Mast Cell Activation Syndrome in a nutshell…

 

Mast cells are a type of white blood cell that serve as an important part of the body’s immune system that act as a “first response team” to invaders, releasing chemicals to protect the body. Mast cells are present in nearly all types of tissue. Without them, we would not survive. In patients who have Mast Cell Activation Disease, the fine line between a healthy functioning system and an excess release of chemicals, or “mediators,” is crossed dramatically.

 “Mast Cell Activation Disease” (MCAD) is an umbrella term that refers to a group of disorders characterized by

  1. The accumulation of pathological mast cells in potentially any or all organs and tissues AND/OR
  2. The aberrant (abnormal) release of variable subsets of mast cell mediators

(Molderings et al, 2011)

In other words, MCAD is either a problem with quantity, or quality. MCAD involves either too many “abnormal” mast cells around the body, and/or the “abnormal” release of too many chemicals into the blood by mast cells. Let’s take the analogy of a college party, for instance. Things can get out of control when your low-key shindig suddenly has

1) too many people show up and the house is jam-packed and flooded with rowdy and loud and inebriated fraternity brothers.

  -> Mastocytosis (quantity problems), or

2) there’s a normal number of people who show up, but the ones that show up are all serious light-weights with sensitive systems that cause them to vomit after one drink.

> Mast Cell Activation Syndrome “MCAS” (quality problems)

(Let’s face it, either scenario is not ideal).

This website focuses on MCAS. The cause of MCAS is still unknown, although more research is emerging that supports a genetic predisposition with the development of the disease, which typically has evidence of a presence since birth. MCAS may not become especially problematic or obvious until certain life periods or stressful life events.

 

Symptoms vary widely between patients. Typically, patients will exhibit:

  • a history of waxing and waning, often “migratory” symptoms
  • multi-systemic problems, often with multiple true co-morbidities and/or mis-diagnoses
  • dermatographism of the skin due to the high concentration of mast cells located there
  • a combination of acute episodes and chronic ongoing debilitating symptoms

Acute episodes that involve degranulation or release of certain chemicals from mast cells may include:

  • an individual and unique spectrum, from a mild reaction to a full-blown anaphylactic response that requires epinephrine and other drugs alongside an emergency room visit.
  • flushing or redness of the face, itching with or without hives on the skin, blood pressure drops, difficulty breathing, abdominal cramping, nausea, vomiting or diarrhea, nasal and eye symptoms, throat tightness or soreness, and headaches.

Common symptom triggers include:

  • emotional stress, exposure to extreme temperatures, and exposure to certain environmental factors, medications or foods. Many patients are sensitive to things like (hidden) mold in buildings, perfumes, chemical odors and cleaning supplies, and shampoo and other hygiene products. Direct sunlight, exercise and mechanical vibration (like those experienced while sitting on a bus) are other common triggers. “Typical” allergens like pets, dust, and seasonal allergens may be frequent triggers. Many patients experience reactions to caffeine, alcohol, and food (often food that they’ve considered “safe” will suddenly trigger a reaction). Foods that are high in histamine, oxalates, dyes, additives or salicylates can also be problematic. There’s a subgroup of patients who are also highly sensitive to insect stings and bites.

Patients often have dozens of the following symptoms:

Cardiovascular signs: tachycardia (high heart rate), blood pressure irregularity (both high and low blood pressure), flushing (especially of the face), syncope (fainting) or pre-syncope (near-fainting), heart racing and blood pressure responses to positional changes, heart disease, intermittent chest pain

Respiratory signs: asthma-like symptoms, sinus inflammation, shortness of breath, cough, rhinitis (nose mucous inflammation), frequent upper respiratory infections and/or pneumonia, shallow breathing patterns/impaired use of diaphragm muscle for breathing

Gastrointestinal signs: bloating, diarrhea and/or constipation, nausea, vomiting, abdominal pain, intestinal cramping, abdominal distention, heartburn, malabsorption of nutrients, delayed gastric (stomach) emptying, H. pylori-negative gastritis (stomach lining inflammation), oropharyngeal burning pain (in middle part of the throat), aphthae (ulcers on the mouth or tongue), ilieocecal valve dysfunction (valve separating small and large intestine), non-cardiac chest pain, food sensitivities, Median Arcuate Ligament Syndrome “MALS” (structural compression of the celiac artery and possible neural structures resulting in abdominal ischemia and pain), microbiome bacterial issues including SIBO (small intestinal bacterial overgrowth)

