Mast cells originate in the bone marrow. They are found in all human tissues and especially at the sites in contact with the environment : skin and mucous membranes. Think of mast cells as first line defense against bodily insults. When triggered they release a lot of mediators that influence the behavior of the local and distant cells in various tissues to maintain homeostasis in the body.
What are mast cell mediators ?
There are different kinds of mast cell mediators. The most familiar ones are:
- preformed mediators : histamine, heparin, tryptase.
- Newly synthesized mediators : prostaglandins, leukotrienes.
Histamine is what is responsible for the wheal & flare response you see when you have skin testing ( that’s why we ask that patients stop antihistamines before any allergy skin testing).
What is the role of mast cells in allergic reactions ?
If you have an IgE mediated allergy to an allergen, those IgEs bind to receptors on mast cell surfaces ( not all allergens cause IgE mediated allergy as there’s cell mediated allergy as well). When an allergen encounter mast cells, they bind their specific IgEs causing a cascade of reactions and releasing various mediators including histamine and tryptase.
What are “mast cell activation diseases” MCAD ?
There is some controversy regarding definition of mast cell diseases. We will define MCAD as any abnormal activation of mast cells with or without proliferation of those cells.
There are generally two types of MCADs: those associated with abnormal proliferation and those who are not. The former includes: mast cell sarcoma, extracutaneous mastocytoma, systemic mastocytosis, cutaneous mastocytosis and they’re all together pretty rare. The latter include what’s known as mast cell activation syndrome which is more common but more challenging to diagnose ( partially because of the controversy of diagnostic criteria). I will focus on MCAS in the next section.
* Systemic mastocytosis can be cutaneous, indolent or severe.
When to suspect MCAD ?
We suspect cutaneous mastocytosis based on physical exam of the skin. We should suspect systemic mastocytosis if there’s a history of idiopathic anaphylaxis, hemonypteral induced anaphylaxis, severe anaphylaxis ( anaphylactic shock), unexplained recurrent gastrointestinal symptoms ( including hepatosplenomegaly) or unexplained musculoskeletal symptoms ( including osteoporosis or osteopenia). We follow the clinical suspicion by checking tryptase level at baseline twice. If the level > 20, we should obtain a BM biopsy. If the level 11.4- 20, we may obtain a bone marrow biopsy for those with urticaria pigmentosa, idiopathic anaphylaxis or hemonypteral induced anaphylaxis. If BM biopsy is not diagnostic of SM, we consider MCAS diagnosis.
What if I don’t have any of the symptoms above, can I still have MCAD ?
Yes. If none of the aforementioned symptoms and lab findings are present then it’s less likely that a bone marrow biopsy is needed as mastocytosis is a less likely diagnosis in that case. But, MCAS can cause a variety of symptoms and findings and should be suspected ( not diagnosed) in any multisystem symptoms where there is no clear diagnosis . Some of the most common symptoms include: urticaria, flushing, pruritus, angioedema, wheezing, throat swelling, syncope, tachycardia, diarrhea, and multiple hypersensitivity reactions (allergic reactions) among others. Clinical suspicion is the first step in making a diagnosis. I typically use a questionnaire that put patients in 3 categories : (unlikely, possible or probable ) mast cell activation. Once the clinical suspicion of MCAS is established, lab assessment is obtained to verify mast cell activation. Ruling out other possible multisystem diagnoses and/or secondary diagnosis is important ( hypothyroidism, celiac, sarcoidosis, amyloidosis, carcinoid, EBV disease, malignance, immunodeficiency, etc). Lastly, response to medications that target mast cells and its mediators should be documented ( anti histamines, cyclooxygenase inhibitors, leukotriene inhibitors, etc).
MCAS can be classified into 1. Primary ( driven by genetic mutation) with or without IgE mediated reactions 2. Secondary driven by IgE dependent hypersensitivity without documented genetic mutations 3.Idiopathic ( no genetic mutation and no documented IgE dependent reactions). In primary MCAS detection of c-kit mutation in blood, bone marrow or tissue is helpful to confirm the diagnosis. Not detecting c-kit mutations, however, does not rule out a primary MCAS (or MCAD).
Why diagnosing MCAS is controversial ?
Since in most MCAS patients there is no evidence of mast cells proliferation, we rely on detecting abnormal activation, usually by detecting abnormal mediators levels. The problem is that there is no standards/consensus to what account as normal mast cells activation vs. abnormal mast cells activation and that’s one reason that makes the diagnosis challenging. Another reason is that most MCAS symptoms are nonspecific and can be seen in a variety of other well known, more common diseases. This lead some physicians to overdiagnose MCAD and many patients to self diagnose it.
Why MCAS affects several organs/tissues ?
As mentioned above, there are a wide variety of mediators released from mast cells and they in turn have effects on multiple tissues/organs in the body causing subacute or chronic waxing/waning or episodic (flares) symptoms.
What labs are usually ordered to diagnose MCAS ?
As expected the labs needed to confirm MCAS include different mediators released by mast cells: tryptase, serum chromogranin A, PGD2 and/or 11-B-PGF2a, heparin, 24 hour collection for PGD2 and/or 11-B-PGF2a and N-methylhistamine, and sometimes a urine test for leukotrienes B4,C4,D4,E4. Screening labs can be done during initial evaluation but unremarkable results in spite of strong clinical suspicion should warrant repeating those tests in association with a flare ( within 1-4 hours).
Why you don’t measure histamine ?
Histamine may be measured during a flare but we avoid measuring it because it has a short half life ( less than an hour).We typically measure its metabolite N-methylhistamine which has a longer half life.
Why lab testing for MCAS is controversial ?
Because 1. Histamine has a short half life and we have to rely on its metabolite N-methylhistamine. 2. PGD2 has a short half life and we have to rely on its metabolite PGF2a 3. Far more PGF2a result from other prostaglandins than from PGD2, making PFG2a not a perfect surrogate marker for PGD2 levels. 4. Heparin and PGD2 samples and urine collections have to remain chilled. 5. PGD2 in urine could be mainly a product of PGD2 release in kidneys and not filtered PGD2. 6. Histamine is also released by basophils.
I have elevated baseline tryptase level. Do I or will I have MCAD?
In absence of clinical suspicion for MCAD you probably don’t have MCAD and there’s currently no strong data to suggest that you will be at a higher risk of developing MCAD. Baseline tryptase levels can be elevated in otherwise healthy people or in a few other medical conditions including chronic kidney disease, familial alpha tryptasemia, leukemias. Acute elevation in tryptase, however, is more likely that not related to MCAD including most IgE mediated reactions.
How do you treat MCAS ?
Treatment of MCAS is highly individualized based on clinical symptoms, other comorbidities, and other medications taken. The most common options :
- Identify clearly any specific triggers : desensitize or avoid.
- Antihistamines : H1 and H2 blockers.
- Leukotriene blockers
# Some details were left out from this summary to simplify an already complex topic.
Ahmad Hamad MD. Board certified in Allergy & Immunology
Allergy Partners in Vienna & Tysons.