Month: August 2023

A Spectrum of Symptoms – Again

Let’s start this post where we started the first post in this series, visiting a support group, a support group which you now know to be one for people with mast cell activation syndrome (MCAS). Here is how four members describe their problems:

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.

Like hypermobility and hypermobile Ehelrs-Danlos Syndrome and like dysautonomia, MCAS occurs on a spectrum among those who have it from mild to severe and localized (sometimes only in the skin) to whole body. Given this diversity, what can the treatment be?

Treatment {1,2,3,5,11, 15}

One of the best summaries of treatment for MCAS that we have seen is in a relatively short pithy journal article by Gerhard Molderings and others. In 2011, he wrote:

“The cornerstone of therapy is avoidance of identifiable triggers for mast cell degranulation such as animal venoms, extremes of temperature, mechanical irritation, alcohol, or medications (e.g., aspirin, radiocontrast agents, certain anesthetic agents). Individual patients may have variable tolerance patterns and avoidance lists, but it is also not uncommon to have no identifiable triggers… Drug treatment of MCAD patients is highly individualized. Curative therapies are not available, and each MCAD patient should be treated in accordance with his [sic] complications. Irrespective of the specific clinical presentation of MCAD, evidence-based therapy consists of trigger avoidance, antihistamines and mast cell membrane-stabilising compounds … supplemented as needed by medications targeting individual mast cell mediator-induced symptoms or complications. {5, pg. 5}”

Said more simply, the first line, or first steps, of treatments for MCAS are 1. finding and avoiding triggers, 2. Antihistamine medications and medications to help prevent the mast cells from releasing inflammatory chemicals, and 3. Treatment of specific symptoms such as headaches, diarrhea, and pain (to list just a few). After this first steps of therapy, there are more advanced levels of therapy.

Non-pharmacological Treatment

Finding individual triggers is sometimes quite hard and sometimes quite easy and as was stated above, sometimes there are no identifiable triggers. Still, for the patient with MCAS, self-monitoring to find the things that make them feel bad is a crucial first step.

Below is a table of common MCAS triggers compiled from a number of sources (some referenced, some not). We divide the list into four main categories. Take a minute to look it over and remember that just because a trigger is common does not mean it is a trigger for any given individual with MCAS, and there can be others not listed here.

Environmental Strong odors. examples: gasoline, perfume Cleaning agents Laundry detergent Mold Dust Venom especially bees Poison ivy, poison oak Pesticides Amalgam dental fillings Rapid temperature changes Changes in barometric pressure Sun exposure

Physical/ Emotional Psychological or emotional stress Strong emotions Self-negativity Extreme mental exertion High sexual arousal Caffeine Physical overexertion Physical stimuli such as vibration, friction, shock or impact Menstrual cycle changes Infection

Dietary Fruits and vegetables with higher levels of pesticides Alcohol Gluten Cow’s milk proteins Baker’s yeast Tomatoes Chocolate Spinach Fermented foods Citrus Preservatives

Medications Antibiotics: Cefuroxime, Vancomycin Anticonvulsants: Carbamazepine, Topiramate Cardiovascular drugs: ACE inhibitors, beta adrenoceptor antagonists Intravenous narcotics: Methohexital, Phenobarbital, Thiopental Local anesthetic: Lidocaine, Articaine, Tetracaine, Procaine Opioids: Meperidine, Morphine, codeine Acidic NSAIDS such as Ibuprofen Nerve medicines: Icatibant, Cetrorelix, Sermorelin, Octreotide, Leuprolide, Bupropion Plasma substitutes: Hydroxyethyl starch, gelatin Muscle relaxants: Atracurium, Miva curium, Rocuronium X-ray contrast materials

We encourage patients with MCAS to start a daily diary in which they note things like:  emotional stress level (which can be noted from 0 = none to 10 = horrible), temperature, barometric pressure, all foods eaten, and especially anything that caused an immediate response. Here in the Pacific Northwest, indoor mold is such a common problem that it is the single most common trigger that patients report to us.

Some of the most difficult triggers to identify can be food triggers. While it can be easy to identify simple single items, identifying groups or families of foods or foods processed in the same way can be difficult. Here is where trial of an elimination diet can be very useful and instructive even though this is not always easy to do. There are a number of good books on this subject and websites. A little research will give more guidance than we can here.

Obviously, once triggers have been identified, effort must  be made to avoid them – changing laundry detergent, changing diet, wearing a mask, etc. – a little effort may produce big rewards.

