Diagnosing MCD

How to diagnose the various forms of Mast Cell Diseases, or MCDs

Editor’s note: we used the term “Mast Cell Activation Diseases” or “MCAD” for years as the umbrella term for all forms of mast cell diseases until about 2020 when it was recognized that not all involve inappropriate or problematic activation.

Some of us are still slowly switching over to the new term “Mast Cell Diseases”, or MCD, which is more inclusive. Many links on my blog will refer to the old incorrect term (MCAD) for now, as it would break a lot of my site to change it. (Working on it.) Last Updated June 26, 2024

The Journey Begins

In the majority of cases, most patients reading this have symptoms of mast cell activation syndrome or MCAS. So most will likely need to diagnose MCAS, which is still a controversial and poorly known diagnosis, even if a very common one. But note that it is a diagnosis of exclusion of Mastocytosis and other potential causes of mast cell activation. (Much like how hEDS and HSD are diagnoses of exclusion too.)

MCAS involves inappropriate (excessive) mast cell activation. (Your mast cells fire off too easily and often and to non-protein triggers like sunlight, vibration, stress, scents, and pressure, along with chemicals and foods.) This causes allergy-like reactions throughout the body. Rule out regular IgE allergies but if you are still reacting despite testing negative for IgE allergies, or to non-organic proteins or chemicals (scents, solvents, perfume, pain, stress, laughter or crying), consider MCAS.

The forms of Mastocytosis involve abnormal numbers or clumps of mast cells throughout the body and can also sometimes be deformed. Sometimes visible on the skin (cutaneous), but sometimes not (systemic, and other forms). They may also be over-active, so you may have a double burden of too many over-active mast cells. (Which sucks, yes.)

And there are some hybrid conditions (MMAS) and other forms of Mastocytosis and Mast Cell Leukemia your doctor can pursue if suspected.

And some people may have the newly discovered (in 2016) diagnosis of HaTS, or Hereditary alpha-Tryptasemia. Which is suspected in patients with elevated basal (non-flaring) serum tryptase of >8 ng/ml, plus signs of hypermobility spectrum disorders or EDS and MC activation also. (But be sure to rule out systemic Mastocytosis with an elevated baseline serum tryptase also.) HaTS involves excess numbers of alpha-tryptase gene copies lending to excess production of tryptase. (See testing below for more.)

Get the Mast Cell Diseases primer from TMS here

In general, if you have a patient presenting with signs of MCAS (flushing, GI trouble, wheezing, itching, swelling from angioedema, hives, headaches, more), but with additional persistent cutaneous spots, be sure to rule out forms of mastocytosis. (Cutaneous and systemic.)

Cutaneous mastocytosis will involve persistent spots on the skin that flare up into hives and usually itch when flaring (having a reaction), but then don’t fully disappear once that flare has died down. (Regular hives, aka “urticaria” just come and go with excess histamine episodes from allergies, MCAS or stress. Key point being, they don’t persist.) Such patients may first present to a dermatologist, since the skin involvement is most noticeable. But any doctor can “spot” this, and make the referral to an allergist or immunologist as needed.

However, someone can have Systemic Mastocytosis with no cutaneous symptoms so do proper work up when warranted. (See below.)

MCAS will involve episodic allergy-like flares and symptoms (flushing, hives, wheezing, sudden onset diarrhea or nausea or gas and bloating, urination, uterine cramping, brain fog, headaches, pain, etc.) and some outright anaphylaxis* sometimes from reactions triggering otherwise normal amounts of typically distributed well formed mast cells. (Mast cells line all body surfaces to signal invasion and ward off infections. They signal the secondary immune system to activate when bacteria or viruses are detected. Whence it often feels like you have allergies when you have a cold.)

You will not usually have an elevated baseline tryptase with MCAS. Make sure you’re not in a flare when you get your baseline tryptase level tested. And if you are always flaring, check your environment for triggers like hidden mold. NB we can react to things like chlorine or fluoride in our drinking water, which can also be tricky to deduce, since it’s ubiquitous. I recommend a ZeroWater pitcher (no affiliation, fairly inexpensive compared to other water filtration solutions) to try testing to see if this helps. (I learned this the hard way myself.)

*Some signs of anaphylaxis include but are not limited to:

  • Skin reactions, including hives and itching and flushed or pale skin
  • Low blood pressure (hypotension)
  • Constriction of the airways and a swollen tongue or throat, which can cause wheezing and trouble breathing
  • A weak and rapid pulse
  • Nausea, vomiting or diarrhea
  • Dizziness or fainting

You will always have symptoms in two or more organ systems during anaphylaxis, even if your throat does not close. (e.g. a BP drop plus flushing or hives is enough. Or sudden nausea or vomiting and dizziness e.g.) Not all experience throat closing. Every body is different. And some can experience blood pressure spikes as well. Talk to your doctor about your signs and best treatment plan including epi-pens and emergency medications like Benadryl.)

