Patient education: Mast cell activation syndrome (Beyond the Basics)

DEFINITION — 

The definition of mast cell activation syndrome (MCAS) is evolving, and there is often a lack of clarity among both doctors and patients about what it is. However, the current agreement among experts is that the diagnosis of MCAS is made when someone has all of the following:

●Severe and recurrent episodes of symptoms of mast cell activation that affect more than one part of the body, either in response to a known trigger or resulting from no identifiable exposure ("idiopathic")

●Increased levels of natural chemicals released by mast cells (called mediators) in the blood or urine, which can be detected during or immediately after an episode of symptoms

●Symptoms that respond to treatments that target mast cells or the effects of the natural chemicals released by mast cells (eg, antihistamines and others)

Diagnosis — To be diagnosed with MCAS with certainty, all three of these components must be true. MCAS is called a "syndrome" because it is a combination of symptoms and laboratory findings that indicate a specific condition for which a direct cause is not necessarily proven. Research is ongoing in the field of mast cell disorders, and it is possible that the diagnostic criteria will change over time.

Prevalence — It is not known how common MCAS is, and estimates have varied significantly, ranging from 1 in 6 people to less than 1 in 1000.

MAST CELL BIOLOGY — 

Mast cells originate in the bone marrow like all other blood cells. However, the cells that will become mast cells are not completely developed ("mature") when they leave the bone marrow. From the bone marrow, the immature cells circulate in the blood briefly and then move into the tissues, where they finish developing. Because they only pass through the blood briefly, mast cells are more difficult to collect and study compared with other types of blood cells.

Mast cells spend most of their lives lodged in tissues, particularly those of the airways, gastrointestinal tract, and skin. They contain histamine and other natural chemicals, which are called "mediators" because they mediate other reactions in the body. When mast cells are activated, they release their mediators within seconds to minutes, and these mediators cause the symptoms that we associate with allergic reactions, as well as with MCAS. They also begin to generate additional new mediators that can cause prolonged or delayed symptoms. However, provided the cause or exposure is removed, a symptomatic episode usually resolves within 24 hours.

Mast cells become activated and release mediators in response to various triggers. The most common trigger for mast cell activation is exposure to an allergen (like pollen, foods, or pet dander) in someone who is allergic to that specific allergen. Mast cells are the most important cell in causing allergy symptoms in people with environmental or food allergies. However, in people with MCAS, allergens do not always play a role.

SYMPTOMS OF POSSIBLE MAST CELL ACTIVATION — 

The most common problem that people with MCAS develop is recurrent episodes of anaphylaxis.

Anaphylaxis — Anaphylaxis is a severe, whole body (ie, "systemic") form of mast cell activation. While experts have struggled to provide a firm definition of anaphylaxis, it is generally agreed upon that anaphylaxis can be diagnosed when someone experiences the rapid onset (generally within less than 30 minutes of an exposure, for those who have identifiable triggers) of suggestive symptoms that involve more than one organ system. Skin symptoms are common, but respiratory, gastrointestinal, and cardiovascular symptoms can also occur. The signs and symptoms of anaphylaxis can include:

●Skin – Itching, flushing, hives (urticaria), swelling (angioedema), especially of the face and hands

●Eyes – Itching, tearing, redness, swelling of the skin around the eyes

●Nose and mouth – Sneezing, runny nose, nasal congestion, swelling of the tongue, metallic taste

●Lungs and throat – Difficulty getting air in or out, repeated coughing, chest tightness, wheezing or other sounds of labored breathing, increased mucus production, throat swelling or itching, hoarseness, change in voice, sensation of choking

●Heart and circulation – Dizziness; weakness; fainting; rapid, slow, or irregular heart rate; low blood pressure

●Digestive system – Nausea, vomiting, abdominal cramps, diarrhea

●Nervous system – Anxiety, confusion, sense of impending doom

More discussion of anaphylaxis is found separately. (See "Patient education: Anaphylaxis symptoms and diagnosis (Beyond the Basics)".)

Symptoms that do NOT suggest MCAS — There are some combinations of symptoms that are not suggestive of MCAS, and people with these conditions do not need evaluations for MCAS.

●Chronic urticaria and/or angioedema in the absence of symptoms elsewhere in the body

●Multiple environmental and chemical sensitivities, provided they are not causing symptoms consistent with mast cell activation

●Multiple food intolerances and/or food aversions not explained by immunoglobulin E (IgE) mediated food allergy, without objective symptoms suggestive of mast cell activation

●Neurologic symptoms (such as seizures or pseudoseizures, weakness or numbness, or other neurologic symptoms) or psychiatric symptoms (such as depression, anxiety, or psychosis), without other objective findings or symptoms suggestive of mast cell activation

●Chronic daily symptoms, such as fatigue, bone/muscle pain, fibromyalgia, headaches, chronic diarrhea, or acid reflux, in the absence of other symptoms or findings

Hereditary alpha-tryptasemia — There is a common genetic trait called hereditary alpha-tryptasemia (HaT). HaT is common, being present in approximately 1 in 20 people in the United States and Europe (which is where most studies have been done so far). HaT results from extra copies of the gene that makes alpha-tryptase. Most people who have HaT do not have symptoms, so it is not considered an illness. However, people who have MCAS can occasionally have HaT as well, and it is believed that having HaT may make the symptoms of MCAS more severe, as described below.

