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.
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.
If your symptoms occurred recently, OR we were able to provoke a skin response during the physical exam, then a random urine may be enough. If the test is normal, then the symptoms and skin response are not related to mast cell problems.
If you have had symptoms in the past but they are not present now, then we will often recommend testing at a later time. It may still be useful to do a random or 24-hour test now (just in case you are currently having lower-grade dysfunction that is constant or frequent).
3. 24-hour urine testing is only used when we are trying to rule out a lower-grade dysfunction that is present all day, or comes and goes throughout the day. I will usually order this test when I cannot be sure about the timing of symptoms (e.g. When a patient has gone home), or when there have been severe symptoms in the past but symptoms now are somewhat more subtle.
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
1. explained to the patient that the diagnosis of mast cell activation requires certain criteria to be met. The diagnosis of MCAS requires that all the following three criteria be met:
●Episodic, objective signs and symptoms consistent with mast cell activation involving at least two of the following organ systems: skin, upper or lower respiratory systems, gastrointestinal, or cardiovascular. Note that subjective symptoms alone (fatigue, difficulty concentrating) in the absence of signs and symptoms in two other organ systems specified above does not warrant an evaluation for mast cell disorders.
●Evidence of systemic mast cell-mediator release, corresponding temporally to the presence of symptoms. In case of frequent recurrent episodes, mediator release should be ideally documented on at least two occasions. Serum total tryptase is the most specific for mast cell activation, and an increase from the patient's baseline to a level of (1.2 x baseline) + 2 ng/mL is considered indicative of mast cell activation.
Other mediators (ie, 2,3-dinor-11-beta-PGF2-alpha, N-methyl-histamine or LTE4 in a 24 hour or spot urine sample) can be used if serum tryptase assays are not available. An increase of more than 100 percent (ie, to 200 percent or greater) above baseline has been proposed as a diagnostic threshold for these mediators, provided that the test result is above the normal range for the assay. Stated differently, to be indicative of mast cell mediator release, the level of one or more of these mediators should at least double after an episode of symptoms, and the doubled value must exceed the upper limit of normal. However, specific cutoff limits for mediators other than tryptase are not well established, so if these are used to support the diagnosis, the clinical presentation should be highly suggestive of mast cell activation.
●Response to medications that stabilize mast cells, reduce mast cell mediator production, block mediator release, or inhibit the actions of mediators.
These labs will be ordered today.
2. Increase antihistamine and continue with other medications. Will await the results of testing before making further recommendations at this time.
3. Allergen avoidance strategies reviewed.
4. All questions were answered.
5. Encouraged MyChart communication
6. Follow up in 4 weeks and prn.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10866766/
MCAS diagnostic criteria
(Must meet all 3 criteria for formal diagnosis)
Criterion 1: Chronic, recurrent multisystem symptoms
2 or more organ systems affected with episodic (flushing, anaphylaxis like) symptoms that respond to mast cell stabilizers or antihistamines.
Skin: Flushing, hives, angioedema, itching, dermatographism
GI: Abdominal pain, diarrhea, nausea, vomiting, reflux
Cardiovascular: Dizziness, presyncope, tachycardia, hypotension.
Respiratory: Wheezing, throat closing, nasal congestion, sinus pressure.
Neurologic: Brain fog, headaches, anxiety, tremors.
Notes:
Symptoms must be recurrent (2 or more episodes) and wax and wane.
Response to treatment (example H1/H2 blockers, cromolyn) strongly supports diagnosis.
Criterion 2: Objective evidence of mast cell activation
Elevated mast cell mediators during/within 4 hours of symptomatic episode
Symptoms can include:
dermatologic symptoms: such as flushing/redness, hives or wheals, itching with or without a rash, swelling
gastrointestinal symptoms: such as bloating, stomach pain/cramps, reflux, nausea, feeling or being sick, diarrhoea, constipation, dumping syndrome
respiratory symptoms: such as sore throat, hoarseness, wheezing, shortness of breath, throat swelling, stridor
cardiovascular symptoms: such as chest pain, low blood pressure, fast heart rate, fainting or light headedness
naso-ocular symptoms: such as nose congestion, eye watering and itching
neurological problems: such as headache, brain fog (memory or concentration difficulties), numbness, pain or tingling skin, anxiety, behavioural issues, rages
musculoskeletal issues: such as joint and muscle pain, osteoporosis (brittle bones), loss of bone mass
genital and urinary issues: such as genital pain or swelling, pain when urinating, vaginal pain, discharge or itching, bladder urgency or loss of control
extreme tiredness
food allergies or intolerances
anaphylaxis
Common medications that can be used for MCAS include:
H1 antihistamines e.g. loratadine, cetirizine, and fexofenadine
H2 antihistamines e.g. cimetidine, famotidine, nizaditine
Mast cell stabilisers e.g. ketotifen, sodium cromoglicate
Anti-leukotrienes e.g. montelukast
Anti-prostaglandins e.g. aspirin, ibuprofen and naproxen
Vit C, Vit D, quercetin, luteolin
Ideally, the previous steps are combined with a biochemical assessment to show evidence of elevated mediator release from mast cells.
This can be challenging because mast cell mediators may only be elevated during an MCAS episode and then return to normal levels. Therefore, the test needs to be done when the symptoms of MCAS are present.
These tests also need to be conducted by an experienced healthcare provider, using an accredited laboratory to ensure that the test samples are handled appropriately.
The specific mediators of interest, and the thresholds required to attribute MCAS, are the subject of ongoing research and debate among the medical community.
No single mediator test is definitive; a positive result is not to say that a person certainly has MCAS and, similarly, a negative result is not sufficient to rule out an MCAS diagnosis. However, when considered alongside other diagnostic evidence, these mediator tests can provide reasonable confidence in a diagnosis.
Tryptase is often one of the first mediators which is tested for in people with a suspected mast cell disorder (using a blood test), and it remains the only mediator test with a specified increase in levels for diagnosis. However, a tryptase test must be conducted within a short time period (less than 4 hours) after an MCAS ‘flare’ and compared to baseline levels collected 24–48 hours later.
Common comorbidities include connective tissue disorders such as Ehlers Danlos Syndrome (EDS), and Marfans, Postural Orthostatic Tachycardia Syndrome (PoTS), Type 2 Diabetes, Anaphylaxis, Autoimmune diseases, Autoinflammatory conditions, Vasculitis and Addison’s Disease.