Mast cell activation syndrome

Mast cell activation syndrome (MCAS) is a disorder where mast cells are normal in number, but release excessive amounts of chemicals known as mast cell mediators including histamine. The symptoms of MCAS can be very similar to that of myalgic encephalomyelitis (ME), and therefore may be confused. Moreover, it is also possible to have ME and MCAS simultaneously.

Signs and Symptoms
In MCAS, the body's mast cells are being created in normal number, but are over responsive to dietary or environmental triggers. Both of these situations might lead an individual to have excess histamine in circulation. Excess histamine can cause severe inflammation and a wide variety of symptoms. Almost any organ system in the body can be affected by MCAS. Because a variety of symptoms can be present, MCAS is commonly misdiagnosed.

A confounding element in diagnosing MCAS is that signs and symptoms occur in almost all areas of the body. The symptoms might wax and wane.

Most patients experience fatigue, fevers, and sensitivity to individualized environmental "triggers." Other commonly identified signs and symptoms are as follows:
 * Hot flashes, irregular heartbeat, high or low blood pressure (hypotension and/or hypertension)


 * vertigo, dizziness, forgetfulness, depression or anxiety, headaches, insomnia, restlessness


 * hives or other visible skin rashes


 * arthritis, muscle pain, bone pain, osteoporosis/osteopenia


 * anaphylaxis (a severe allergic reaction)


 * Malabsorption and gastrointestinal distress leading to low iron and low Vitamin D and low Vitamin B12

Diagnosis
MCAS can be difficult to diagnose as the cause of the syndrome is still considered to be unknown. In 2010, a criteria for diagnosing MCAS was proposed by Dr. Cem Akin and colleagues. These criteria suggest that two or more organ systems must be affected; this can include gastrointestinal, cardiovascular, skin, or respiratory. If given anti-histamine or mast cell therapy, the patient's symptoms must improve. Thirdly, the patient should be tested for serum tryptase, an enzyme secreted by mast cells during the peak of a symptomatic episode. If tryptase is >15ng/mL, the patient may have MCAS. Urine and blood tests should be collected more than once to confirm a positive diagnosis. Prostaglandin and histamine levels can be also be tested.

Clinicians
There are a very few mast cell specialists working in the United States. An expert is Dr. Lawrence Afrin formerly at the University of Minnesota now in in Armonk, NY. Drs. Clem Akin and Mariana Castells run a mastocytosis clinic at Brigham and Women's Hospital in Boston, United States. More integrative doctors are beginning to be aware of mast cell activation syndrome, but it remains elusive in both treatment and diagnosis.

Comorbidities
Afrin et al. (2016) found the most common comorbities in MCAS, occurring in over 10% of patients, were
 * gastroesophageal reflux disease (GERD) 35%
 * hypertension 29%
 * multiple/atypical drug reactions 23%
 * abdominal pain not otherwise specified 22%
 * hysterectomy/oophorectomy 21%
 * hyperlipidemia 20%
 * cholecystectomy 20%
 * environmental allergies 19%
 * tobacco abuse 18%
 * asthma 18%
 * diabetes mellitus type 2 17%
 * hypothyroidism 17%
 * headaches 17%
 * depression 16%
 * sinusitis 16%
 * fibromyalgia 16%
 * anemia of chronic inflammation 15%
 * sleep apnea 15%
 * frequent upper respiratory tract infections 15%
 * miscarriage 15%
 * pharyngitis (sore throat caused by inflammation) or tonsillitis 14%
 * dysmenorrhea 14%
 * thromboembolism 13%
 * frequent or atypical infections 13%
 * obesity 13%
 * osteoarthritis 13%
 * anxiety/panic 12%
 * vertebral disease 12%
 * cardiovascular malformations 12%
 * dermatitis 11 %
 * presyncope or syncope 11 %
 * interstitial cystitis 11 %
 * chronic kidney disease 10%
 * POTS 10%

MCAS is often diagnosed in patients that have been previously diagnosed with Ehlers-Danlos syndrome (EDS), a heritable connective tissue disorder, and with postural orthostatic tachycardia syndrome (POTS), a form of orthostatic intolerance. Both of these conditions are also commonly co-morbid with ME. The overlap between EDS, POTS, and MCAS is thought to be due to increased tryptase production.

An extra copy of the gene TPSAB1 has been noted as a possible cause for increased tryptase production. The TPSAB1 has also been implicated in pruritus, unexplained, gastrointestinal symptoms, and in other diseases including the recently discovered Hereditary Alpha Tryptasemia.

A small study by Novak et al. (2022) found decreased cerebral blood flow and small fiber neuropathy were very common in MCAS patients.

Myalgic Encephalomyelitis and Chronic Fatigue Syndrome
Most MCAS pstients have fatigue, and approximately half have cognitive dysfunction, and many symptoms of ME/CFS are also found; this may result in other a misdiagnosis of chronic fatigue syndrome or be the result of having both illnesses. The rate of post-exertional malaise, which is now considered the hallmark of ME/CFS, is unknown in MCAS patients.

