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.)
- 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
- 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
- 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
- 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
- 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
- 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.
- 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
- Amin, K., The Role of Mast Cells in Allergic Inflammation, Respiratory Medicine (2012) 106, 9-14.
- 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.
- 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
- 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
- Amin, K., The Role of Mast Cells in allergic Inflammation. Respiratory Medicine (2012) 106, 9-14; doi:10.1016/j.rmed.2011.09.007
- 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.
- 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.
- 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