A final thought about triggers. Looking for triggers when one feels ill and stressed can be hard. Take this slowly. It can be easy to let the search for triggers make a person feel frightened of their world. This is not helpful. Get support as needed. We will talk more about this at the end.

First Line Drugs and Supplements

In any conversation about medications and MCAS, the first recommendation is that the patient look at the medications they are taking. As you can see above, there are a number of medications which can trigger MCAS flare-ups. So, when in doubt, the patient is advise to review their medication list with their physician or pharmacist.

When starting new medications for MCAS, one author gives some clear suggestions:

… Medications should usually be added one at a time, with an adequate interval of time between the addition of successive drugs. Some patients need to begin medications at a lower dose and then gradually escalate to a standard dose. Patients need to be told that the time for noticing an initial symptomatic response may be a few weeks. {3, pg. 234}

The treatments for MCAS are not instantaneous. Patience is needed.

The first line medications used in MCAS are targeted at limiting or blocking the effect of mast cell mediators.

• Medications used to block histamines: hydroxyzine, doxepin, diphenhydramine, loratadine, fexofenadine, cetirizine, ranitidine, cimetidine, famotidine.
• Medications used to block leukotrienes: monteleukast, zileuton, ketotifen.
• Medications used to block cytokines: low-dose naltrexone.

Another first line of defense is medications which stabilize the mast cells so that they do not release their mediators so easily. These medications may include: cromolyn sodium and ketotifen.

There are also a number of supplements which may inhibit mediators and/ or stabilize the mast cell. Some of these are: quercetin, Vitamin C, bromelain, flavonoids, reservatrol, melatonin, cannabinoids, curcumin.

Some of the medications and supplements listed above are available over the counter. It is always important to work with your physician rather than attempting to self-medicate.  Some medications and supplements can have interactions and can cause problems when taken in combinations.

Advanced Treatments {6,15}

For difficult cases of MCAS resistant to the first line of treatment, there can be more advanced treatments. In a deeply referenced review article, Gerard Molderings and colleagues review not only the first line, basic treatments but also go on to describe second, third fourth and fifth lines of therapy. {15}. While we will not go into depth about these higher levels of treatment here, this open access article might be instructive to the inquisitive patient and/ or their provider in a case not making the desired progress.

Pain in MCAS {6}

Three quarters or more of patients with MCAS have MCAS-driven pain. Part of this may be due to the fact that mast cells frequently live close to nerve/ blood vessel bundles, and several of the mediators released by mast cells are also nerve transmitter molecules which can cause pain nerves to fire. {6. Pg E851}. Mast cell mediators can also cause direct inflammation of the nerves, called neurogenic inflammation. This inflammation may be limited to a small area, more widespread or even body wide. In many cases the first line medications and supplements described above will help with this pain.

Getting Help

One of the biggest challenges facing patients with MCAS can be finding a knowledgeable health care provider to work with. While many allergists and rheumatologists are experts at diagnosis and management of MCAS. More and more geneticists are playing a role in healthcare too and can be an excellent source of guidance. Knowledge of MCAS treatment is not limited to specialists though.

We have seen many primary care physicians who have a high level of knowledge and skill with MCAS cases. Lists of primary care physicians usually start with medical and osteopathic doctors specializing in family or internal medicine.  In Oregon and Washington plus a number of other states, naturopathic physicians may also be included in the list of primary care doctors. While a skilled naturopath can be helpful with the medications discussed here, they may also be particularly helpful with supplements and with guidance regarding elimination diets. We have known many excellent and highly skilled chiropractic physicians, and in some regions of the country, they may function as primary care physicians. However, it is our understanding  that in most states, while chiropractic physicians can give guidance on supplements, they cannot prescribe drugs, and so would be limited with more advanced cases of MCAS.

If you suspect that you have MCAS, we strongly encourage you not to try to self-diagnose. Do have a conversation with your primary care provider first. See what they think. If you do not have a primary care physician, seek out a social media support group where there is a ‘hive-mind’ of knowledge regarding local practitioners such as who knows how to manage MCAS, who is accepting patients, and who might accept your insurance. We have found several national MCAS support groups on Facebook. If you have MCAS and cannot find a local group, perhaps you might start one. If you have Ehlers-Danlos Syndrome, there are also a number of online support groups. In Oregon, the Oregon Area Ehlers-Danlos support group on Facebook is an excellent resource including for MCAS.  

