What Is Mast Cell Activation Syndrome?

Medically reviewed by Dr. Kate Rowland, MD, MS, FAAFP

Your immune system is complex — a combination of cells, chemicals and organs work together to ward off invaders that could wreak havoc on your system. Of course, if you’re familiar with a chronic illness like an autoimmune disorder, you also know how this can go awry: Suddenly a system designed to protect you is now the cause of your symptoms.

The same can happen when your mast cells, an important type of defender cell found in your immune system, aren’t functioning as they should. If you live with a condition related to inappropriate mast cell activation, instead of keeping you healthy, your mast cells may start sending wrong signals at the wrong times and cause a wide variety of uncomfortable symptoms.

To shed more light on the subject, here’s what you should know about mast cell activation, especially if you live with a chronic illness.

What are Mast Cells?

Mast cells are a type of white blood cells and work as part of your immune system. They help regulate, release and direct hundreds of mediators such as histamine or tryptase to activate your body’s inflammatory defenses.

Their role from an evolutionary perspective is to fight off microorganisms (bacteria, viruses, parasites or fungi) — anything dangerous that enters the body from the outside world. This includes initiating an allergic reaction against substances they perceive to be toxins to get them out of the body.

These “first responder” mast cells are found throughout your body. They’re mostly gathered where your body comes into contact with elements of the outside environment, like your skin, respiratory system, gastrointestinal tract, and genital and urinary tracts, as well as all your other systems, including the central and peripheral nervous systems. Mast cells also play a pivotal role in regulating growth and development of tissues throughout your body, including wound healing.

“They’re an integral part of the immune system,” Lawrence Afrin, M.D., senior consultant in hematology/oncology at Armonk Integrative Medicine in Purchase, New York, told The Mighty. “They provide us substantial help in resisting and recovering from assaults upon the body, whether they be infections, or toxins or trauma.”

What Is Mast Cell Activation Disorder?

Mast cell activation itself occurs in almost everybody and is adaptive — it’s a key function of your immune system. For some people, however, their mast cells may go haywire and start sending out the wrong mediators in the wrong amounts at the wrong times to the wrong places. At this point, your mast cells may be the cause of your symptoms as opposed to a defender against harm.

“Doctors and patients like to joke about how patients with mast cell problems have twitchy mast cells,” Artemio M. Jongco III, M.D., Ph.D., assistant professor at the Feinstein Institutes for Medical Research at Northwell Health, told The Mighty, adding:

In patients without mast cell problems, this only occurs when it’s appropriate. But in patients with mast cell disorders, it’s nonspecific reactions to different things in the environment that cause their mast cells to do this whole rigmarole, and then that’s why they have the allergy-like symptoms.

The terminology used to refer to mast cell activation syndrome can be a little confusing. Afrin said mast cell activation disease (MCAD) is generally used to refer to all types of chronic mast cell dysfunction that occurs on a spectrum of severity. Mast cell activation syndrome (MCAS) is a very common (though underrecognized) form of MCAD that can cause a wide variety of symptoms due to inappropriate mast cell activity.

Symptoms of Mast Cell Activation Syndrome

Inappropriate mast cell activation may be caused by a trigger — like an allergen, stress or virus — but it’s not always possible to pinpoint a specific trigger. Because mast cells can misbehave in so many different ways, no two cases of MCAS will look exactly the same, said Afrin.

Regardless, some of the most commonly reported MCAS-related symptoms you can experience include:

Breathing difficulties: Tightening or swelling in the throat, nasal congestion, wheezing, chest tightness
Skin issues: Hives, itchiness, swelling, flushing
Heart and vascular trouble: Fainting, fast heart rate, heart palpitations, dizziness, low or high (or alternating high and low) blood pressure
Gastrointestinal issues: Nausea, abdominal cramping or pain, vomiting, diarrhea
Chronic pain, usually widespread spread across many tissues and areas
Other nervous system symptoms: Anxiety, headaches, confusion, fatigue
Anaphylaxis

Mighty contributor Sabrina Cannella explained what MCAS feels like for her in the article, “What Life is Like With Mast Cell Activation Syndrome“:

My body is in a constant state of reaction. I [experience] allergy-related symptoms every day. But when my tolerance is running low, I experience a more severe reaction known as anaphylaxis, and that tends to be when my throat swells and I have difficulty breathing. To put this into perspective, during a good month I can have one to two anaphylactic reactions requiring the emergency room, but when my disease flares I can find myself reacting multiple times weekly.

