MSAS (Mast Cell Activation Syndrome)

Mast cells are allergy cells responsible for immediate allergic reactions. They cause allergic symptoms by releasing products called “mediators” stored inside them or made by them. In allergic reactions, this release occurs when the allergy antibody IgE, which is present on the mast cell surfaces, binds to proteins that cause allergies, called allergens. This triggering is called activation, and the release of these mediators is called degranulation.


Some of these mediators are stored in granules in the mast cells and are released quickly and others are made slowly only after the cell has been triggered. Mast cells can also be activated by other substances, such as medications, infections, insect or reptile venoms. These responses, while not desirable, are made by “normal” mast cells. They are called “secondary activation” because they are due to (secondary to) external stimuli.

Sometimes mast cells become defective and release mediators because of abnormal internal signals. Certain mutations in mast cells can produce populations o identical mast cells – called clones – that overproduce and spontaneously release mediators. The spontaneous production of mediators in these clonal mast cell disorders is called “primary activation”. These abnormal cells can grow uncontrollably and are unusually sensitive to activation in a condition called mastocytosis.

Idiopathic Mast Cell Activation Syndrome.  MCAS is a condition in which the patient experiences repeated episodes of the symptoms of anaphylaxis – allergic symptoms such as hives, swelling, low blood pressure, difficulty breathing and severe diarrhea. High levels of mast cell mediators are released during those episodes. The episodes respond to treatment with inhibitors or blockers of mast cell mediators. The episodes are called “idiopathic” which means that the mechanism is unknown - that is, not caused by allergic antibody or secondary to other known conditions that activate normal mast cells.  It appears to underlie symptoms experienced by patients with varying forms of dysautonomia. 

14 to 17% of the general population may be affected.

Evaluation for MCAS starts with determining whether the symptoms occur in separate attacks and are typical symptoms of an anaphylactic reaction without a clear cause. Mast cell mediators increase during the episode. Those mediators should be measured during acute episodes and at baseline looking for elevations during symptoms. Finally, the improvement with treatment using inhibitors of mast cell mediators completes the diagnosis.  

The symptoms most consistent with anaphylaxis are:

An unusual form of myocardial infarction called Kounis syndrome can appear.

The trademark similarity between all patients with MCAS is the presence of multiple unexplained symptoms (usually inflammatory with or without allergic) in many, if not all, organ systems.

When the patient with an already definitively diagnosed ailment-particularly a patient with chronic multisystem organ morbidity, generally of an inflammatory theme-presents for evaluation, it is important for the physician to consider whether or not the presenting symptoms are typical for the definitely diagnosed ailment.  If not, it is important to consider the possibility that a comorbid (and potentially underlying/unifying) illness may be present.  The severity of MCAS often permanently "steps up" to a higher baseline level following severe physical or psychosocial stress.

Patients with a wide assortment of symptoms in multiple or all organ systems  including idiopathic dysautonomia, IBS, interstitial cystitis, idiopathic anaphylaxis, and some subsets of fibromyalgia, etc) that are not explained by some other conditions should consider MCAS as a possible underlying diagnosis. 

Systemic findings in MCAS: Fatigue, malaise, pain, and inflammation.  Integumentary: Flushing, rash, skin lesions, hives, urticaria pigmentosa,.  Ocular/Ophthalmologic: Waxin and waning inflammation of the conjunctival tissue, often described as burning, sandy, dry or gritty, difficult focusing, blepharospasm (trembling of the eyelid), visual disturbances, pupilomotor dysfunction.  Otologic: Tinnitus, ear pain, hearing loss, and ear drum spasms.  Sinonasal: Congestion and frequent infections.  Oral/pharyngeal: Mouth sores, sore throat, and difficulty swallowing.  Lymphatic: Swollen lymph nodes and enlarged spleen.  Pulmonary: SOB, bronchial constriction, and dyspnea.  Cardiovascular: Non-cardiac chest pain, palpitations, tachycardia, HTN, hypotension, syncope, POTS, arryhthmias, and Kounis syndrome (allergic angina).  GI: Abdominal pain, diarrhea, constipation, nausea, IBS, gastroparesis.  Neurological: Memory and word finding difficulties, headache, neuropathic pain, difficulty in concentrating.  Urinary and genitourinary: Urinary tract infections and interstitial cystitis.  Musculoskeletal and joint: Muscle, joint or bone pain.  Neuropsychiatric: Anxiety, depression, and sleeplessness.  Endocrine/metabolic: Wide array of abnormal hormonal and metabolic laboratory results, especially common ferritin and magnesium levels and brittle bones.  Hematology: Coagulation and easy bruising.  Immunologic: Infections and environmental hypersensitivities, autoimmune disease and cancers.

Mediators.  Mast cells are known to produce many molecules that cause inflammation, but only a few mediators or their stable breakdown products (metabolites) have been found reliably elevated in episodes of MCAS and measurable in commercial laboratory tests.  Increases in serum mast cell tryptase (>20 ng/mL)  and in urine levels of N-methylhistamine, 11B,  23BPT  (2,3-Dinor 11 Beta-Prostaglandin F2 Alpha, 24 Hour, Urine), and/or Leukotriene E4 (LTE4), urine n-methylhistamine, serum chromogranin A, and heparin are the only useful tests in diagnosis of MCAS.

Blood and urine testing - tryptase, n-methylhistamine 24h, and beta-prostaglandin. For the 24h urine collection, try to collect within 4 hours of a flushing event, to keep refrigerated in between collections, and to transport in an ice bag.