Research on the relationship between mast cells and ME is in its infancy. One study found that individuals diagnosed with moderate to severe ME have been noted to have higher amounts of dysfunctional mast cells in circulation.

At a two-day physician summit in Salt Lake City, Utah in March 2018, physicians discussed the relationship between chronic fatigue syndrome and mast cell activation syndrome.
 * Charles Lapp: "I see a lot of this. I think it's one of the many overlap syndromes that we've been missing for years."
 * Susan Levine: "I suspect 50% to 60% of ME/CFS patients have it. It's a very new concept."...In Levine's experience, MCAS often manifests in patients being unable to tolerate certain foods or medications. "If we can reduce the mast cell problem, we can facilitate taking other drugs to treat ME/CFS," she said. However, she also cautioned, "It's going to be a subset, not all ME/CFS patients."

Common triggers
Mast cell degranulation can be triggered by a wide range of foods absorbed via the alimentary tract; environmental exposures inhaled through the nose such as mold, diesel fuel and chemical fragrances; emotional or physical stress; exercise; direct skin contact with chemicals, and even sunlight. While many lists exist describing the range of possible triggers, many people tolerate triggers others cannot and a person’s list of triggers can be highly individual.

Elimination diet
Treatment of MCAS invariably involves trigger identifcation and avoidance. The Royal Prince Alfred Hospital in NSW, Australia has developed an elimination diet that focuses on reducing common food chemical triggers such as salicylates, amines, glutamates and particular additives.

Vitamin C
Numerous studies have found Vitamin C to be inversely correlated with histamine and that the administration of Vitamin C reduces blood histamine levels. It does this potentially through several mechanisms: by inhibiting mast cell production; by increasing diamine oxidase (an enzyme that breaks down histamine and is chiefly found in the gut); by inhibiting mast cell degranulation (and the release of histamine in the first place), and by inhibiting histidine decarboxylase (the enzyme that forms histamine).

Magnesium
Like Vitamin C, magnesium is a co-factor in the production of diamine oxidase. Magnesium deficiency has been seen to increase mast cell production in some cases; therefore magnesium supplementation may be helpful in controlling mast cell division.

Antihistamines
Over-the-counter H1 and H2 antihistamine blockers such as Allegra (Fexofenadine), Zyrtec (Cetirizine), Claritin (Loratadine), and compounded Zaditor/Zaditen (Ketotifen) are common treatments for MCAS. It is recommended that the patient should consult a physician for secondary symptom treatment or targeted mast cell therapies.

Some patients also use herbal antihistamine supplements such as quercetin or take diamine oxidase (DAO), an enzyme normally produced by the body that breaks down histamine, as a supplement.

Prescription drug treatments include Xolair (Omalizumab), which has been proposed as a possible mast cell stabilizer and is used in allergic asthma and chronic urticaria.

Leukotriene inhibitors
These include Montelukast and Zafirlukast.

Mast cell stabilizers
These include oral cromolyn sodium (Gastrocrom) and Ketotifen (Zaditor/Zaditen).

Acetylcholinesterase inhibitors
In 2015, a large German study found 29% of ME/CFS patients had elevated autoantibodies to M3 and M4 muscarinic acetylcholine receptors, as well as ß2 adrenergic receptors. A 2016 Australian study found that ME/CFS patients had significantly greater numbers of single nucleotide polymorphisms associated with the gene encoding for M3 muscarinic acetylcholine receptors. One study found that acetylcholine via muscarinic receptors strongly inhibited the release of histamine in mucosal mast cells. Mestinon, an acetylcholinesterase inhibitor, and vagus nerve stimulators can increase the amount of acetylcholine circulating in the peripheral nervous system.

Omalizumab
Omalizumab is an anti-IgE monoclonal antibody approved for treating other allergic diseases. In a study of 55 French patients with mast cell disorders, 43 patients achieved a "best response" and 76.7% of the responding patients achieved a persistent response (three months or longer.) Median time to first response was 2 months and median time to best response was 6 months. One severe adverse event occurred, with researchers suggesting this recommends initiating treatment in hospital, but otherwise found the safety profile acceptable.

Sauna
There is some limited evidence that sauna may be useful in antihistamine resistant urticaria, an allergic skin condition that involves mast cell activation and the production of excess histamine.

Notable studies

 * 2016, Characterization of Mast Cell Activation Syndrome - (Full text)
 * 2011, Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology - (Full text)
 * 2020, Diagnosis of mast cell activation syndrome: a global "consensus-2" - (Full text)
 * 2019, Doctor, I Think I Am Suffering from MCAS: Differential Diagnosis and Separating Facts from Fiction - (Full text)

Learn more

 * MCAS: Treatment - Mast Attack