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Dysautonomia is an umbrella term for dysfunction of the autonomic nervous system. Postural orthostatic tachycardia syndrome (POTS) is one such condition and is common in individuals with hypermobility spectrum disorder (HSD) and with hypermobile Ehlers-Danlos Syndrome (hEDS).

Dysautonomia involves dysfunction of the autonomic nervous system which encompasses a wide range of symptoms. The autonomic nervous system is responsible for regulating automatic bodily functions such as heart rate, digestion, kidney function and blood pressure. When the autonomic system is not functioning properly it can cause issues such as lightheadedness, malnutrition and unstable blood pressure. Additionally, dysautonomia can cause dehydration. Individuals with dysautonomia frequently have an imbalance in the hormonal system within the kidneys that is responsible for fluid and electrolyte regulation. These hormones control how much water as well as how much of the body’s electrolytes are released in the urine. This hormonal imbalance can result in chronic dehydration and deficiency in certain minerals including sodium, potassium and magnesium. An effective way to combat this dehydration and accompanying loss of minerals is to supplement electrolytes. 

How the body utilizes salt, magnesium and other individual electrolytes is complex and beyond the scope of this article but in general, symptoms of low electrolyte levels include dizziness, lethargy, abnormal heart rate, digestive upset, muscle cramps, muscle weakness and numbness or tingling in limbs, fingers, and toes

To ensure sufficient sodium levels, recommendations in the literature for salt intake vary from 8-10 grams to 10-12 grams. We have found that appropriate levels can vary substantially from one person to the next. One way to manage salt intake when seeking to improve symptoms of dysautonomia is to start with about 3gm of added salt per day and increase by 1 gram per day up to a maximum of 12 gm per day depending on symptoms. In other words, if  you feel best at 9 gm/ day, that should be your intake unless symptoms change. Doctors can also test for sodium levels using a blood test which can assess the efficacy of supplementation. 

Increasing sodium intake may be sufficient to relieve symptoms of dysautonomia but you may find that including other minerals is more beneficial for you. If you choose to take an electrolyte supplement that is more than just sodium, there are many on the market to choose from. Some contain sugar, and others  contain artificial sweeteners such as stevia which may or may not appeal to you. Additionally, electrolyte supplements contain varying amounts of sodium and other vitamins and minerals such as potassium, magnesium, B vitamins and calcium. With so many choices on the market we wanted to make it a little easier to explore your options.  We have compiled a list of electrolyte supplements along with some of the nutrition content and cost so you can easily compare some of the options out there. 

For those of you who prefer other options you can make on your own here are a few recipes we recommend. Note that ⅛ tsp of salt contains approximately 300 mg of sodium.

• Seltzer with ⅛ tsp a mint leaves in a tea ball with a squeeze of lemon or lime juice
• Coconut water, lemon juice, maple syrup or honey and ⅛ tsp salt. Try this one blended.
• Raspberry lemon magnesium citrate,⅛ tsp salt and water.
• Blend ½ cup strawberries, juice of 1 lime, water and ⅛ tsp salt. Add a little honey if you prefer more sweetness.

Keep in mind that electrolyte replacement is not always sufficient for management of dysautonomia and it is just one tool you can implement to manage symptoms. We encourage you to talk to your doctor about what will work best for you.

Electrolyte Comparison Chart:

Written by Jennifer Oechsner PTA

Diet, HSD, hEDS and Gut Problems

Through the past two blog posts we have considered the kind of tummy problems which often plague people with hypermobility spectrum disorder (HSD) and hypermobile Ehlers-Danlos syndrome hEDS). As we have discussed, there are medical treatments for many of these problems and sometimes treatments which physical therapists can provide, but diet is such an important topic that we will devote this third and final post to it.

As important as diet is, our discussion must be limited — for two reasons. First, any clinician who treats patients with HSD and hEDS will tell you that while there are many common patterns, every patient’s presentation and experience is different. This variability is true with diet too. While there are some good general rules for diet and even some specific dos and don’ts for certain illness patterns, there are no fixed rules for everyone. A short way of saying this is that just because a food may be considered healthy, doesn’t mean it will work for you.

Second, there is still so much that is not known. In reviewing the medical literature for this post, we looked for actual studies with subjects in which different dietary approaches were taken and evaluated with different subjects. These are very rare. There is a desperate need for real research in this area. Yet there are a few science-based healthcare providers trying to shine a light in this area. One of those is Heidi Collins, MD.

Dr. Collins is a physiatrist, a medical doctor specializing in physical medicine and rehabilitation, who has given a number of talks on this subject which are available on YouTube and through the Ehlers-Danlos website. Dr. Collins also has hEDS. We will rely on her lecture notes a good deal here.

The Overall Goal:

After so many words being devoted to how gut problems for most people with HSD and hEDS can be understood through the model of structure, nervous system, inflammation, and the functional overlap between these, it seems a good idea to  start with two goals for diet.

1. Avoid or reduce negative food reactions.
2. Maximize nutrition for optimal health.

General Dietary Guidelines {21, 22, 23, 27}

These general guidelines are focused on reducing gut inflammation and with this gut wall permeability (“leaky gut”) and maximizing nutrition.

