Update on Mast Cell Activation Syndrome

MAST CELLS — specialized white blood cells that reside in tissue rather than the bloodstream or lymphatic system — are a key component of a body’s immune system. They serve as sentinels, and warn the body when they detect invading bacteria, viruses or fungi — even venom and toxins.¹

But as with just about every system in individuals’ bodies, mast cells are prone to various disorders. While mast cell disorders are fortunately rare (the most common, mastrocytosis, which is an overaccumulation of mast cells in tissue, affects only about one in 10,000 people²), when they do occur, the effects can be life-threatening.

While even less common than mastrocytosis, mast cell activation syndrome, or MCAS, involves malfunctioning mast cells sending out chemical signals for an infection or poisoning that isn’t actually occurring. Similar to an allergy, the immune system ramps up to fight the nonexistent threat, leading to an inflammatory response that is similar to an allergic reaction: racing heart, lowered blood pressure, itchy or flushed skin, possibly hives and difficulty breathing.³ In extreme cases, MCAS can lead to anaphylaxis — a systemic failure of the body that can quickly lead to death if not immediately treated.

While there is neither a cure nor a vaccine, MCAS usually can be successfully managed by addressing symptom relief and trigger avoidance.

What Is MCAS?

Mast cells were first described in 1863, but their role in the immune system was suspected since 1949. It was only in 2010 that our understanding of mast cell disorders was classified in its current form.⁴

Mast cells are produced in the bone marrow and circulate as stem cells before migrating into tissue: lungs, digestive tract and connective tissue, as well as the skin and mucus membrane. They are particularly common in any part of the body that may come in contact with the external world — and, thus, infectious agents or toxins.

These cells have a unique structure: They are covered with a series of pattern recognition receptors that will react to specific molecular components associated with bacteria, viruses, fungi or parasites. On the interior, but near the surface, are dozens to as many as 1,000 granules, each containing a specific chemical that will stimulate or regulate the immune system if released.⁵

In some people (and researchers do not yet understand the underyling causes of MCAS), the mast cells are chronically overactive. Those chemical mediators, primarily histamine, are released frequently — sometimes in overreaction to a known allergen, and other times for no discernible reason.⁶

Because the immune system isn’t attacking the person’s body, MCAS is not considered an autoimmune disease.⁷

Researchers classify MCAS into a variety of subtypes based on either the suspected underyling cause,⁸ other co-existing conditions,⁴ the severity of symptoms or organs involved⁹ and others. There is no single, accepted classifcation system at this time.

The three most common classifications fall into these groups:

• Genetic: Certain mutations in a person’s DNA are linked to an increased likelihood of developing MCAS. Hereditary alpha tryptasemia (HαT), for instance, is linked to a duplicate TPSAB1 gene, leading the mast cells to increase production of the α-tryptase enzyme.¹⁰ Other genetic abnormalities thought to play a role in MCAS include the KIT gene and the RCCX complex.11 Importantly, some of these mutations are not inherited, but may be acquired after conception through random mutations triggered by radiation, toxins or aging, or just chance.
• Hypersensitivity: MCAS flare-ups can be caused by a variety of triggers, from temperature changes to stress, food and odors, or even medications.⁴
• Idiopathic: In some cases, no particular cause can be determined. (A recent study determined that relatively few cases of MCAS are actually idiopathic.¹²)

Women are significantly more likely to be diagnosed with MCAS than men, and those with a Caucasian family background are also more heavily represented among MCAS diagnoses.¹³ It is also known that MCAS runs in families — although it is thought that it is not an inherited gene that regulates mast cells, but rather an inherited epigenetic mutation.¹⁴ (Epigenetics is the ability of the body to turn certain genes off through enzyme regulation. One well-known example is that while humans still carry the gene for fur, as our distant ancestors had, somehow the gene is not activated in modern humans. Researchers do not yet understand this mechanism very well.)

It is also notable that symptoms generally begin in childhood — although there is a well-documented pattern of diagnosis often not being made until middle age¹⁵ (frequently due to individuals not bringing symptoms to the attention of their physician).

In addition, individuals who have certain other conditions or disorders are also more likely to develop MCAS. These include Ehlers-Danlos syndrome,¹⁶ postural orthostatic tachycardia syndrome,¹⁷ primary immunodeficiency, CD4 lymphocytopenia,¹⁹ IgE-dependent allergy⁹ and mastocytosis — although MCAS can develop first, and then mastocytosis. Researchers are unclear about the link between the two disorders involving mast cells.¹⁹

MCAS Symptoms and Progression

MCAS usually manifests with symptoms similar to those of common allergies:

• Itchy skin
• Flushing
• Low blood pressure
• Hives
• Feeling light-headed
• Abdominal pain
• Constipation or diarrhea
• Congestion
• Shortness of breath

But an MCAS flare-up is differentiated from an allergic reaction in that it will involve at least two bodily systems:²⁰ 

• Skin
• Respiratory system
• Cardiovascular system
• Digestive tract

With MCAS, flare-ups will grow not only more severe over time, but are also likely to increase in frequency. However, within that larger time frame measured in years and decades, there are also often periods of relative calm. In addition, many individuals with MCAS will find that flare-ups are triggered by a widening pool of catalysts.