Caution:  Patients taking aspirin or nonsteroidal anti-inflammatory drugs (NSAID) may have decreased concentrations of prostaglandin F2 alpha. If possible, discontinue for 2 weeks or 72 hours, respectively, prior to collecting a specimen. 

Total serum mast cell tryptase should be drawn between 30 minutes and two hours after the start of an episode, with baseline level obtained many days later.  If it is persistently above 20 ng/mL cut-off defined as one of the WHO criteria for systemic mastocytosis, then further evaluation should be directed toward systemic mastocytosis. The urine tests are performed on a 24 hour collection of urine that is started immediately.   It should be noted that without wide awareness of the diagnostic criteria for MCAS within the medical community, physicians with knowledge of systemic mastocytosis may mistakenly tests only for serum tryptase, which is commonly elevated in systemic mastocytosis, yet in most cases is within normal limits in MCAS patients.

If there are skin lesions suggestive of the cutaneous forms of mastocytosis, they should be biopsied to look for the disease.

Since these are not standard laboratory tests, patients should work with their local allergist who can communicate with emergency and lab personnel to assure they are ordered and completed in a timely fashion. 

A serum tryptase level during an attack of flushing or symptoms suggestive of a flare of her POTS syndrome.   Explained that there is currently no scientific evidence of any association between mast cell activation syndrome, POTS or hyper flexible Ehlers Danlos syndrome.  To establish whether she has risk of mast cell activation syndrome she needs to have a tryptase level drawn within 4 hours of an attack and compare this to her baseline. (Kohn, A. and Chang, C., 2020. The relationship between hypermobile Ehlers-Danlos syndrome (hEDS), postural orthostatic tachycardia syndrome (POTS), and mast cell activation syndrome (MCAS). Clinical Reviews in Allergy & Immunology, 58, pp.273-297.)

Treatment.

The goals of treatment are both diagnosis and patient relief. The immediate goal is to provide relief for the patient. Lack of response to these treatments suggests that MCAS is not present.  The treatment of acute episodes should follow the recommendations for treatment of anaphylaxis, starting with epinephrine, if indicated by the severity of symptoms.

Antihistamines, such as the first generation histamine type 1 receptor blockers diphenhydramine and hydroxyzine, can be effective for itching, abdominal discomfort and flushing, but their use may be limited by side effects (sleepiness). Second generation antihistamines, including loratadine, cetirizine and fexofenadine, are preferable due to fewer side effects.

Treatment with histamine type 2 receptor blockers, such as ranitidine or famotidine, can be helpful for abdominal pain and nausea.

Aspirin blocks production of prostaglandin D2 and can reduce flushing.

Montelukast and zafirlukast block the effects of leukotriene C4 (LTC4) and zileuton blocks LTC4 production, so these reduce wheezing and abdominal cramping.

Corticosteroids are helpful for edema, hives and wheezing but should only be used as a last resort.

Omalizumab (which blocks binding of IgE to its receptors) has been reported to reduce mast cell reactivity and sensitivity to activation which can reduce anaphylactic episodes. 

Avoid beta-blockers as they can cause mast cell degranulation.

Mast cell cocktail (AS)

MSAS, patient hand-out. 

Currently there is a lot of controversy about Mast Cell Dysfunction (MCD), the Mast Cell Activation Syndrome (MCAS), and other syndromes that may have some partial overlap. In my personal opinion, much of the confusion is over terminology. MCAS is a specific term that should only be used for people who meet certain criteria on testing. Some people with MCD may have symptoms that are similar to MCAS, and may respond to treatment. Many other people have autonomic dysfunction (dysautonomia), with very similar symptoms as MCD but no mast cell involvement. Or, mast cells may be a small part of dysautonomia. Finally, many people have histamine problems (allergies, urticaria, or otherwise) that are not related to mast cell dysfunction.

In addition, mast cells are involved in lots of diseases without the presence of MCD or MCAS, and the mast cell tests may be positive for any number of reasons.

With all of the above confusion, all we can do together is to catalog symptoms and decide whether treatment should be tried, and whether other tests need to be done. It may be helpful to have an allergist or immunologist involved … but if the allergist says that MCAS isn’t present and there isn’t anything else that they can do, it is probably best to come discuss the situation with me (as a multi-system consultant) and the primary care provider (as the person who knows your health conditions the best). We will usually be able to come up with a medication solution to reduce your symptoms.


Timing of urine tests for mast cell dysfunction.

When we suspect mast cell dysfunction, there are several nuances to consider about testing.  We may need to do either a one-time urine collection ("random" or "spot") or a 24-hour collection.

The purpose of testing is to determine if your symptoms are caused by recent mast cell dysfunction. The urine tests may also find evidence of lower-grade dysfunction that is constant or frequent.  Testing may also reflect evidence that we find on physical exam.  If you have symptoms but the test is negative, then the symptoms are not due to mast cell dysfunction. 

Please keep in mind that the urine tests may also be positive if there is histamine dysfunction, such as some cause of urticaria or seasonal allergies.

Keep in mind that the goal of all of this isn't a diagnosis for all of your problems. Instead, we are looking to see if a certain group of medications may be useful for you. Only a small number of people have Mast Cell Activation Syndrome (MCAS), but more people can have mast cell dysfunction as part of a more complicated set of problems.

The presence of KIT D816V mutation is one of the minor criteria for diagnosis of SM and mutation testing can assist in diagnosis, particularly in limited specimens. KIT D816 mutations seen in the core-binding factor acute myeloid leukemia (AML). Cases of t(8;21) or inv(16)-bearing acute myeloid leukemia without D816