Mast Cell Activation Syndrome (MCAS) 1

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2023.07.12 Mast Cell Activation Syndrome Blog. 1

Different But the Same

Four people with chronic health problems met in a support group. They all have the same problem, see if you can tell what problem the four group members share. {2}

The first member shares that they have a lot of skin problems – redness itching, hives. They also have a lot of sneezing plus bouts of diarrhea. The second member struggles with mild low blood pressure, mild headaches, cough, mild shortness of breath, mild diarrhea, nausea, mild abdominal cramping. The third member has long-standing and prolonged problems with: feeling inflamed all over, skin problems like the first member, almost constant diarrhea combined with frequent nausea, a chronic cough, fatigue, and depression. The fourth member has truly been disabled by their problems:  daily sweating, frequent fevers, severe skin problems, shortness of breath with wheezing, severe gut pain plus cramping and frequent vomiting, almost constant diarrhea, and worst of all, unpredictable episodes of anaphylactic shock for which they must carry an epi-pen.

Baffled? Well, you are not alone. At first glance, these four people seem to have only a few symptoms in common and the ones they do have do not immediately seem to point to any one disorder or problem. So, it may not come as a surprise that their doctors struggled to identify their problem as well.

These four people all have Mast Cell Activation disorders. Member one has localized reactions. Member two has mild whole-body reactions. Member three has chronic reactions and member four has severe whole-body reactions.

Why is this topic important to our patients? Because these disorders are recognized by many clinicians as common in patients with hypermobility spectrum disorders and hypermobile Ehlers-Danlos Syndrome. Additionally, they are becoming recognized as common in the population.

Mast Cells {8, 9, 10}

So, what are these mast cells and why are they giving these four people so many problems? Mast cells are actually a very good thing. We really want to have them in our bodies. In fact, they are so good that virtually all mammals have them showing that they are a very old feature of our physiology from an evolutionary perspective.

They are considered to be a part of the immune system. Mast cells are sentinels. They perform many functions but first and foremost they guard the body against foreign substances and invaders such as bacteria, viruses, dirt, thorns, splinters and such.

Mast cells sense and release their mediators in response to a number of different kinds of substances including foreign chemicals and toxins and venoms. They also release in response to some internal proteins of the body. And they release their mediators in response to foreign invaders to the body such as bacteria, viruses, thorns, splinters and generally dirt. Sometimes they link up with the proteins used by the immune system, especially immunoglobulin E (IgE, a protein used by the immune system), to create an allergic reaction, sometimes they do not.

There are more than 60 identified mediators released by the mast cells. One of the strongest functions of the mediators is to create inflammation. Inflammation is not infection. It is one of the first lines of defense of the body. The word inflammation comes from the same root as the word flame. So, when you think of inflammation, think red, hot, swollen, painful.

There are mast cells all over the body. They are born in the bone marrow as immature cells and then travel through the blood to mature and reside in the connective tissue. They are especially found wherever our body comes in to contact with the external environment such as the skin, digestive tract and the respiratory tract including the nose and throat. They are commonly grouped around nerves, blood vessels and lymphatic vessels. (The lymphatics are the backup waste removal system of the body.)

Hopefully, you can see even from this brief description how good it is to have mast cells. But like the person in the nursery rhyme, when they are good, they are very good and when they are bad, they can be very bad.

Mast Cell Diseases {1,2,3,9,10,11}

A purple circle with a white background Description automatically generatedThere are a number of diseases which are caused by mast cells. And this topic can become very complex very quickly involving genetics, epigenetics, immunology, oncology, and a great deal of biochemistry. We will try to keep it simple both for you and because we too are limited in how far we can go down this deep rabbit hole.

A mast cell full of mediator granules. Image courtesy of WikiMedia Commons                                                                                                                 

In very general terms, mast cell disorders fall into two categories: those involving too many mast cells and those involving mast cells which are too sensitive and release their mediators too easily. But these two categories can overlap where there are both too many mast cells, usually imperfectly formed or defective, plus where cells are hypersensitive and too quick to release their inflammatory mediators.

Mastocytosis

The most common term used for too many mast cells is mastocytosis. In this condition, mast cells grow wildly and are called clonal or monoclonal cells. The process of this wild growth is called neoplasia which is the word used to describe tumor formation. (This does not necessarily mean cancer.)  Mastocytosis can be localized and just in the skin, or throughout the body — systemic.