1. Eat small meals at frequent intervals. Smaller meals can help your system digest food and eating 4-6 meals, or 3 meals and 2-3 snacks, can help avoid cravings and keep blood sugar level.

• Drink plenty of fluids, especially water minimizing or eliminating caffeine and alcohol. The US Academy of Sciences suggests 3-4 liters of water through the course of a day depending on activity level. Adding electrolytes to this is quite common especially for people with signs and symptoms of dysautonomia. Often, sodium is tracked to attain the right level of electrolyte replacement with a target of 3-20,000 mg per day. (Note 1,000 mg is 1 gram. Only the MOST SEVERE cases of POTS would supplement at the 20-gram level). Both POTS and MCAS do not tolerate alcohol well. Depending on the level of dysautonomia, some to no caffeine may be tolerated.

• Eat real food. Popular nutrition author Michael Polan coined the phrase, “Eat food, mostly plants, not too much.” And overall, this is a good summary of a healthy diet.
  • Never eat long shelf-life processed or preserved foods. In other words, avoid additives and preservatives as well as artificial flavors and colors. For sensitive individuals, avoiding preservatives can include the additives in the packaging materials.
  • Eliminate rapidly absorbed carbohydrates. Nutritionists have developed the glycemic index. This is a scale from 0-100 comparing how rapidly a carbohydrate is absorbed into the bloodstream compared to pure glucose (100). Only carbohydrates have a glycemic index rating, oils, fats, proteins do not. The lower the rating of the carbohydrate the better, and as a rule staying at 50 or below is helpful. There are books available which give the glycemic index of specific foods. With this important guideline there are some other important recommendations:
    • No artificial sweeteners or “natural” non-sugar sweeteners such as aspartame (NutraSweet) , neotame, advantame, sucralose and saccharin, stevia, agave, monk fruit extract, sorbitol, lactilol, xylitol.
    • No high fructose corn syrup.
    • Consume natural sugars such as honey, molasses, brown sugar, coconut sugar, cane, or beet sugar conservatively – in other words in moderation.
    • Eat organic fruit in moderation.
  • Consume non-GMO vegetables, seeds, and nuts. GMO means “genetically modified organism.” Telling which foods are GMO can be challenging. Do your best. In the meantime, remember, feeling afraid of your food can be as harmful as eating a few things that are not perfect for you.
  • Limit red meat.
  • Eat salt liberally (especially if you have signs of dysautonomia or POTS).

• Avoid your triggers. After reading the blog posts about MCAS, we hope you are on the lookout for foods, environmental factors, and emotional states that trigger feeling ill.

• Generally, eating foods high in dietary fiber such as whole grains, raw or lightly cooked non-starchy vegetables and most fruits, is helpful in moving waste through the digestive system.

• Eat probiotics and prebiotics daily. Probiotics are supplements of the bacteria that live in your gut. This is a rapidly evolving area of nutrition and food science. Prebiotics are foods which pass through the gut and into the colon. This normally means that they are high in various kinds of fiber which feed the gut bacteria. Examples of pre-biotics can include: potatoes, bananas, barley, oats, asparagus, burdock root, garlic, leeks, onions, soybeans, yams, apples, apricots, carrots, green beans, peaches, raspberries, tomatoes. Those of our readers who have irritable bowel syndrome may note that some of the items on this list are irritants for your condition, so avoid them. Also, some patients, especially those of northern European heritage, may find that members of the nightshade family (tomatoes, potatoes, bell peppers and eggplant) cause increased inflammation.

Common Dietary Exclusions {13, 21, 22, 23, 27}

Some foods may increase the body’s load of histamine, one of the main inflammatory chemicals involved in MCAS. Some foods that are considered to be high in histamine include: alcoholic beverages; fermented foods and those with vinegar in them; foods with gluten (bread, beer, and others); chocolate (sigh!); aged cheeses; leftovers (the longer a food is left over the more histamine builds up); preserved meats; soy milk and soy products; some fruits including strawberries, citrus and bananas; some vegetables including spinach, eggplant, tomato and avocado. The low FODMAP diet discussed below may suppress the release of histamine.

Milk and gluten sensitivities are more common among patients who are on the hypermobility spectrum. And even more than sensitivity, full celiac disease is more common among hypermobile patients. As a rule, and especially when testing foods to see if they are triggers, eliminating casein, gluten and zein can be a good place to start; this means eliminating dairy, wheat, and corn. If corn is found to be a trigger or poorly tolerated, then caution may be needed regarding the food source of meat consumed. Many commercially farmed animals are fed a diet high in corn and so their tissues may be full of corn protein whereas grass-fed meat or free-range poultry will not be.

Finally, alcohol consumption should be limited as both dysautonomia/ POTS and MCAS usually respond poorly to alcohol consumption.

There is no fixed rule about what foods need to be eliminated from the diet. This is very individual. We recommend collaborating with a practitioner who takes an individual approach.

FODMAP Diet {24, 25, 26, 27}

A common diet for irritable bowel syndrome (IBS) and at times for small intestine bacterial overgrowth is the FODMAP diet. FODMAP is an abbreviation and refers to a diet low in “Fermentable Oligo-, Di-, Monosaccharides, And Polyols.” These substances are found in many common foods.

