosis (bone thinning), elevated eosinophils (a type of white blood cell), or persistent digestive symptoms

When these features are present, your doctor might recommend a bone marrow biopsy to diagnose mastocytosis or identify early signs of clonal mast cell disease.

Screening for Secondary MCAS (Triggering Allergies)

Your doctor should conduct detailed allergy testing, including blood tests for specific IgE antibodies to various allergens, and possibly skin prick testing when appropriate. Common triggers include bee and wasp stings, foods, and medications.

Genetic Testing

If your baseline tryptase is 8 ng/mL or higher, your doctor should consider genetic testing for hereditary alpha tryptasemia. This genetic condition affects your baseline tryptase levels and represents an important risk factor for more severe reactions.

Step 5: Ruling Out Other Conditions

MCAS shares symptoms with numerous other conditions, making it essential to consider alternatives. Conditions that can look like MCAS include:

• Heart problems: Heart attacks, aortic valve stenosis, heart rhythm problems
• Hormonal disorders: Low thyroid function, low blood sugar, adrenal insufficiency
• Digestive disorders: Inflammatory bowel disease, certain tumours
• Infections: Severe bacterial or viral infections causing septic shock
• Neurological conditions: Seizure disorders, brain tumours, migraines
• Psychiatric conditions: Panic disorder, somatoform disorders

The key advantage of requiring laboratory confirmation through tryptase testing is that it helps distinguish true MCAS from these other conditions with high accuracy.

Treatment Approaches

Conventional Medical Management

Once diagnosed with MCAS, treatment typically involves several strategies:

Emergency Preparedness

• Carry epinephrine auto-injectors (EpiPens) at all times
• Patients should have at least two auto-injectors and know how to use them
• Wear medical alert jewellery

Daily Preventive Medications Most patients need to take preventive medications every day for life, including:

• H1 and H2 antihistamines (blocking histamine at different receptors)
• Mast cell stabilisers like cromolyn sodium or ketotifen (preventing mast cells from releasing chemicals)
• Leukotriene receptor antagonists like montelukast (blocking leukotriene effects)
• Low-dose aspirin in selected cases (to inhibit prostaglandin production)

Avoiding Triggers It’s critically important to identify and avoid whatever triggers your mast cell activation. This might include specific foods, medications, insect stings, temperature extremes, or physical exertion.

Disease-Specific Therapies

For secondary MCAS with identified allergens: Allergen immunotherapy (allergy shots) is usually recommended for venom-induced anaphylaxis, gradually building tolerance to the allergen.

For primary MCAS with mastocytosis: In patients with high mast cell burden, medications that reduce mast cell numbers might be considered. Newer targeted therapies like midostaurin can block abnormal mast cell growth and prevent them from releasing their chemicals, often rapidly improving symptoms and quality of life.

For combined forms: Omalizumab (Xolair), a medication that blocks IgE antibodies, can be helpful for patients with both MCAS and severe IgE-mediated allergies. Patients with severe mixed MCAS may require multiple medications tailored to their specific situation.

Alternative and Complementary Approaches

Many patients explore complementary approaches alongside conventional treatment. If you’re considering alternative therapies, keep these principles in mind:

1. Never replace essential conventional therapies: Epinephrine and proven mast cell stabilisers can be life-saving
2. Discuss everything with your healthcare provider: Some supplements or dietary changes might interact with medications or trigger mast cell activation
3. Be cautious about unproven claims: Unfortunately, MCAS has attracted some questionable treatments with little scientific evidence

Common complementary approaches patients try include:

• Low-histamine diets (avoiding foods high in histamine or that trigger histamine release)
• Quercetin (a plant compound with natural antihistamine properties)
• Vitamin C (potentially helps stabilise mast cells)
• DAO (diamine oxidase) supplements (an enzyme that breaks down histamine)
• Probiotics.

However, strong scientific evidence for these approaches specifically in MCAS is limited. They should complement—not replace—proven medical treatments. Also please note that some with MCAS react to ingredients that are safe/benign for many. For example some seem to react to Hydroxypropyl methylcellulose – a very common ingredient in supplements (its in the capsule). This is why powders or liquids might be best.

Common Diagnostic Pitfalls

Several issues can complicate MCAS diagnosis:

Over-diagnosis: Many patients referred for suspected MCAS ultimately have other conditions or less severe mast cell activation that doesn’t meet MCAS criteria. Using strict diagnostic criteria helps prevent unnecessary diagnoses and ensures patients receive appropriate treatment for their actual condition.

Under-diagnosis: Conversely, patients with legitimate MCAS may go undiagnosed if blood tests aren’t done at the right times or if doctors aren’t familiar with the condition.

Misinterpreting elevated baseline tryptase: An elevated baseline tryptase level by itself doesn’t mean you have MCAS. It can occur in mastocytosis, hereditary alpha tryptasemia, other blood disorders, kidney disease, and occasionally in healthy people.

Attributing all symptoms to MCAS: Even if you have confirmed MCAS, not every symptom you experience is necessarily caused by mast cell activation. You still need to consider and evaluate for other health conditions.

Conclusion

MCAS diagnosis requires a careful, systematic approach combining assessment of your symptoms, laboratory confirmation through blood tests, evaluation of treatment response, and investigation of underlying causes. The consensus criteria developed by international experts provide a framework that helps identify patients who will truly benefit from mast cell-directed therapies while avoiding misdiagnosis.

If you’re experiencing recurring severe symptoms affecting multiple body systems that might suggest mast cell activation, proper evaluation by healthcare providers familiar with MCAS is essential. This includes getting tryptase measurements during acute episodes (which means someone needs to draw blood during a reaction—planning ahead with your doctor is crucial), thorough investigation for underlying conditions like mastocytosis or allergies, and development of a treatment plan tailored to your specific situation.

As research advances our understanding of mast cell biology and hereditary factors like alpha tryptasemia, diagnostic approaches and treatment options continue to evolve. While living with MCAS can be challenging, accurate diagnosis and appropriate treatment can significantly improve quality of life and prevent life-threatening reactions.

Important Note: This article is for educational purposes only. If you think you might have MCAS, work with qualified healthcare provider. They will be able to properly evaluate your symptoms, order appropriate testing, and develop a safe treatment plan. Never attempt to diagnose or treat yourself based on information alone.

References

Valent et al., (2020) Diagnosis, Classification and Management of Mast Cell Activation Syndromes (MCAS) in the Era of Personalized Medicine (click here)

Valent et al. (2019) Proposed Diagnostic Algorithm for Patients With Suspected Mast Cell Activation Syndrome (click here)