Included in the types of mastocytosis are localized tumors which may be benign (i.e., not cancerous) or malignant (cancerous). There is a category of mast cell disorders in which too many mast cells grow but are not neoplastic – called mast cell hyperplasia. And a category where they are cancerous and circulate in the blood, a form of leukemia. While patients with hypermobility and hypermobile Ehlers-Danlos Syndrome can be afflicted by a disorder involving too many mast cells, these conditions are rare, and the too-sensitive disorders are the rule.

Mast Cell Activation Syndrome (MCAS)

When mast cells become overly sensitive and release their mediators too quickly causing unneeded inflammation, this is called Mast Cell Activation Syndrome (or disease or Disorder), abbreviated MCAS. There are five categories of MCAS.

  1. Primary MCAS. This is a case where mastocytosis is present AND the mast cells are too sensitive. (Mastocytosis may occur without MCAS too.) This may be limited to the skin or systemic. In recent years, a genetic defect in a factor which helps the mast cells mature has been found, a KIT D861V mutation.
  2. Secondary MCAS. As we have said, mast cells work intimately with the immune system and IgE. In secondary MCAS an allergic reaction hypersensitizes the cells. Tests for genetic defects are negative in contrast to primary MCAS.
  3. HaT+ MCAS. In the last few years, scientists have found a genetic defect which affects an enzyme: alpha tryptase. This can lead to elevated blood levels of alpha tryptase, which is an important mast cell mediator. Since this defect is genetically transmitted and so runs in families; the defect is identified with a genetic blood test.
  4. Mixed forms of MCAS. This is a category in which there is some combination of mastocytosis, allergy, and/ or HaT+. Patients with Mixed MCAS may be at a very elevated risk of anaphylaxis which is a severe life-threatening allergic reaction. These patients tend to be particularly sensitive to bee stings and need to carry an epi-pen.
  5. Idiopathic MCAS. In these cases, the criteria for diagnosing MCAS are met (see below) but there is no mast cell neoplasia, no allergic reaction and no HaT genetic defect. This is thought to be the main type of MCAS among patients with hypermobility.

MCAS and POTS {7}

If you have been following these blog posts, you may have read our description of dysautonomia and POTS (postural orthostatic tachycardia syndrome). Dysautonomia is an imbalance of the automatic (aka autonomic) nervous system and can occur as a result of a number of different kinds of disease processes but is very common in patients with hypermobility and hypermobile Ehlers-Danlos Syndrome. POTS is the more severe end of the dysautonomia spectrum and results in racing heart and feeling dizzy or ill with sustained standing. There are several mechanisms in the body which can cause this, in one of these mechanisms, the least common, the “fight or flight” half of the autonomic nervous system gets stuck in a fast forward or “on” mode. This is called hyperadrenergic POTS.

We found one study which evaluated a solid number of patients (177) for MCAS and analyzed the results in-depth. As a result, the authors concluded that there are some patients with MCAS in whom the excessive release of histamine in their system, which causes opening of blood vessels, was a factor in their POTS. They concluded that patients with POTS who report flushing, reddening of their face or chest, as part of their symptoms, should be evaluated also for MCAS.

MCAS and Hypermobility Spectrum Disorder (HSD)/ Ehlers-Danlos Syndrome (hEDS) {3, 13}

In preparing this blog post, we searched the literature for information that might clarify what the relationship is between HSD/hEDS and MCAS. The strongest article we found in the search concludes:

There is currently no scientific evidence of any association between MCAS, POTS, or hEDS. We are not refuting that a possible association between these clinical entities may exist; we are simply arguing the need for reevaluation of these associations in light of new considerations, such as updated diagnostic criteria and updated guidelines for each. Furthermore, a scientific approach is warranted in linking these clinical entities. An evidence-based, common pathophysiologic mechanism between any of these two conditions, much less all three conditions, has yet to be described. {13, pg. 293}

Wow. Ok. So, before you ask the question “if there’s no proof, why am I bothering to read this blog?,” please let us give you some context. In a few words, what these authors are doing, and doing very well with an exceptionally well written article is saying to the research community “get on it people!.”

These authors are correct, there has been too little research in the connections between MCAS and HSD.hEDS (and too little research between the connection between POTS and HSD.hEDS.)

Why is this so? The first reason is the natural evolution of medical knowledge. The association between MCAS, POTS and hEDS has been noticed by clinicians for some time. Clinicians are empirical (trial and error) scientists who need to know right now what researchers have decades to figure out. And it often does take researchers decades to  really define all the aspects of a problem — IF they are ‘on it’. In this case, that problem is: how many hypermobile patients have MCAS and why?