Decision Tree

If you have small itchy spots on your skin (anywhere) that turn into hives when flaring, but never fully disappear after the flare, along with several signs of mast cell activation or anaphylaxis (wheezing, itching, hives, nausea, asthma, cramps, diarrhea, frequent urination, flushing or swelling – angioedema – in the skin or around lips or eyes or elsewhere), look into Cutaneous Mastocytosis. (This makes CM semi-easy to suspect.)

If you have an elevated baseline (non-flared) tryptase level (>3 ng/ml) and are not living in a moldy environment that may be keeping you constantly flared or triggered (mold is a HUGE mast cell trigger), look into Systemic Mastocytosis and or HaTS or other forms of mast cell disease as appropriate (see below). (If you are living or working in a moldy environment, try traveling and getting tested away from that environment to see if your baseline tryptase is indeed high or low outside of that environment. Even just taking a hotel room or staying with a friend for a few days in your same area may work.)

Mastocytosis

Signs of Systemic Mastocytosis from the AAAAI:

Mastocytosis may be suspected when there are persistent symptoms of mast cell mediator release, especially in the absence of known triggers (emphasis mine, JG) of mast cell mediator release, such as allergy or certain medications. Patients may experience one or more of the symptom groups listed.

Symptoms of Mastocytosis include:
•    Anaphylaxis
•    Itching, flushing, hives, swelling
•    Wheezing or shortness of breath
•    Sinus congestion and pressure
•    Throat swelling
•    Palpitations, changes in blood pressure, dizziness, fainting
•    Nausea, vomiting, abdominal pain, diarrhea
•    Uterus cramps/bleeding
•    Bone or muscle pain, osteopenia, osteoporosis
•    Headache, brain fog, anxiety, short memory span, depression

Potential triggers for mast cell mediator release in mastocytosis include:
•    Heat, cold or sudden temperature changes
•    Stress: emotional, physical, including pain
•    Environmental: weather changes, pollution, odors, perfumes, chemicals
•    Allergens: pollen, pet dander, dust mites
•    Exercise
•    Fatigue
•    Food or beverages, including alcohol
•    Drugs (opioids, NSAIDs, antibiotics and some local anesthetics) and contrast dyes
•    Venoms (bee, wasp, mixed vespids, spiders, fire ants, jelly fish, snakes, biting insects, such as flies, mosquitos and fleas, etc.)
•    Infections (viral, bacterial or fungal)
•    Mechanical irritation, friction, vibration
•    Vaccines

From The Mast Cell Diseases Society (TMS), testing for all of the above (except HaTS) can include:

Tests

Bone Marrow Biopsies when suspecting SM (to search for excess mast cells in clumps there, be sure to use proper staining!) (see TMS Testing Page)

KIT mutations (see TMS testing page) to confirm SM (though it is not present 100% of the time).

Routine and Follow-up Testing for Systemic Mastocytosis (SM) and Smoldering SM (see TMS testing page)

Diagnostic Workup for Advanced Systemic Mastocytosis Variants or Associated Hematological Diseases (see TMS testing page)

MCAS

WHEN ALL FORMS OF MASTOCYTOSIS and other MCDs have been ruled out, and you are still having anaphylactoid reactions in the absence of true IgE mediated allergies (or in addition), then try to test for MCAS. If you are constantly flaring/reacting, check your home or work environment for any constant triggers, especially mold or chemicals that may be constantly triggering you. Try to keep a journal of your reactions, especially if they are not constant. This can help find your triggers. (They differ for all of us.)

HOWEVER: testing for MCAS is notoriously difficult, expensive and unreliable. Essentially, you are trying to capture evidence of a rise in mast cell mediators in blood or urine after a flare.

They are primarily looking for a rise in serum tryptase of over 20% plus 2 ng/ml over your baseline non-flared tryptase levels. So, you will get one or more baseline tryptase tests. Then, try to get a test as or after you’re reacting to something. (This can be tricky and even a bit dangerous.) The flared tryptase level should be 1.2 x baseline + 2 ng /ml higher than your baseline. But you may not succeed at this for numerous reasons, including, well, being in anaphylaxis, or stuck on the toilet and unable to get to the ER for the test. (And may not even run it if asked or ordered.)