FODMAPS are a large class of small nondigestible carbohydrates, containing 1-10 sugars which are poorly absorbed in the small bowel. FODMAPs can be found in a range of very common and different foods such as fruits, vegetables, legumes, and cereals, honey, milk and dairy products, and sweeteners … All FODMAPs are potential triggers, but fortunately, not all FODMAPs exacerbate abdominal symptoms in the same IBS patient… The low-FODMAP approach is not simply an “avoidance diet”. It is a diagnostic tool to test the patients’ tolerance to some foods, enabling them to eliminate them from their diet and to make significant changes to lifestyle. (24, pg. 1-2)

Since there are many foods that are considered high in FODMAPs, we do not feel it would be useful to go into a list of them here. This may simply serve to frighten some readers who would benefit from the diet. Instead, we recommend working with a practitioner who can give support and advice, or at least obtaining one of a number of good books available on how to implement the diet preferably one with specific recipes.

We will note though that one of the problems with a low FODMAP diet is that the foods consumed may result in a low intake of dietary fiber leading to or worsening constipation. It is recommended that patients on the low FODMAP diet supplement fiber.

Supplements {21}

 As mentioned earlier in this post, Heidi Collins, MD, is a medical doctor who has specialized in working with patients with hypermobility and hypermobile Ehlers-Danlos syndrome. She has found in her practice that many hypermobile patients are significantly deficient in numerous nutrients. Most notably she has found the need for supplementing Vitamin B6, vitamin D3, vitamin C, vitamin B12, zinc and often iron. In certain situations, she recommends taking quercetin, a supplement which can support mast cell stabilization, curcumin as an anti-inflammatory. We recommend her lecture on this subject for more specific dosage recommendations. {21}

In 2024, we hope to look at some of the following topics and how they relate to hypermobility: sleep apnea, fibromyalgia, and dystonia. Until then, Cheers!

Zebbie & Mark

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

References:

1. Wong, S., et. al, The Gastrointestinal Effects Amongst Ehlers-Danlos Syndrome, Mast Cell Activation Syndrome and Postural Orthostatic Tachycardia Syndrome. AIMS Allergy and Immunology, 6(2): 19-24, DOI: 10.3934/Allergy.2022004
2. Beckers, A.B., et. al., Gastrointestinal Disorders in Joint Hypermobility Syndrome/ Ehlers-Danlos Syndrome Hypermobility Type: A Review for the Gastroenterologist. Neurogastroenterology & Motility 2017; 29:e13013: 1-10; doi.org/10.1111/nmo.13013
3. Castori, M., et. al., Gastrointestinal and Nutritional Issues in Joint Hypermobility Syndrome/ Ehlers-Danlos Syndrome, Hypermobility Type. American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 169C: 54-75 (2015); doi 10.1002/ajmg.c.31431.
4. Thwaites, P, et. al., Hypermobile Ehlers-Danlos Syndrome and Disorders of the Gastrointestinal Tract: What the Gastroenterologist Needs to Know. Journal of Gastroenterology and Hepatology 37 (2022) 1693-1709; doi:10.1111/jgh.15927
5. Farmer, A.D. & Aziz, Q., Visceral Pain Hypersensitivity in Functional Gastrointestinal Disorders. British Medical bulletin 2009; 91: 123-136; doi:10.1093/bmb/ldp026.
6. Camilleri, M., The Leaky Gut: Mechanisms, Measurement and Clinical Implications in Humans. Gut 2019 August; 68(8): 1516-1526. Doi:10.1136/gutjnl-2019-318427
7. Freiling, T., et. al., Evidence for Mast Cell Activation in Patients with Therapy Resistant Irritable Bowel Disease. Z. Gastroenterol 2011; 49:191-194. http://dx.doi.org/10.1055/s-0029-1245707.
8. Gottfried-Blackmore, A., et. al., Open Label Pilot Study: Non-Invasive Vagal Nerve Stimulation Improves Symptoms and Gastric Emptying in Patients with Idiopathic Gastroparesis. Neurogastroenterol Motil. 2020 April; 32(4): e13769.doi:10.1111/nmo.13769
9. Frokjaer, J.B., et. al., Modulation of Vagal Tone enhances Gastroduodenal Motility and Reduces Somatic Pain Sensitivity. Neurogastroenterol Motil (2016) 28, 592-598; doi:10.1111/nmo.12760
10. Cirillo, G., et. al., Vagus Nerve Stimulation: A Personalized Therapeutic Approach for Crohn’s and Other Inflammatory Bowel Disease. Cells 2022, 11, 4103; https://doi.org/10.3390/cells11244103
11. 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.
12. Uy, P., et. al, SIBO and SIFO Prevalence in Patients with Ehlers-Danlos Syndrome Based on duodenal Aspirates/ Culture. The American Journal of Gastroenterology 116, PS218-S219, October 2021; doi:10.14309/01.ajg.0000774444.60980.27
13. Danese, C., et. al., Screening for Celiac Disease in Joint Hypermobility Syndrome/ Ehlers-Danlos Syndrome Hypermobility Type. American Journal of Medical Genetics Part A 9999:1-3.
14. Torres, J., et. al., Crohn’s Disease. Lancet 2017; 389: 1741-1755; http://dx.doi.org/10.1016/S0140-6736(16)31711-1.
15. Alomari, M., et. al., Prevalence and Predictors of Gastrointestinal Dysmotility in Patients with Hypermobile Ehlers-Danlos Syndrome: A Tertiary Care Center Experience. Cureus, 2020, 12(4): e7881; doi.10.7794/cureus.7881
16. Asamoah, V., https://www.ifm.org/news-insights/identifying-ibs-root-causes/?utm_campaign=gi&utm_content=263702330&utm_medium=social&utm_source=linkedin&hss_channel=lcp-3054131
17. Rao,SSC, et. al., Small Intestinal Bacterial Overgrowth: Clinical Features and Therapeutic Management. Clinical and Translational Gastroenterology 2019; 10:e00078. https://doi.org/10.14309/ctg.0000000000000078
18. Porter, R., et. al., Ulcerative colitis: Recent Advances in the Understanding of Disease Pathogenesis. F1000Research 2020, 9(f1000 Faculty Rev): 294: 27 April 2020.
19. Kucharzik, T., et. al., Ulcerative Colitis – Diagnostic and Therapeutic Algortihms, Deutches Aertzeblatt International 2020; 117: 564-574
20. Farzaei, M, et. al., The Role of Visceral Hypersensitivity in Irritable Bowel Syndrome: Pharmacological Targets and Novel Treatments. J Gastroenterol Motil, 22(4), October 2016, 558-574; http://dx.doi.org/10.5026/jnm16001.
21. Collins, H., Diet and supplement Guidelines for Persons with Ehlers-Danlos Syndrome. You Tube: https://www.youtube.com/watch?v=pEfuB-UWRZM. 2020.
22. Collins, H., Nutritional Approaches to Treating GI Concerns in Persons with Ehlers-Danlos Syndrome. You Tube: https://www.youtube.com/watch?v=VxChn-pFS-s . 2020.
23. Brown, A., et. al, Existing Dietary Guidelines for Crohn’s disease and Ulcerative Colitis. Expert Reviews Gastroenterology and Hepatology 5(3), 411-424 (2011)
24. Bellini, M., et. al., Low FODMAP Diet: Evidence, Doubts, Hopes. Nutrients 2020, 12 (148); doi:10.3390/nu12010148, 1-21
25. Hill, P., et. al., Controversies and Recent Developments of the Low-FODMAP Diet. Gastroenterology and Hepatology, 13(1), January 2017, 36-45.
26. Barrett, J., How to Institute the Low-FODMAP Diet. Journal of Gastroenterology and Hepatology 2017; 32(Suppl. 1), 8-10.
27. Stott, P. J and Purdin, H. Taming the Zebra, It’s Much More than Hypermobility. Portland, OR: Tamed Zebra Publishing. C. 2023. ISBN 979-8-9892794-0-1. Chapter 6, pages 95-115.