TYPES OF MCAS — 

Experts have classified people with MCAS into groups based on the underlying condition that contributes to mast cell activation. Note that people with any type of MCAS must meet all three criteria for MCAS. (See 'Definition' above.)

●The most common group is made up of people whose triggers are allergens or other specific identifiable exposures. These people often have standard allergies (eg, to a food, inhaled allergen, medication, or bee stings), which can be demonstrated with skin testing or blood tests and which cause mast cell activation, but their repeated reactions are so severe that the usual treatments (over-the-counter medicines) are often insufficient.

●The least common group is made up of people with a clonal mast cell disorder, such as systemic mastocytosis. "Clonal" means that a single abnormal mast cell has grown out of control and has created a large population of abnormal cells. Within this group, some people (an estimated 1 in 5000 or so) have a genetic change in a specific molecule (KIT) on the surface of mast cells that causes the cells to increase in number and react more often, with or without specific exposures.

Some people with clonal mast cell disorders also have an identifiable trigger, such as bee sting allergy. These patients may also have hereditary alpha-tryptasemia (HaT) and tend to have the most severe symptoms.

●Another uncommon group is made up of people with MCAS who do not have another identifiable disorder (ie, no identifiable allergies and no clonal mast cell disease) but do have HaT.

●A final group, also uncommon, has neither a clonal disorder nor an allergic disorder and also does not have HaT. This group is the most challenging to manage since triggers cannot be identified or avoided.

TESTING FOR MCAS — 

An important part of the diagnosis of MCAS is demonstrating that mast cells have been activated and have released their chemical mediators into the blood. If elevated mediators are not detected, then the diagnosis of MCAS cannot be made with certainty. When this happens, it is important to try to determine if the person has a completely different type of problem. (See 'What other conditions cause symptoms like MCAS?' below.)

However, the mediators released by mast cells are cleared rapidly, so the blood must be drawn soon after an episode of symptoms. Other mediators are cleared so quickly that a more practical approach is to measure their more stable breakdown products in a urine sample collected during the 24 hours after an episode of symptoms.

Blood test for tryptase — When mast cells are activated in the tissues, they release a mediator called tryptase, which is sometimes detectable in the blood. Although not every symptomatic episode caused by mast cells (eg, developing sneezing and itchy eyes on exposure to a cat in a cat-allergic person) results in enough tryptase being released that it can be detected in the blood, systemic reactions involving more than two organ systems generally should lead to an increase in total serum tryptase if it is due to mast cell activation.

Blood for tryptase should be drawn within about three hours of symptom onset but no sooner than 30 minutes after symptoms begin. This means that you must go to a lab with an order from your provider or to an urgent care facility or emergency department to have this done. A form explaining how to collect blood for tryptase is provided, but you also need an order from your provider.

Meaning of a high tryptase — If you have a tryptase level that is elevated (to any degree), it does not necessarily mean that you have MCAS. Most people with elevated levels of tryptase in their blood all the time have the common genetic trait called hereditary alpha-tryptasemia (HaT). As described previously, HaT does not cause MCAS, and most people with HaT have no symptoms. However, if you have MCAS or other symptoms caused by mast cells, HaT can make your symptoms worse.

If your tryptase level is normal when you are not having symptoms but increases significantly when you are having symptoms, this is suggestive of a reaction caused by mast cells and potentially MCAS. Health care providers consider an increase of 20 percent plus 2 ng/mL over your baseline level (if your level is not elevated at baseline) or an increase of approximately 69 percent (if your level is increased at baseline) as a meaningful increase.

Urine tests — The breakdown products of other mast cell mediators that are cleared quickly from the blood can still be detected in a urine sample. Like tryptase, some amount of these mediators is present in urine all the time. Your doctor may instruct you to start collecting your urine in a special container for 24 hours after an episode of symptoms. The urine should be refrigerated as you are collecting it and returned to a laboratory within a day or so of finishing the collection. It must be kept cold until the time it is tested at the laboratory, which means it must be shipped or delivered on ice. These urine tests also must be repeated during a period of no symptoms (or at least 24 hours after an episode), and then the increase during the event can be compared with the levels when you have no symptoms. What qualifies as a significant increase is not currently agreed upon. For one of the mediator metabolites, a breakdown product of prostaglandin D2, it has been proposed that levels should at least double during an event to be consistent with MCAS.