How Is Mast Cell Activation Syndrome Diagnosed?

Making a mast cell activation syndrome diagnosis is tricky because specific diagnostic criteria are still fairly new and need more research, especially since there are so many ways MCAS can present from patient to patient.

In one approach, your doctor may do a series of blood tests to measure the level of one specific mast cell mediator, tryptase, in your blood. They’ll measure your baseline tryptase when you’re not experiencing symptoms — either before or after a flare — and require you to get a blood test within four hours of a mast cell activation flare.

They’ll compare your two blood tests and if the tryptase in a flare is at least 20% over your baseline level (without symptoms) plus an additional two nanograms per milliliter. This must be accompanied by typical MCAS symptoms in at least two organs and your symptoms must respond to mast cell-targeted treatment.

But there’s a problem with this approach. Afrin and Jongco said often a patient’s blood won’t show elevated tryptase levels even when they have obvious mast cell activation problems.

“The fact is that the vast majority of patients who just grossly, obviously are sick because of inappropriate mast cell activation … their tryptase levels just don’t go up,” Afrin said. “That’s just the way the disease behaves in most people who have MCAS.”

“Patients who seem to have symptoms that are suspicious for a mast cell problem may not necessarily have the bloodwork or other objective tests to back that up,” added Jongco. “That doesn’t disqualify you from having a mast cell problem, and so this is what frustrates a lot of patients.”

Because of the overlap of mast cell activation syndrome symptoms with many other chronic illnesses, Jongco said he typically makes a diagnosis of exclusion. He’ll first rule out other possible conditions, like making sure patients experiencing gastrointestinal issues get a colonoscopy or doing a thorough food allergy test, before making an MCAS diagnosis to be more certain.

Afrin, however, said there are other ways to test for mast cell activation and whenever possible, doctors should make an effort to gather evidence from laboratory tests to make an MCAS diagnosis.

Blood and urine tests measuring other mediators — about 10 can be measured in clinical practice out of more than 1,000 total mast cell mediators discovered so far — can help doctors make the diagnosis. Sometimes doctors can also examine certain tissue biopsies, such as from the gastrointestinal or genital or urinary tracts, to find evidence of MCAS.

However, these tests are not always an accessible option for everyone. Many mediators, Afrin said, are heat-sensitive and must be collected, shipped and stored in cold temperatures to specialty labs.

In cases where extra lab testing isn’t available, Afrin said that’s when doctors may make a clinical diagnosis based on your symptoms, excluding other possibilities and testing mast cell-targeted treatments.

What to Know About Mastocytosis

Included in the mast cell activation disease spectrum are two types of mastocytosis — cutaneous mastocytosis and systemic mastocytosis. These both are pretty rare and involve an overproduction of mast cells in the body — in addition to inappropriate release of mediators — and have very clear diagnostic guidelines.

Cutaneous mastocytosis most often affects children and primarily involves your skin. It’s fairly easy for a doctor to diagnosis by biopsying a lesion on your skin. It most commonly causes brown, itchy patches on the skin that increase over time.

In about a quarter of children with cutaneous mastocytosis, the disease goes away on its own in adolescence, but in adults, there’s no cure. In both children and adults, managing potential triggers and using certain medications can help reduce your symptoms.

Systemic mastocytosis is even rarer than cutaneous mastocytosis (there are about 10 cases of cutaneous mastocytosis for every case of systemic mastocytosis). It almost always affects adults and causes a variety of symptoms from inappropriate mast cell activation of the mast cells and sometimes from excessive numbers of mast cells gathered in your tissues and organs such as your liver, bone marrow and small intestines.

You may have heard people refer to this form of mastocytosis as cancerous. However, Afrin said unless it’s a very rare aggressive form, it doesn’t act like a typical type of cancer and you have a good chance to live a normal life span with treatments to manage the symptoms from the cells’ inappropriate release of mediators.

“The great majority of people who have mastocytosis, they actually have a very slowly progressing form of mastocytosis,” Afrin said. “Technically, it’s a cancer, but in truth, we already know that the lives of those people with that majority form of mastocytosis are not cut short like cancer typically does.”