Hypermobility and Your Tummy {1, 5}

We have been talking about the effects of hypermobility spectrum disorder (HSD) and hypermobile Ehlers-Danlos Syndrome (hEDS) on digestion and the tummy in general. In the first blog post on this topic, we looked at the kinds of problems caused not only by hypermobility but also by the frequently associated conditions of dysautonomia (including the condition called POTS) and mast cell activation syndrome (MCAS).

HSD/hEDS can lead to structural problems in the gut. Dysautonomia can lead to imbalance of the nervous system control of gut movements. MCAS creates inflammatory problems. Because the systems of the body are so interdependent, classifying gut problems as structural, nervous system or inflammatory is not in many cases an adequate model. So, the problems that arise in the overlap of function between these different systems are described as “functional diseases”. This chart give a visual representation.

Functional gastrointestinal diseases often do not fit precisely into the diagnostic criteria for specific conditions and are often chronic and painful as well. One gastroenterology clinic reports that up to 40% of their patients present with functional GI diseases. {5, pg. 124}

In this post, we will look at some general principles involved with treating gut problems which are common among people with HSD or hEDS. This is a big and complex area and involves topics not normally at the center of your author’s profession (physical therapy), so our discussion will be somewhat superficial. That is as it should be since we believe. Our goal is to give you a general model of gut problems found in HSD/hEDS.  If you are having serious gut problems, you will need the specific and individual guidance of a physician regarding specific medications, diet and therapies.  The guidance of your primary care physician, your gastroenterologist and/ or your naturopathic physician will be invaluable.

Please note, if you are looking for a discussion of diets, we will approach this in the third and final post of this series.

Structural Problems {3, 4, 6}

The increased stretchability of the gut wall in HSD/hEDS can decrease peristalsis — the movement of food through the GI tract – leading to constipation. In general, movement which causes contraction of the abdominal muscles can spur peristalsis. For example, walking and also many core strengthening exercises cause  “massaging” of the abdominal organs. Direct, gentle massage to the abdomen by a specially trained physical therapist or massage therapist may also be helpful.

Ptosis, or a drop in position, of an internal organ can sometimes also be helped by a physical therapist or massage therapist with special training in visceral manipulation, a form of very gentle manual therapy.