Our next blog post series will look at digestive problems and gut pain in hypermobility spectrum disorder and hypermobile Ehlers-Danlos Syndrome.

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

So Many Weird Symptoms

Welcome back. We have been talking about a confusing and challenging problem which clinicians know to very often be associated with hypermobility and hypermobile Ehlers-Danlos Syndrome, although we do not know why.

Take a moment to look at the following table. Can you see what all of these symptoms  might have in common?  

Constitutional – fatigue, temperature sensitivity, sweats, chills, decreased appetite, weight gain or loss, chemical sensitivities	GI System – diarrhea, constipation, nausea, vomiting, bloating, difficulty swallowing, abdominal pain, bad absorption. Diabetes
Teeth – deterioration of teeth and gums despite good hygiene	Immunological – increased vulnerability to infections, autoimmunity, poor healing
Eyes/ Ears – blurred vision, dry eyes, twitching lids, ringing, hearing loss	Liver/ Gall Bladder – abnormal liver tests; gallbladder inflammation
Nose/ Mouth – Nose bleeds, congestion, post-nasal drip, chronic sinus irritation or infections. Burning mouth, sores, white patches, abnormal color or texture	Reproductive/ Urinary – painful urination, frequent urination, incontinence, bladder pain, chronic kidney disease, cystitis, vaginal inflammation, endometriosis, painful intercourse, painful periods, decreased libido
Thyroid — Hypothyroidism, hyperthyroidism	Musculoskeletal – joint pain, bone pain, thinning of the bones, muscle pain, tendinitis
Lungs/ Breathing – Sore throat, hoarseness, chronic cough, laryngitis, wheezing, shortness of breath, obstructive sleep apnea, sensitivity to smells and odors.	Lymph System – enlarged lymph nodes, inflamed spleen
Heart/ Circulation – chest pain, palpitations, high blood pressure, high cholesterol, POTS, Raynaud’s disease	Nervous System/ Brain – numbness, tingling, muscle weakness, seizures, low muscle tone or too much muscle tone, headaches, memory deficits, brain fog; changes in taste, hearing, smell, vision; sleep disorders/ insomnia, restless leg syndrome
Blood – changes in blood tests with too many or too few of different cell types	Skin  — rashes, sores, small red spots, hives, hair loss, brittle fingernails, warts, skin tags

We have been talking about diseases involving mast cells. Mast cells are born in the bone marrow and migrate in an immature form to the tissues of the body where they mature. They are all over the body but especially in places where the internal environment comes into contact with the external world – skin, respiratory system and gut. They are part of the immune system and closely linked to some kinds of allergic reactions. Mast cells give off chemicals called mediators, the first job of which is to create inflammation which is a defensive reaction of the body. Health mast cells are essential. Unhealthy mast cells can create all kinds of problems.

There are two main types of mast cell diseases. In one type of disease, too many mast cells grow in the body. In the second type, mast cells are too sensitive and release their mediators too quickly and easily leading to inflammation. This inflammation can either be either local, often in the skin, or whole body (“systemic”). The too many and too sensitive diseases are not mutually exclusive. Both problems may occur at the same time. Since the great majority of cases of mast cell disease in hypermobility are thought to be of the ‘too sensitive’ type, this will be our focus in this article.

MCAS

Back to our list (above). This is a list of symptoms which can result from mast cells being too sensitive. This is called Mast Cell Activation Syndrome (MCAS or MCAD, mast cell activation disease). In MCAS, the patient is sensitive to one or many, often ordinary, things which can trigger a flare up of limited or systemic inflammation affecting one or several organ systems. These “triggers” can range from dietary to inhaled things like molds to strong emotions or sometimes just heat or cold. While there are common triggers, each individual with MCAS is unique in their triggers.

If you take a moment to look at this list with the eyes of a physician trying to diagnose, you may begin to see how almost every symptom on this list can be caused by anywhere from one-to-many different diseases. This is part of what makes MCAS sometimes so challenging to diagnose. And to make things even more complex, patients with MCAS can present with symptoms that are anywhere on a spectrum from mild to severe, and one individual with MCAS may go through periods of mild symptoms and periods of severe symptoms.

Diagnosing MCAS {1, 2, 3, 4, 9, 10, 11, 14}

So how IS MCAS diagnosed? The current medical consensus is to follow a three-step process.

Criteria One: The first step is to begin to connect the dots of seemingly unrelated symptoms.