DIAGNOSIS — 

The diagnosis of MCAS requires that all three components of the definition are present (see 'Definition' above). Demonstrating that mast cell mediators are increased in the blood or urine during or shortly after an episode of symptoms sometimes requires time and repeated blood draws and urine tests.

TREATMENT

What can I try on my own? — Often, when patients have symptoms that seem like an allergy, they try to identify a soap, detergent, chemical, food, or other exposure that is leading to their symptoms. However, in MCAS and in other forms of mast cell activation, these kinds of exposures may play a minor role or no role at all, and patients and families can eliminate large numbers of foods or experiences. This can negatively impact the quality of life, nutrition, or both in a major way. Therefore, while it is reasonable to attempt elimination of suspected triggers of symptoms, this should be done one step at a time. If avoidance of a suspected trigger does not improve symptoms, then that food, medication, or exposure should be reintroduced, and, following a reasonable period, a new suspected trigger may be avoided to assess improvement.

People can also try over the counter allergy medications, such as nonsedating antihistamines, intranasal corticosteroid sprays, or antihistamine eye drops, depending on their symptoms.

Treatment depends on the type — The treatment for MCAS may depend on what type a person has. In nearly all cases, treatment includes various medications that either reduce mast cell activation or block the mediators that mast cells release. These treatments include a variety of antihistamines and medicines that block other chemicals (eg, montelukast, zafirlukast, or zileuton). Depending on the type, there are other, more powerful medications that may be appropriate (eg, omalizumab and others).

Anyone with MCAS should carry epinephrine. Information about how and when to use epinephrine is found separately. (See "Patient education: Using an epinephrine autoinjector (Beyond the Basics)".)

WHAT OTHER CONDITIONS CAUSE SYMPTOMS LIKE MCAS? — 

Many individuals have more than one common allergic problem and may also have nonallergic disorders. As an example, an individual with allergic rhinitis and asthma might also have certain food intolerances, acid reflux, or irritable bowel syndrome. In such a scenario, the patient may suspect that all of these symptoms are explained by the unifying diagnosis of MCAS. However, if mast cell mediators are not elevated and symptoms do not respond to treatments targeting them, then the more appropriate diagnoses are the far more common individual allergic disorders caused by mast cell activation and non-mast cell-mediated disorders resulting from other causes.

There are some notable disorders that can cause symptoms similar to MCAS but have very different treatments, particularly if your symptoms do not respond to treatments that reduce mast cell activation or block mast cell mediators. If your doctor does not think you have MCAS, it is important to try and find another explanation for your symptoms so that you get the correct treatment. Some of the conditions that can be confused with MCAS are listed below.

Not all of these disorders would be considered in each person’s case. Some cause just certain symptoms that can resemble MCAS. For example:

●Disorders that cause episodes of flushing can be seen with several rare cancers and noncancerous tumors of the gastrointestinal tract, thyroid, and adrenal glands.

●Disorders that cause episodes of lightheadedness or changes in blood pressure or heart rate include fainting (ie, vasovagal syncope) and autonomic nervous system dysfunction as seen in people with postural orthostatic tachycardia syndrome (POTS).

●Disorders that cause episodes of throat symptoms or problems breathing include panic disorder and panic attacks, vocal cord dysfunction, and recurrent blood clots to the lungs.

●Disorders causing episodes of gastrointestinal symptoms, such as acid reflux, irritable bowel syndrome, and various food intolerances.

●Disorders that cause episodes of swelling (but not hives) include recurrent swelling due to angiotensin-converting enzyme (ACE) inhibitors (a blood pressure medicine) or other medications that work similarly, as well as the rare disorder hereditary angioedema.

WHERE TO GET MORE INFORMATION — 

Your health care provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our website (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for health care professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient education: Anaphylaxis (The Basics)
Patient education: Hereditary alpha-tryptasemia (The Basics)
Patient education: Food allergy (The Basics)
Patient education: Drug allergy (The Basics)
Patient education: Allergy to insect stings (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient education: Anaphylaxis symptoms and diagnosis (Beyond the Basics)
Patient education: Anaphylaxis treatment and prevention of recurrences (Beyond the Basics)
Patient education: Using an epinephrine autoinjector (Beyond the Basics)
Patient education: Food allergy symptoms and diagnosis (Beyond the Basics)
Patient education: Allergy to penicillin and related antibiotics (Beyond the Basics)
Patient education: Bee and insect stings (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Mast cell disorders: An overview
Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis
Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis
Systemic mastocytosis: Determining the subtype of disease
Advanced systemic mastocytosis: Management and prognosis

The following organizations also provide reliable health information:

●American Academy of Allergy, Asthma & Immunology (www.aaaai.org/conditions-treatments/related-conditions/mcas)

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