More severe issues such as hemorrhages, bowel perforations and hernias are all structural problems of the gut that very much need evaluation by a physician. As a rule, any new strong pain in the abdomen or new bulge in the abdominal wall should be evaluated by a physician. Bowel movements with black or tarry stool also should be brought to the attention of a physician. In rare cases, there is a problem called an intussusception in which the bowel folds back in on itself. This causes strong pain. While it can often be managed non-surgically, especially in children, it is a medical emergency and needs to be evaluated by a physician.

In our last post, we mentioned “leaky gut syndrome” which certainly sounds structural and is. In leaky gut syndrome, the normally tight interconnections between cells of the gut become loose allowing food particles and bacteria to penetrate deep into the gut wall and at times enter the blood stream. This can lead to whole body immune reactions as the body fights to remove foreign particles and bacteria. While there is controversy among medical doctors regarding this condition, the gastroenterology literature lists it as an inflammatory condition. The inflammatory problems need to be addressed first. Management by a gastroenterologist and/ or a naturopathic physician can be immensely helpful.

Inflammatory Problems {14, 16, 17, 18, 19}

As mentioned in our last post, there are three main inflammatory diagnoses which are more common in the HSD.hEDS population: irritable bowel syndrome (IBS), Crohn’s disease and ulcerative colitis. Of these three diagnoses, IBS is more generic. Although, there are several different types including IBS-diarrhea  (IBS-D) predominant, IBS-constipation (IBS-C) predominant, IBS-mixed (IBS-M) in which alternating diarrhea and constipation may occur, and IBS-unspecified (IBS-U).

IBS

A number of factors may be underlying these IBS types including bad digestion, infections, food sensitivities or allergies, and stress or anxiety.  

Some people with IBS have been found to be low in their production of bile acids which are created in the liver and assist digestion – here supplements may be helpful.

Another problem can be imbalanced bacteria in the gut called dysbiosis, or small intestine bacterial overgrowth of fungal overgrowth (SIBO or SIFO) . Treatment approaches here consist largely of antibiotics, probiotics and sometimes a strict diet aimed at starving the bacterial overgrowth by consuming only foods absorbed higher in the gut than where the overgrowth occurs.

In some, foreign bacteria or even protozoa have taken up residence in the gut. Treatment with antibiotics is the norm in these cases. A proportion of people with IBS report that it came after an infection. This creates yet another type of IBS, post infection IBS (IBS PI).

Sensitivity or allergies to food have led to some dietary approaches which will be looked at later.

Finally, anxiety or stress can be a big factor in IBS, and here too we will talk more about the nervous system below.

Ulcerative Colitis

As the name ulcerative colitis suggests, it is primarily limited to the colon and the rectum. Bleeding from the rectum and bowel movement urgency are common complaints. Here again, a mix of genetic, immune system and environmental factors are thought to be involved. Ulcerative colitis is associated with the western diet, urban living, pollution, and antibiotic use. Oddly, smoking appears to provide some protection.

The primary mainstream medical approach to managing ulcerative colitis is medication based. There are a number of medications available. Steroids are used for more severe  cases. We will look into some current thinking on diet in post three. A precaution that is recommended for ulcerative colitis is regular colonoscopies for early detection of more serious disease such as colon cancer.

Crohn’s Disease

Crohn’s disease is a relapsing, remitting problem (comes and goes) but also progressive and frequently leads to bowel damage and disability. About half of people with Crohn’s develop complications that require surgery.  As with ulcerative colitis, there are a number of different medication options available depending on the severity of the case. Steroids are often used for moderate to severe cases. As with ulcerative colitis, patients are monitored for any signs of more severe pathologies which can develop.

Nervous System Problems {5, 8, 9, 10, 20 }

Gastroparesis

An overactive “fight or flight” nervous system, sympathetic system, can lead to slowing of the movement of food through the gut. This can be part of dysautonomia in people with HSD or hEDS, or can result from a history of severe illness, injury or life traumas. This slowing or even stoppage leads to constipation, often chronic constipation. There is literature to indicate that stimulation of the “rest and digest” nervous system, the parasympathetic system, through the Vagus nerve can be helpful. We will discuss this below.

One of the causes of gastroparesis among people with chronic pain can be the use of opioid medications. If one is using opioid medications for pain relief, it is important to discuss the potential side effects with the prescribing physician or with the pharmacist. Medications to prevent constipation may be prescribed or the opioid prescription may be changed or modified.

Visceral Nerve Hypersensitivity

There is an emerging body of literature which supports a theory that in many painful, chronic gut problems a big part of the problem is overly sensitive gut nerves. This is also an emerging and valuable theory in general chronic pain management for the rest of the body as well. In gastrointestinal literature, this is called visceral pain hypersensitivity (VPH). Neurophysiologists have called the wider theory for other areas of the body central sensitization.

The nerves are the communication pathways of the body. Nerves can become overly sensitive in the aftermath of injury or illness. This can occur at three levels: at the end of the nerve, at the spinal cord, and/ or in the brain.