In some syndromes like this, there are screening questionnaires which ask specific questions to see if the clinician should dig deeper in the direction of a particular diagnosis. While there are questionnaires available for MCAS, we have not yet found any which have been scientifically validated. So, at this point, the first step toward diagnosing MCAS is simply to look at the list above, or one like it, and check off every symptom that echoes a concern or problem that the patient has. If there are more than a few, MCAS should be considered.

Criteria Two: The second step is to look for elevated levels of mast cell mediators within a short period of time after a flare up of symptoms.

Mast cells have long been a subject for serious study because of how complex they are and how many different functions they perform in the body with much still to be learned. In fact, while reading for this post, we found that authors did not even agree on how many mast cell mediators there are. Estimates ranged from 60-100. Of these mediators, many cannot be isolated by regular medical testing laboratories, and some that can be isolated are so expensive that testing is cost-prohibitive. However, the consensus of scientists is that one test is the first and most important.

The most common test for MCAS is a blood serum test for tryptase. Normal levels of tryptase in the blood range from 0-11.4 ng/mL (nanograms per milliliter of blood). The object of testing for serum tryptase is to see if there has been a surge of tryptase levels in association with a flare up of symptoms. A positive test is a serum tryptase level of 14ng/mL or higher. However, it can be very easy to get this test wrong.

The serum tryptase blood sample is stable and can be kept at room temp, refrigerated or even frozen and the test is reliable, but the sample must be taken at the right time. When a patient with MCAS encounters something that triggers a flareup, tryptase levels in the blood surge but then begin to fall off after two hours. This means that a blood sample for a tryptase test must be collected within that window of time which can be hard or impossible for some patients to do.

In the last post we talked about a type of MCAS called hereditary alphatryptasemia (which is much easier to call HaT). This is a hereditary condition which can be identified by genetic testing. The literature recommends that patients with a blood level of tryptase of 8ng/mL or higher have the genetic test for HaT. {1}

A secondary mediator test is for the chemicals left by the breakdown of histamine in the urine. Urine is collected over a 24-hour period. One practical problem with this test is that the urine sample must be kept chilled, or the test will give a false negative – a test saying there is not a problem when there is. {3}

 Criteria Three: The third step for a textbook positive diagnosis of MCAS is that the patient’s symptoms improve or resolve in response to certain medications. As we will explore in the next part of this series, the most common medications for MCAS are often old well-established anti-allergy medications, antihistamines. There are also medications which help to stabilize mast cells, so they are less likely to release their mediators.

Given some of the complexities we have described here, it might not surprise you that in clinical practice physicians can have a hard time getting a textbook level diagnosis. Because the potential side effects of the medications are generally quite low, some physicians will opt to go straight to a trial of medications if they recognize a pattern in symptoms. The complexity of this process has been recognized in scientific literature.

“…MCAS is a very complex disease from the clinical molecular level (including mediators, genes, and epigenes)… As such, a clinical diagnosis of MCAS – i.e., a case of MCAS worthy of treatment – virtually certainly will never rest on meeting merely a single diagnostic criterion (e.g., a single laboratory test meeting a specific threshold). As is the case with most syndromes, the diagnosis of MCAS will continue for many years to rest on the demonstration of a specific constellation of findings in the context of other findings also congruent with the diagnosis.” {4, pg. 145}

How Common is MCAS? {4, 5, 13}

As we pointed out in the last post, there is still much research needed to clarify the scope of MCAS as a problem. As Kohn and Chang point out:

There have been no epidemiologic studies on mast cell activation syndromes either, and the epidemiology of these syndromes has been more difficult to estimate, as they have only recently been defined. {13, pg. 283}

Estimates in the general population range from “rare” to 17% {4, pg. 139}. One of the leading scientists in this area of study, scientist Gerhard Molderings, writing with other leaders in the field stated in 2011:

MCAD comprises disorders affecting functions in potentially every organ system by release of mediators from and/ or accumulation of genetically altered mast cells. There is evidence that MCAD is a disorder with considerable prevalence and thus should be considered routinely in the differential diagnosis of patients with chronic multisystem polymorbidity of unknown cause. In most cases of MCAD, diagnosis is possible by relatively non-invasive investigation. Effective therapy often consists simply of antihistamines and mast cell membrane-stabilising compounds supplemented with medications targeted at specific symptoms and complications. {5 pg. 6}

In the third and final post of this series, we will look at how MCAS is treated.

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

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}

There 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