Mast Cell Activation and Chronic Illness

Research suggests there may be connections between certain chronic illnesses and mast cell activation syndrome. Conditions with a strong association with mast cell activation involvement include:

Crohn’s disease
Irritable bowel syndrome (IBS)
Postural orthostatic tachycardia syndrome (POTS)
Multiple sclerosis
Rheumatoid arthritis
Diabetes
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Sjögren’s syndrome
Guillain-Barré syndrome
Hypermobile Ehlers-Danlos syndrome

Mast Cell Activation and Ehlers-Danlos Syndrome

There’s actually a possibility, Afrin said, that inappropriate mast cell activation may be related to connective tissue issues that cause classic hypermobile Ehlers-Danlos syndrome (EDS) symptoms like overly flexible joints, stretchy or elastic skin, and chronic pain.

Genetic mutations in genes that regulate the structural protein collagen lead to all 12 other subtypes of EDS have been identified. Researchers haven’t yet found the genetic underpinning of hEDS, by far the most common type of EDS.

While researchers are looking at several potential genetic causes of hEDS, one area of interest relates to genetic changes in hEDS patients’ mast cells. Mast cell genetic mutations may cause perfectly normal connective tissue proteins to be assembled incorrectly — and lead to other hallmark hEDS symptoms.

“Many of these hEDS patients have a large number of other issues that you really can’t attribute to any anomaly in the connective tissue, but you can easily attribute to inappropriate mast cell activation,” Afrin said, adding:

We’re beginning to wonder whether maybe what’s going on here is thanks to chronic inappropriate production and release of certain mast cell mediators that are integral to guiding the growth and development of connective tissues, maybe this is why we’re getting malformed connective tissues in the hEDS patients. … Maybe that’s why we can’t find any mutations in any of the connective tissue proteins. Because maybe they’re completely normal. It’s just that they’re not being assembled into fully formed connective tissue correctly.

Mast Cell Activation Treatment

No matter what type of MCAS you’re facing, with proper treatment, you’ll likely be able to manage your MCAS symptoms for a better quality of life.

You and your doctor will work to find a drug regimen that targets your symptoms. For many people, that includes antihistamines like loratadine (brand name: Claritin), cetirizine (brand name: Zyrtec) and fexofenadine (brand name Allegra).

According to Jongco, MCAS patients often take these medications at as much as five times the daily recommended dose as someone with typical allergies might take. Jongco said that while antihistamines are typically safe drugs, you’re more likely to experience side effects at these higher doses.

“Patients need to always be warned that yes, increasing the antihistamine dose might make you feel better but that comes at the cost of you might actually start developing the side effects because the dose is so high,” Jongco said. “You’re going to start probably developing some of the side effects that we know, including the drowsiness, including difficulty urinating, maybe some blurry vision.”

Afrin added that you may need to try several drugs until you find what helps, a process that may include trying a drug for a month and seeing how you feel before switching or adding another. Most people, Afrin said, end up taking more than one drug for the best outcome.

“It’s an extraordinarily complex disease, so it’s pretty unlikely the patient’s going to find just one ‘keeper’ that’s going to significantly improve all their symptoms,” Afrin said, adding:

Likely they’re going to find one ‘keeper’ that’ll significantly improve some symptoms, and then over time, will come to identify other ‘keepers’ that will significantly improve other symptoms. And in that fashion, over time, they’ll come to piece together what in the end will probably be a pretty small cocktail of mast cell-targeted drugs, which collectively get the patient to the goal.

Sometimes this isn’t possible, but if you realize your MCAS symptoms flare during stressful moments or a food you come into contact with, you can also work to minimize those triggers. Jongco often recommends patients supplement their vitamin D intake, since other allergic conditions like asthma and eczema seem to respond well to appropriate vitamin D levels, though more research is needed on how vitamin D affects mast cells in particular.

The Takeaway

Like so many chronic illnesses, mast cell activation syndrome can be difficult to diagnose and hard to treat. So if you’ve been struggling with undiagnosed MCAS symptoms for years that turn out to be a mast cell activation-related issue, know it’s definitely not “all in your head.”

“Many doctors, and even family members and acquaintances, start to think it’s all in your head. Even the patient starts to think they’re ‘crazy,'” Afrin said, continuing:

It’s pretty hard to be so ‘crazy’ as to come up with the particular set of symptoms that these patients come up with. No, it’s much more likely that there’s something real that’s going on in them. It’s just something that’s complex and poorly understood. … In the end, it’s like any disease: once you find the right diagnosis, then you give them the right treatment for that diagnosis, and they get a good bit better.