Neuropsychiatric signs: difficulty with memory and concentration, anxiety, depression, insomnia (difficulty sleeping), lightheadedness, vertigo (sensation of the room spinning), headache and/or migraine, neuropathic pain (abnormal nerve-related pain sensations), polyneuropathy (degeneration of peripheral nerves), lower attention span, organic brain syndrome (decreased brain function due to a medical disease), tinnitus (ringing in the ears)

Ophthalmologic signs: conjunctivitis (pink eye), difficulty in focusing with vision, increased “floaters” in eye, intermittent blurred vision, general eye irritation and redness, decreased oxygen to optic nerve resulting in decreased ability to differentiate between contrasting shades

Organ Signs: hepatic splenomegaly (enlargement of both liver and spleen), hyperbilirubinemia (elevated bilirubin in the blood), elevation of liver transaminases, hypercholesterolemia (high cholesterol in the blood), Splenomegaly (enlarged spleen), Lymphadenopathy (lymph nodes enlarged, abnormal consistency or abnormal number)

Cutaneous Signs: urticaria pigmentosa (rash and itchy skin), flushing, hives, efflorescences (spots on skin) with/ without pruritus (itching), telangiectasia (red lines on skin from small blood vessels), flushing, angioedema (swelling of the lower layer of the skin), abnormal bleeding, frequent bruising, delayed skin healing from injury, abnormal sweating, abnormal body odor, hair loss

Musculoskeletal Signs: muscle pain and aches, osteoporosis/osteopenia (decreased bone mineral density), bone pain, migratory arthritis, fibromyalgia

Other Signs: fatigue, asthenia (feeling weak), fever, environmental sensitivities (odors, chemicals, vibration, animals, etc.), Interstitial cystitis (bladder pain and increased urinary frequency), unexplained weight loss or gain, poor tolerance to exercise, idiopathic anaphylaxis, sensitivity to sunlight and/or extreme cold and heat, odd reactions to insect stings, difficult menses (females), thyroid and adrenal issues, poor tolerance to medications or anesthesia, poor tolerance to alcohol, fermented foods, processed foods, and foods high in histamine

 

 

There are two general schools of thought for the diagnosis of MCAS, presented below.

Proposed MCAS Diagnostic Criteria by Molderings and colleagues (updated version, published in 2016):

Major Criterion:

  1. Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release syndrome)

 

Minor Criteria:

  1. Multifocal or disseminated dense infiltrates of mast cells in bone marrow biopsies and/or in sections of other extracutaneous organ(s) (e.g., gastrointestinal tract biopsies; CD117-, tryptase- and CD25-stained)
  2. Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25%) in bone marrow smears or in histologies (minor criterion 1 for SM)
  3. Mast cells in bone marrow express CD2 and/or CD25 (minor criterion 2 for SM)
  4. Detection of genetic changes in mast cells from blood, bone marrow, or extracutaneous organs for which an impact on the state of activity of affected mast cells in terms of an increased activity has been proven
  5. Evidence of a pathologically increased release of mast cell mediators by determination of the content of tryptase in blood, N-methylhistamine in urine, heparin in blood, chromogranin A in blood, or other mast cell-specific mediators (e.g., eicosanoids including prostaglandin PGD2, its metabolite 11-β-PGF2α, or leukotriene E4)
  6. Symptomatic response to inhibitors of mast cell activation or mast cell mediator production or action (e.g., histamine H1 and/or H2 receptor antagonists, cromolyn)

 

Diagnosis of MCAS made by either (1) the major criterion plus any one of the minor criteria or (2) any three minor criteria.

_____________________________________________________________________________________________________________

Proposed MCAS Diagnostic Criteria by Valent et al. (2012):

Major Criteria:

  1. Absence of any known disorder that can better account for symptoms
  2. Typical clinical symptoms (flushing, pruritus, urticaria, angioedema, nasal congestion, nasal pruritus, wheezing, throat swelling, headache, hypotension, diarrhea)
  3. Increase in serum total tryptase by at least 20% above baseline plus 2 ng/ml during or within 4 h after a symptomatic period OR transient increase of another established mast cell mediator
  4. An objective response of clinical symptoms to anti-mediator drugs, such as histamine receptor blockers or ‘mast cell targeting’ agents, such as cromolyn

*All major criteria must be satisfied to meet diagnosis

_____________________________________________________________________________________________________________

Clinically, the diagnosis is made with a combination of the patient history, the absence of a disease that better accounts for the symptoms after a thorough differential diagnosis process, and (ideally) evidence of either an elevated mast cell mediator in the blood or urine (see chart below), or signs of abnormal mast cells when special staining is applied to tissue biopsies (such as the GI tract) or bone marrow biopsy.