Pain is not as simple as a stimulus of some kind sending a signal to the brain like a finger pushing a doorbell button. The nervous system is a learning organ and can get too efficient with pain signaling at different levels. In the gut nerves, there are electric particles (ions) which travel through cell wall channels causing the pain signal to start up the nerve. These channels can get stuck open or become too passable making the signal too quick to start. At the spinal cord, there are gate keeper cells that decide which signals make it all the way to the brain, and these can get stuck open.

Finally, the brain can become too efficient at creating the perception of pain. Until they hit the brain though, the nerve signals coming from the body are just signals. The brain has to interpret them. Pain is the brain’s estimate that the body is being harmed or threatened and it does not always get it right. When they hit the brain, the pain signals spread out into a number of brain areas. So, the interpretation of the signals is heavily affected by the experiences already stored in the brain.

If there has been a lot of pain already, the chemical receptors for pleasure which balance the pain impulses in more healthy situations can be depleted. Past history of trauma especially physical and/ or sexual trauma and especially in childhood, can magnify the brain’s sensitivity to pain signals. Similarly, anxiety, depression, confusing medical explanations, high emotional stress levels, and other illnesses creating stress affect the brain’s sensitivity.

Therapies for visceral pain hypersensitivity have been slow in coming. At a basic level, anything that makes the person healthier is likely to help. Knowledge is power, and the knowledge alone that the problem is mostly in the nervous system and not an undiagnosed life-threatening illness can be helpful. Any psychological support including treatment of depression can help. Good and enough sleep are foundational to caring for VPH. Movement in the form of light exercise can be helpful.

Overall, there are several strategies for managing visceral hypersensitivity with medications. One approach is to give medications which target serotonin receptors in the gut. Similarly, there are several other nerve receptors in the gut that are the subject of study to find medications that help to block the pain nerves.

There is a close relationship between the mast cells which we have talked about in other posts and the gut. There is some indication that in a few cases mast cell stabilizing medication can help VPH. {5, 127}. Medications which block histamine receptors, and also, medications which stabilize mast cells have been used for visceral hypersensitivity.

Finally, there is indication here too that stimulation of the nervous system’s “rest and digest system”, the parasympathetic nervous system, through the Vagus nerve, can be helpful with VPH.

Vagus Nerve Stimulation

Most of the conditions which affect the gut, even if classified as inflammatory,  have a nervous system component usually in the form of increased activity of the sympathetic nervous system. In the involuntary (autonomic or automatic) nervous system, the parasympathetic nervous system works in opposition to the sympathetic. The parasympathetic system is often called the “rest and digest” system and stimulating it by stimulating the biggest nerve of the system, the Vagus nerve, can help calm the whole nervous system. There can be many results from this: decreased gut pain and cramping and bloating, decreased anxiety, improved sleep, improved body temperature regulation, and more.

The Vagus nerve starts at the base of the brain and travels through the neck, into the chest, through the breathing diaphragm and into the abdomen. Along the way, it connects by branches to every major organ system including the heart, glands and gut. More than thirty years ago, experimentation  started with surgically implanting wires in the neck to electrically stimulate the Vagus nerve. This form of treatment was so successful for severe anxiety and depression and for epilepsy that it earned FDA approval. In Australia it is approved for migraine treatment. However, it had/ has the problem of requiring surgery.

Over the last 20 years, anatomists have found that there is an isolated area of the ear which can be stimulated using a common, inexpensive, comfortable electrical stimulation device called a TENS (or TNS = transcutaneous electrical nerve stimulator). A growing body of research is showing that this can be helpful for many kinds of problems in which better health will result from calming or soothing the nervous system. This includes IBS, gastroparesis (constipation) and dysautonomia symptoms.

TENS Vagus nerve stimulation, often abbreviated as tVNS, is slowly becoming more known by physical therapists in the US. Here at Good Health Physical Therapy and Wellness we have a simple protocol which we teach which has been useful to many.

In the third and final post in this series, we will briefly consider current thinking on diets for the conditions affecting many people with HSD/hEDS.

Until then, cheers!

Zeborah Dazzle, PT, WWF

Mark Melecki, PT, DPT, OCS

References:

1. Wong, S., et. al, The Gastrointestinal Effects Amongst Ehlers-Danlos Syndrome, Mast Cell Activation Syndrome and Postural Orthostatic Tachycardia Syndrome. AIMS Allergy and Immunology, 6(2): 19-24, DOI: 10.3934/Allergy.2022004
2. Beckers, A.B., et. al., Gastrointestinal Disorders in Joint Hypermobility Syndrome/ Ehlers-Danlos Syndrome Hypermobility Type: A Review for the Gastroenterologist. Neurogastroenterology & Motility 2017; 29:e13013: 1-10; doi.org/10.1111/nmo.13013
3. Castori, M., et. al., Gastrointestinal and Nutritional Issues in Joint Hypermobility Syndrome/ Ehlers-Danlos Syndrome, Hypermobility Type. American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 169C: 54-75 (2015); doi 10.1002/ajmg.c.31431.
4. Thwaites, P, et. al., Hypermobile Ehlers-Danlos Syndrome and Disorders of the Gastrointestinal Tract: What the Gastroenterologist Needs to Know. Journal of Gastroenterology and Hepatology 37 (2022) 1693-1709; doi:10.1111/jgh.15927
5. Farmer, A.D. & Aziz, Q., Visceral Pain Hypersensitivity in Functional Gastrointestinal Disorders. British Medical bulletin 2009; 91: 123-136; doi:10.1093/bmb/ldp026.
6. Camilleri, M., The Leaky Gut: Mechanisms, Measurement and Clinical Implications in Humans. Gut 2019 August; 68(8): 1516-1526. Doi:10.1136/gutjnl-2019-318427
7. Freiling, T., et. al., Evidence for Mast Cell Activation in Patients with Therapy Resistant Irritable Bowel Disease. Z. Gastroenterol 2011; 49:191-194. http://dx.doi.org/10.1055/s-0029-1245707.
8. Gottfried-Blackmore, A., et. al., Open Label Pilot Study: Non-Invasive Vagal Nerve Stimulation Improves Symptoms and Gastric Emptying in Patients with Idiopathic Gastroparesis. Neurogastroenterol Motil. 2020 April; 32(4): e13769.doi:10.1111/nmo.13769
9. Frokjaer, J.B., et. al., Modulation of Vagal Tone enhances Gastroduodenal Motility and Reduces Somatic Pain Sensitivity. Neurogastroenterol Motil (2016) 28, 592-598; doi:10.1111/nmo.12760
10. Cirillo, G., et. al., Vagus Nerve Stimulation: A Personalized Therapeutic Approach for Crohn’s and Other Inflammatory Bowel Disease. Cells 2022, 11, 4103; https://doi.org/10.3390/cells11244103
11. 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.
12. Uy, P., et. al, SIBO and SIFO Prevalence in Patients with Ehlers-Danlos Syndrome Based on duodenal Aspirates/ Culture. The American Journal of Gastroenterology 116, PS218-S219, October 2021; doi:10.14309/01.ajg.0000774444.60980.27
13. Danese, C., et. al., Screening for Celiac Disease in Joint Hypermobility Syndrome/ Ehlers-Danlos Syndrome Hypermobility Type. American Journal of Medical Genetics Part A 9999:1-3.
14. Torres, J., et. al., Crohn’s Disease. Lancet 2017; 389: 1741-1755; http://dx.doi.org/10.1016/S0140-6736(16)31711-1.
15. Alomari, M., et. al., Prevalence and Predictors of Gastrointestinal Dysmotility in Patients with Hypermobile Ehlers-Danlos Syndrome: A Tertiary Care Center Experience. Cureus, 2020, 12(4): e7881; doi.10.7794/cureus.7881
16. Asamoah, V., https://www.ifm.org/news-insights/identifying-ibs-root-causes/?utm_campaign=gi&utm_content=263702330&utm_medium=social&utm_source=linkedin&hss_channel=lcp-3054131
17. Rao,SSC, et. al., Small Intestinal Bacterial Overgrowth: Clinical Features and Therapeutic Management. Clinical and Translational Gastroenterology 2019; 10:e00078. https://doi.org/10.14309/ctg.0000000000000078
18. Porter, R., et. al., Ulcerative colitis: Recent Advances in the Understanding of Disease Pathogenesis. F1000Research 2020, 9(f1000 Faculty Rev): 294: 27 April 2020.
19. Kucharzik, T., et. al., Ulcerative Colitis – Diagnostic and Therapeutic Algortihms, Deutches Aertzeblatt International 2020; 117: 564-574
20. Farzaei, M, et. al., The Role of Visceral Hypersensitivity in Irritable Bowel Syndrome: Pharmacological Targets and Novel Treatments. J Gastroenterol Motil, 22(4), October 2016, 558-574; http://dx.doi.org/10.5026/jnm16001.

Patients with hypermobility spectrum disorder (HSD) or hypermobile Ehlers-Danlos Syndrome frequently also have problems with their gut. Symptoms can include but are not limited to gastric reflux (“GERD”), heartburn, constipation, diarrhea, belching, bloating, cramps, nausea, difficulty swallowing, abdominal pain, cramping, difficulty swallowing, feelings of fullness. One author wrote about gastrointestinal (GI) problems in HSD/hEDS as follows:

“GI manifestations should be considered major contributors to disability in JHS/EDS-HT [joint hypermobility syndrome/ Ehlers-Danlos Syndrome Hypermobility Type]. However, the scarce knowledge of their pathophysiologic basis explains why surgery and standard pharmacologic treatments are usually of minor effect at the long-term, with great frustration for patients and practitioners.” {3, pg. 68}

HSD.hEDS/ POTS/ MCAS and the Gut {1, 11}

In past blogs, we have talked of the connection between hypermobility and dysautonomia (which may or may not include postural orthostatic tachycardia syndrome, POTS) and mast cell activation syndrome (MCAS). While these three syndromes are recognized by many clinicians as occurring with increased frequency together, both the real frequency of these associations and their reasons have not yet been made clear in the medical literature. Even so, the potential overlap between these three syndromes can provide a useful model for understanding some of the issues patients face with their gut.

Weak or overly stretchy connective tissue in the gut can lead to structural problems as a result of HSD/ hEDS.

The imbalance of the involuntary nervous system which is dysautonomia can lead to problems with nervous system governed movements of the gut.

And MCAS results in inflammation which can also lead to many symptoms.