This does not necessarily mean you do not have MCAS. An increasing number of doctors are thankfully now willing to give a “presumptive” or working diagnosis of MCAS for this reason, and let you start treating for same. Ideally they should let you start treating for same even before you can get the testing done, though you may wish to stop treatment while trying to get tested. There’s no need to keep suffering, when much MCAS treatment is relatively cheap and easy to access, including OTC antihistamines, plus some mast cell stabilizers.

From TMS:

“An increase in the serum level of tryptase, above baseline and within a narrow (generally accepted as one to two hour) window of time after a symptomatic episode, is proposed as the preferred method for providing evidence of mast cell involvement.3-5 An international consensus article provides a method for calculating the required minimum rise in serum tryptase:5

After a reaction, a level of serum tryptase that is a minimum of 20% above the basal serum tryptase level, plus 2 ng/ml, will meet the second criterion for a mast cell activation event. For example, if a patient had a basal (baseline level, at least 24 hours after a reaction) serum tryptase level of 8 ng/ml, a 20% rise, plus 2 ng/ml, would be 11.6 ng/ml. To meet the above criterion for serum tryptase, the patient would need a post-reaction serum tryptase level above 11.6 ng/ml. The calculation would be conducted as follows:

(8 ng/ml x 1.2) + 2 ng/ml = 11.6 ng/ml

(basal level, plus 20%) + additional 2 ng/ml = the serum tryptase level, after a reaction, that must be exceeded in order to meet a rise in serum tryptase considered a mast cell activation event

Me Jan again: In addition to the above, some smart doctors may order a 24 hour urine N-methylhistamine and or PGD2 metabolites test. (Two mast cell mediators that commonly rise in flares.) This is notoriously unreliable and difficult to pass, as PGD2 (or its metabolites) disappear within 2 minutes at room temperature. And the human body is already 98.6 on average, so… it’s tricky to do. (You need to chill the pee hat between uses/including before first use, chill the storage jug they give you, and maybe even also some additional frozen mason jars for chilling individual batches away from the collection jug so a new warm one doesn’t degrade the last catch. (Do not freeze your urine samples/collection. Just keep chilled/refrigerated.)

Then, take the jug ON ICE to the lab, who must ALSO keep it chilled at all times or, no luck. If they’re shipping your frozen aliquot across country to get to the only lab that process them? You have to also hope the FedEx truck doesn’t get stuck in traffic in the sun and it heats up there. Yes, this has been a proven problem. And yes, you have to keep a lot of stuff in your fridge. Don’t say I didn’t warn you!)

The TMS go on to add this key post script that may bring relief to many:

TMS does recognize, however, that capturing a mediator rise is not always easy (emphasis mine, JG), and depends on many factors, internal and environmental. We have seen 24-hour urine samples test negative simply because the lab technician did not refrigerate the sample in a timely manner (when the test was repeated and handled properly, the result was positive). Therefore, we support the use of a clinical diagnosis and advise that the patient continues to be treated when the following criteria have been met:7

  • An exhaustive work-up has ruled out other medical conditions with similar symptoms and presentations
  • The patient has exhibited consistent symptoms of mast cell activation in 2 or more organ systems during the same period of time, such as skin, gastrointestinal tract, central nervous system, etc.
  • The patient responds to antimediator therapy
  • The patient is monitored on a regular basis, with testing for mediator rises performed periodically, by a mast cell or other specialist and/or in conjunction with an established local allergist or other physician
  • The patient is evaluated for other disease processes on an ongoing basis in order to be inclusive of any new changes in the patient’s condition”

Hereditary Alpha Tryptasemia Syndrome (HaTS) aka “Familial Tryptasemia”

Diagnosing HaTS involves getting a baseline serum tryptase (or two), and, if suspected, a genetic test that has been developed for it. From Dr. Lyons:

“The first step in diagnosing HαT involves having your physician measure a total serum tryptase level. In the large majority of individuals with HαT, serum tryptase levels are over 8 ng/mL. Most genetic sequencing techniques available for clinical use are unable to determine the number of α– and β-tryptase encoding sequences anyone has.  However, a specialized test that uses a technology called droplet digital polymerase chain reaction (ddPCR) is available for clinical use from a Clinical Laboratory Improvement Amendments (CLIA)-certified clinical laboratory: https://genebygene.com/tryptase/  The assay run for clinical use is the same assay that was developed by Lyons et al. in 2016. Tryptase genotyping by ddPCR should be considered in symptomatic individuals with elevated basal serum tryptase levels, and is currently the only test available to confirm the diagnosis of HαT.”

More information on HaTS:

Video: Update from Josh Milner MD of the NIH on study of CTDs (like/including EDS)/MCAD/POTS aka “Familial Tryptasemia” – high tryptase level not required 2015 via Dysautonomia International. See articles below for study results published since October 2016:

Please apprise me of any updates or corrections needed, thank you.