Keep in mind that…

  1. Tests performed while flared or symptomatic are more likely to be positive.
  2. Certain medications can influence the results of the tests. (see chart below)
  3. If urine is not continuously chilled, the tests could provide a false negative.
  4. Many patients require several rounds of testing before seeing a positive result.
  5. “First Line” testing is typically blood and urine tests, and then re-examination of past tissue biopsies with mast cell staining. Bone marrow biopsies are typically not performed unless the patient has a tryptase level above 20, or other “red flags.”
  6. The above criteria are only specific to MCAS. (The Mastocytosis diagnostic criteria are clearly outlined in the World Health Organization’s classification that was updated in 2016).

There are few centers in the U.S. that specialize in MCAS, and they often have long wait times. Patients are encouraged to seek a provider who is willing to work with them in this process, even if that person does not have a background in the disease. (Certain MCAS specialists may be willing to provide phone consults for other providers to assist). It often takes a ruthless search for that one practitioner who is willing to take a thorough history and get on board at finding the root issue. Many recent graduates in naturopathy and functional medicine are becoming well-versed in MCAS. Allergists and hematologists may also be a good resource, although some will only test tryptase in order to rule out Mastocytosis and won’t order the tests for MCAS.

Common Chemical Mediators Tested in Patients with Suspected MCAD

Mast Cell Mediator Interpretation of Value Clinical Notes (2017) Reference for Lab Values
24-hour Urine N-methyhistamine (NMHIN) Normal:

Age 0-5: 120-510 mcg/g creatinine

Age 6-16: 70-330 mcg/g creatinine

Age >16: 30-200 mcg/g creatinine

HIGH levels common with MCAD; Keep sample chilled continuously; diet can influence histamine level by ~30%; DAO supplementation and anti-histamine medications can affect this test result Mayo Clinic
24-hour Urine Prostaglandin D2

(PGD2)

Normal:

100-280 ng

HIGH levels common with MCAD; Keep sample chilled continuously; aspirin and other NSAIDs can affect this test result; urine more accurate than blood test Mayo Clinic/ Inter Science Institute
24-hour Urine Prostaglandin 9a,11b-F2

(PGF2a)

Normal:

375-800 ng *

HIGH levels common with MCAD; PGF2a is (more stable) metabolite of PGD2 (PGF2a believed to be superior for MCAS detection); Keep sample chilled continuously; aspirin and other NSAIDs can affect this test result; urine more accurate than blood test Inter Science Institute
Tryptase (serum) Median normal values:

Age <6 months: 6 ng/ml

Children & Adults: 3-4ng/ml

 

High >11.5 ng/ml

(or may use formula comparing to baseline level for cut-off)**

Criterion for consideration of SM: >20 ng/ml

HIGH levels common with MCAD; Baseline testing at least 24 hours after acute episode; acute measurement within 15 mins-4 hours of episode Mayo Clinic
24-hour Urine Leukotriene E4

(LTE4)***

Normal:

< or = to 104 pg/mg creatinine

HIGH levels common with MCAD; Keep sample chilled continuously; Zileuton/Zyflo medication may affect this test result; Urine Leukotriene B4, C4, and D4 may also be ordered Mayo Clinic
stat chilled Plasma Heparin (PH) via Chromogenic Anti-Factor Assay

“Anti-XA Assay”

Upper reference value:

0.02 to 0.05 anti-Xa IU/ml, depending on lab

HIGH levels common with MCAD; Specific/sensitive mast cell marker but metabolizes quickly even when refrigerated so has to be centrifuged within 30 mins. and must be kept cold Vysniauskaite et al, 2015
Serum Chromogranin A Normal:

< 93 ng/ml (all ages)

HIGH levels common with MCAD; high levels may also indicate heart conditions, kidney problems or neuroendocrine tumors; proton pump inhibitors (PPI’s) can affect this test result Mayo Clinic

 

 

 

 

 

While there is no “cure” for MCAS, 2/3 of patients will experience significant symptom relief once they find the right treatment combination that works for them.

The prognosis for MCAS vs. other types of MCAD are different. With cases of Mastocytosis or Mast Cell Leukemia, life expectancy may be shorter than average. However, with MCAS it appears that life expectancy is normal.