And, any specific flare-up can progress rapidly. If not treated, a severe flare-up can lead to anaphylaxis as quickly as an allergic reaction, even within minutes, requiring immediate hospitalization.²⁰ 

MCAS Diagnosis

There is no single test to confirm a diagnosis of MCAS, and the initial symptoms are similar to, and even indistinguishable from, numerous other conditions.

However, the 2010 Working Conference on Mast Cells (held in Vienna) came up with a three-part diagnostic standard:²¹ 

1. Individual presents with the above symptoms, including at least two systems being affected
2. Mast cell-derived mediators are found at elevated levels in the individual’s blood or urine during a symptomatic episode
3. The individual’s symptoms respond to treatment for MCAS

If an individual presents with symptoms consistent with MCAS, a blood test may be ordered during the next flare-up to compare with a test from the same individual during a symptom-free period. The two samples will be compared for tryptase levels. An elevated measurement (above 11.4 ng/mL) may be an indicator of MCAS.⁴ Elevated levels of other mediators, including histamine (blood), histamine metabolites (urine) and prostaglandin D2 metabolites (urine) may help confirm a suspected diagnosis of MCAS, particularly if the tryptase results are not clear cut.⁹ 

Final confirmation will generally come from prescribing drugs to stabilize the mast cells, or to counter the mediators. Cromolyn sodium (Gastrocom) can be given orally to prevent mast cells from releasing mediators from their granules.²⁰ If an individual meeting the above criteria responds positively, this is generally enough to make a positive diagnosis.

MCAS Treatment

Since there is presently no cure for MCAS, treatment consists of addressing symptoms and, if triggers for previous flare-ups are known, avoiding them as much as possible.

As mentioned previously, cromolyn sodium can help stop flare-ups by preventing degranulation in mast cells. Additional drugs that may be tried are antihistamines to counter the mediators released by the mast cells, and aspirin (which blocks production of prostaglandin D2) to reduce inflammation. Individuals should also be instructed to carry at least two epinephrine self-injectors in case of a severe flare-up.⁹ 

In serious flare-ups in which anaphylaxis is developing, hospitalization is needed.

Future flare-ups can be reduced by prescribing a histamine receptor blocker, including famotidine when the gastrointestinal tract is a frequent source of symptoms and cetirizine or fexofenadine when the skin is a primary source of symptoms.²² Leukotriene inhibitors, including montelukast and zafirlukast, help relieve wheezing, while zileuton blocks production of LTC4, achieving the same result.

In individuals in which none of the above treatments are providing an adequate level of relief, there is some evidence that combining naltrexone and immune globulin can be effective, particularly in patients with both MCAS and postural orthostatic tachycardia syndrome.²³ 

Individuals who are dealing with multiple conditions will be treated to address all of them, in addition to MCAS.

Ongoing Research

Since it is believed that epigenetics may be the underlying cause of MCAS, one promising area of research is in treating epigenetic disease.²⁴ 

However, because MCAS is such a rare condition, there is relatively little primary research listed on the U.S. Food and Drug Administration’s ClinicalTrials.gov website.

Other studies are looking into mast cell disease as a whole, with just under 200 recent or ongoing trials, some of which may create spillover progress in understanding MCAS. Among those trials are one ongoing study to build a baseline of KIT D816V mutation rates in patients with suspected clonal mast cell disease.²⁵ Another is an effort to create a tissue bank built around samples from individuals who suffer from, or are suspected to have, an allergic or mast cell disease. This biobank would be used to benefit future research into these conditions.²⁶ 

Lastly, recent studies were conducting primary research into mast cell precursors (the stem cells created in the marrow that then travel through the blood until embedding in tissue), primary research into how mast cell proliferation is regulated, and determining the normal range of tryptase levels in premature newborns. 

Looking Ahead

Until researchers are able to determine the specific reasons some patients develop MCAS, treatment improvements will largely involve faster diagnosis.¹⁵ If there is an average gap of three decades between the onset of symptoms and diagnosis, that is one area that is clearly ripe for improvement. Better communication with individuals affected by MCAS, and encouraging them to share symptoms they may not feel are serious enough to warrant sharing, are the most likely path to earlier treatment.