The second factor here is a matter of definitions. Before you can research a problem well, you must define it. And the precise diagnostic definitions for both hEDS and MCAS have both been published relatively recently. The diagnostic criteria for hEDS were published in 2017 and the leading paper on the diagnosis of MCAS appeared in 2012. It can take time for the connection between problems to be quantified (often by studies that look back across a number of years at patient cases) and then hypotheses about the reason for the connection to be formed and tested. There simply has not yet been enough time for clear evidence to emerge. Yet, clinicians need to know right now.

In part 2 of this blog series on MCAS, we will start with talking about diagnosis. Here is a little spoiler though. It is tricky to diagnose. All of the many different kinds of symptoms can occur in many other diseases, and there are some challenges to getting accurate testing. Even before that though, given how recently the diagnostic criteria have been defined, there are more than just a few physicians out there who may not know or even consider MCAS as a diagnosis. The first hurdle to getting it diagnosed can be having the possibility come into the physician’s mind for consideration.

Until then, cheers!

Zebbie & Mark

Zeborah Dazzle, PT, WWF & Mark Melecki, PT, DPT, OCS

Good Health Physical Therapy and Wellness.

References (Note: all the references below are open access on the internet.)

  1. Valent, P., et. al., Diagnosis, Classification and Management of Mast Cell Activation Syndromes (MCAS) in the Era of Personalized Medicine. International Journal of Molecular Sciences, 2020, 21, 9030; doi:10.3390/ijms21239030
  2. Valent, P., et. al., Mast Cell Activation Syndromes: Collegium Internationale Allergologicum Update 2022. Int Arch Allergy Immunol 2022; 183: 693-705; doi:10.1159/000524532
  3. Senevirante, S.L., et. al., Mast Cell disorders in Ehlers-Danlos Syndrome. American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 175C:226-236, 2017, doi: 10.1002/ajmg.c.31555
  4. Afrin, L., et. al., Diagnosis of Mast Cell Activation Syndrome: A Global “Consensus – 2”. Diagnosis 2021, 8(2): 137-152, https://doi.org/10.1515/dx-2020-0005
  5. Molderings, G.J., et. al., Mast Cell Activation Disease: A Concise Practical Guide for Diagnostic Workup and Therapeutic Options. Journal of Hematology and Oncology 2011, 4:10, http//WWW.jhoonline.org/content/4/1/10
  6. Wirtz, S. & Molderings, G.J., A Practical Guide for the Treatment of Pain in Patients with Systemic Mast Cell Activation Disease. Pain Physician 2017, 20:E849-E861.
  7. Shibao, C., et. al., Hyperadrenergic Postural Tachycardia Syndrome in Mast Cell Activation Disorders, Hypertension 45(3), 1 March 2005, 385-390, https://doi.org/10.1161/01.HYP.0000158259.68614.40
  8. Amin, K., The Role of Mast Cells in Allergic Inflammation, Respiratory Medicine (2012) 106, 9-14.
  9. Valent, P., et. al., Definition, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal. In Arch Allergy Immunol 2012; 157: 215-225. DOI:10.1159/000328760.
  10. Alvarez-Twose, I., et. al., Current State of biology and Diagnosis of Clonal Mast Cell Disease in Adults. International Journal of Laboratory Hematology 2012; 34: 445-460, doi:10.1111/j.1751-553x.2012.01427.x
  11. Valent, P., et. al., Advances in the Classification and Treatment of Mastocytosis: Current Status and Outlook Toward the Future. Cancer Res. 2017 March 15; 77(6): 1261-1270. Doi:10.1158/0008-5472.CAN-16-2234
  12. Amin, K., The Role of Mast Cells in allergic Inflammation. Respiratory Medicine (2012) 106, 9-14; doi:10.1016/j.rmed.2011.09.007
  13. Kohn, a., Chang, C., The Relationship Between Hypermobile Ehlers-Danlos Syndrome (hEDS), Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS). Clinical Reviews in Allergy & Immunology (2020) 58: 273-297; https://doi.org/10.1007/s12016-019-08755-8.
  14. Leru, P.M., et. al., Mast Cell Activation Syndromes – Evaluation and current Diagnostic Criteria and Laboratory Tools in Clinical Practice (Review). Experimental and Therapeutic Medicine 20:2348-2351, 2020. Doi:10.3892/etm.2020.8947.
  15. Molderings, G., et. al., Pharmacological Treatment Options for Mast Cell Activation Disease. Arch Pharmacol (2016) 389:671-694; doi:10.1007/s00210-016-1247-1