“Symptoms often initially manifest during adolescence or even childhood or infancy but are recognized only in retrospect as MCAD-related. Clinical features and courses vary greatly and range from very indolent with normal life expectancy to highly aggressive with reduced survival times.”

(Molderings et al 2011)

That being said, quality of life is clearly dramatically impacted by any form of MCAD. Many patients with MCAS have limitations in their ability to work and face hurdles in terms of receiving quality affordable care options. Most patients report significant financial and relationship stressors and have to alter their lifestyle significantly in order to reduce triggers.

“The lifespan for those with MCAS appears to be normal, but the quality of life can range from mildly impaired to severe discomfort, often to the point where patients are home-bound and unable to work.”

(Afrin, 2014)

 

The following information is not intended to be medical advice, and it is not all-inclusive. If you think you have MCAS, please consult your doctor for diagnosis and to come up with an individualized treatment plan.

 

Mainstream medical approach to MCAS treatment:

Patients begin by working with their doctors to identify medications that may help stabilize their symptoms. The trial and error process can take months or even years to find the right combination, dosage and brand. Keep in mind that many patients react to fillers/additives and may need to trial many versions of the same active ingredient before ruling it in/out.

A patient may be prescribed a combination of the following types of medications:

  • Emergency Medications for use in anaphylaxis
    • Ie) Auto-injectable Epinephrine, inhaled medications for airway, and diphenhydramine
  • Medications that block the action of released mast cell mediators
    • Ie) Antihistamines (H1 and H2 blockers, diphenhydramine), leukotriene antagonists, TNF antagonists, IL-1 antagonists
    • Medications to address osteoporosis/osteopenia if present
  • Medications that inhibit the release of mast cell mediators
    • Ie) Cromolyn (oral or inhaled), tyrosine kinase inhibitors, Omalizumab, benzodiazepines, cannabidiol
  • Medications that inhibit the production of mast cell mediators
    • Ie) NSAIDS (with caution), steroids, Vitamin C
  • Cellular therapy and stem cell transplants are very rarely used, and always in the case of aggressive MCAD.

 

Holistic additions to MCAS treatment:

Holistic care aims to address the root cause(s) and trigger(s) of the mast cell activation, and also strives to foster lifestyle modifications for long-term management. It’s important to create a care team that incorporates multiple areas for healing success (ie- doctor who focuses on MCAS such as hematologist or primary care doctor, physical therapist, allergist, acupuncturist, mental health specialist, naturopath, etc.) Some patients find symptom relief with more natural/herbal approaches to treatment, such as Quercetin.

It is strongly recommended to pursue care with a functional medicine doctor or naturopath who can help evaluate additional underlying causes contributing to or flaring the symptoms. This professional can help evaluate whether the following factors are present that may impede progress:

Heavy metal toxicity, mold toxicity, Lyme disease and co-infections, Ehlers Danlos Syndrome, POTS, Epstein-Barr Virus, parasites, poor integrity of the gut’s bacterial microbiome, adrenal and hormonal imbalances, thyroid issues, celiac disease or gluten intolerance, additional bacterial infections/viruses, and so much more.

 

Additional Tips:

  • Prepare yourself for acute episodes
    • Obtain medical alert ID bracelet or necklace.
    • Carry emergency medications at all times and stash them in car, gym bag, etc.
    • Carry card or paper that summarizes medical instructions for the event of an ER visit. Include past medical history, emergency contact, conditions, and medication list.
    • Consider purchasing a mask to wear if needed for contact with smokers, perfumes, cleaning supplies, etc.
  • Complete a thorough assessment of any and all potential triggers
    • Environmental
    • Dietary
    • Medication-based
    • Physical
  • Assess environment for stealthy hidden contaminants (ie-mold in the walls of a building, chemicals in skin products and cleaning supplies, etc.)
  • Evaluate your lifestyle/schedule and reduce as many daily stressors as possible.
  • Ensure adequate sleep, clean drinking water, organic food, and HEPA-filtered air for maximal success.
  • Consider ways to assist your body in detoxification. This may reduce overall reactivity.
    • Epsom salt baths, sweating, and colonics may be useful.
    • Focusing on certain foods and supplements may help this process.
  • Focus on a positive mindset and make sure to address any unresolved emotional trauma. Therapy, meditation, prayer, yoga, affirmations, reading and podcasts can all be helpful with this.
  • Consider a temporary symptom log as you are adjusting foods and medications, to be discontinued once you find a stable baseline.

 

 

 

 

On the role of diet:

When patients are diagnosed they are often limited in the number of foods they can tolerate. Working with a nutritionist can help to ensure adequate nutrients and calories in the diet. Many experts recommend elimination of processed foods, refined sugar, caffeine, grains/gluten, alcohol, and dairy.

Typically, a “low histamine diet” is very restrictive in addition to avoidance of food allergies in patients with MCAS. An elimination diet may be helpful in the first few weeks to determine exact triggers, but it’s unhealthy to make massive long-term unnecessary dietary restrictions. Identify what foods may trigger a true allergic reaction – and of course eliminate anything that triggers anaphylaxis.

There are many different types of eating plans for patients with chronic illness, and it’s important to remember that there is no single cookie-cutter approach that works best. Food decisions MUST be individualized and made while factoring in other diagnoses too (such as SIBO or other gastrointestinal ailments).

When patients are first diagnosed, they often get bogged down with a list of high histamine foods to avoid. It’s important to keep in mind that:

  1. Histamine is one of the hundreds of mediators released by mast cells.
  2. The website resources that cite histamine levels are very variable. There are a number of factors that influence how much histamine is present in different food sources.
  3. Eliminating foods on the “high histamine list” blindly (without factoring in individual response to such foods) can eliminate healthy options that the body may need for healing, and often leads to a short and restrictive list of “safe foods”
  4. It’s possible that our mast cells react to certain healthy foods sporadically because they are reacting to toxins (such as pesticides or preservatives) added to the food, or the way it was processed, and not necessarily the food itself.

Take-home message: be wary of a strict low histamine diet or the elimination of foods based on internet findings vs. your own body’s individual response. A diet rich in fruits and vegetables and minimal in inflammatory foods like grains, processed foods, dairy, alcohol, preservatives, and refined sugar should be encouraged for patients with MCAS. Just as you’re giving attention to what you’re putting in the body, make sure you’re maximizing efforts to help with elimination of triggers and detoxification in order to reduce the collective “bucket” of things that could trigger mast cell activation. Working with a holistic practitioner to identify all of the puzzle pieces is strongly encouraged.

 

 

There are many challenges alongside the diagnosis of MCAS, a condition which has only been coined for the last decade or so. There’s debate about the etiology of MCAS and the role of genetics, and appropriate universal diagnostic criteria and patient classification. We are lacking clear universal clinical guidelines for this patient population. The research is still in it’s infancy and there’s a great need for continued research to connect the dots between MCAS and other conditions as well. We can speculate based on studies about the role of mast cells in certain tissues and in conjunction with certain diseases, but there are still many holes and gaps in our knowledge and understanding of the disease.

In general, there exists a very real discrepancy between the management of patients by allergists as opposed to true MCAD specialists, and yet there are so few specialists in the United States, each of whom have lengthy wait lists and have barriers in terms of insurance coverage if you’re traveling from another state (and sometimes even if you have good same-state coverage). And globally, there’s a huge void of knowledge and acceptance of the condition in mainstream medicine, similar to the struggles of other conditions that are difficult to diagnose, like Lyme disease.

We need better diagnostic testing options and reinforced protocols or training of lab technicians to increase testing accuracy. We need better clinical screening tools, and the development of clinical prediction rules that could be more based on history and physical exam to assist in raising suspicion of the disease. We need specialty centers that provide holistic care.

In the US, we are often lacking insurance coverage of this disease, making it difficult to find adequate treatment and access to prescriptions needed. Some medications are not available at all and others are available at outrageous amounts. This is true for many diseases and some of what we need as a MCAS community is unfortunately dictated by the much bigger medical system picture.

Despite all of these challenges, there are a growing number of resources for the disease (see Resources and Reading List sections) and it’s slowly but surely gaining awareness, particularly in the realm of functional medicine doctors and naturopaths. These practitioners are wonderful resources for getting at the root issues that may be underlying or predisposing a patient to excess mast cell activation.

The role of awareness and advocacy is an important one that both patients and healthcare practitioners should embrace. This site aims to contribute to those efforts as well as to provide individualized social support for patients – check out the Social Support section!

Mast Cells United is run by volunteers – please reach out and Contact Us if you see any opportunities to get involved!

 

This content is Copyright © Mast Cells United and is for informational purposes only, and should not be used as a substitute for medical advice. Always seek the expertise of a qualified medical professional for personal health questions and guidance in diagnosis and treatment.

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