As you can see, the effects of each of these syndromes can overlap with each other and can all meet to cause gastrointestinal, or more easily said – gut, problems. While not all gut problems encountered by hypermobile patients fit neatly into this structure-nervous system-inflammatory reference, we will start with it as an organizing principle here because it does assist understanding.

Structural Problems {3, 4}

The connective tissue changes of HSD or hEDS may result in a number of structural problems in the gastrointestinal tract. One of these problems can be altered compliance, stretchiness, of the gut wall. There should normally be a certain amount of tension, or recoil, in the gut wall. This assists the movement of food through the gut tube in the process called peristalsis. Changes to the gut wall can be one of the factors involved with sluggish peristalsis which when severe leads to gastroparesis and constipation.

The gut wall has a lot of arteries feeding it and veins taking blood away. Connective tissue structural changes can alter the tensions in the blood vessels which help keep the blood flowing smoothly. Blood can pool and not be efficiently removed by the veins causing symptoms.

While not common, weakened connective tissue in the gut wall and blood vessels can lead to hemorrhages or perforations.

Hernias in which the gut pushes out through a weak area in the abdominal wall (abdominal hernia) or in the breathing diaphragm (hiatal) are particularly common in HSD and hEDS.

The organs in the abdomen, including the uterus plus small and large intestines, are held in place by a number of ligaments, which are of course made of connective tissue. If these sag or stretch, the intestines will no longer sit in their normal position. This is called organ ptosis and can lead to pinching or kinking or sluggish blood flow for that organ. In severe cases, a prolapse may occur where the organ drops down far out of its normal position. Examples of two prolapses are the rectum coming out of the anus or the uterus protruding from the vagina.

There can be other structural problems of the gut in HSD and hEDS, but these are the main ones which have been documented in the literature so far.

Inflammatory Problems {2, 7, 10, 14}

Three inflammatory bowel diagnoses in which the occurrence of hypermobility are increased are irritable bowel disease (IBS), Crohn’s Disease and ulcerative colitis. {2} IBS is the more generic diagnosis with Crohn’s disease and ulcerative colitis being more specific sub diagnoses. While these disorders are listed as inflammatory disorders, there are also significant contributions to them from the immune system and the nervous system. In fact, while all of these overlapping diagnoses are inflammatory, the cause is unknown and thought to involve a number of factors including intestinal bacteria, genetic and environmental causes. {14}

While the causes of IBS are multifactorial, there is evidence that in a number of patients with treatment resistant IBS there is an increased number of mast cells as well as mast cell activity in the gut. {7} This points to the overlap with MCAS.

Nervous System Problems {5, 8, 9, 10, 15}

Food being digested by the gastrointestinal tract is pushed forward in the small and large intestines by contractions of muscles in the gut wall. These contractions are largely affected by the involuntary nervous system. When these contractions are impaired in their strength or speed of contraction, this is called dysmotility. Dysmotility has been found to be common in patients with HSD/hEDS. If the contractions are severely slowed down or stopped, this is gastroparesis which results in constipation, and constipation is a common complaint among hypermobile patients.

Another common complaint among patients with hypermobility is abdominal pain. This may be mild to severe and in worst cases profoundly affect the patient’s life. As for the body as a whole, pain is a perception created by the brain based on its best estimate that the body is being hurt. Local nerves in the gut send signals to the spinal cord which filters them and passes on the strongest and most urgent. When these signals get to the brain, they are interpreted by a complex interaction of a number of brain areas. The precise combination and contribution of the different brain areas is unique to every individual person and is called a pain signature. Scientists who study pain have come to believe that in many cases of chronic or recurring pain, the nervous system has become sensitized and overly efficient at creating pain. This is called visceral hypersensitivity.

This sensitization can happen at the nerves in the gut, in the spinal cord, in the brain, or in any combination of these. When the nerves become sensitized, then the nervous system becomes as much or more a part of the pain problem than any local disease or dysfunction. Because the nervous system is in great part a learning organ, many things can contribute to making the brain’s damage estimate too strong. How long the problem has been going on, anxiety, depression, history of physical or sexual abuse especially in childhood, past gut disease can all be major factors in the nervous system developing visceral hypersensitivity.

Disorders of Function {2, 3, 7, 12}

Many of the gut problems which affect people with HSD/ hEDS fall in the category of “functional” problems. This means that they are not predominantly structural or neurologic or inflammatory but have overlapping physical causations.

Because food sensitivities and allergies are often a part of mast cell activation syndrome, some people are very challenged to maintain a balanced, gut -friendly diet. A balanced diet requires the right combination of protein, low-sugar carbohydrates and fats. The  challenges of finding a diet that does not worsen symptoms such as diarrhea, constipation, bloating, gas, cramping can lead to other problems as well as nutritional imbalances.  

GERD is gastroesophageal reflux disease. This means that stomach acids wash up, or reflux, into the lower part of the esophagus causing irritation and pain and “heart burn”.

An inflamed gut, which occurs in Crohn’s disease, irritable bowel syndrome and ulcerative colitis may lead to a “leaky gut” in which bacteria or tiny food particles passing through the gut can pass between the normally tight junctions between the gut cells and access the blood. This can lead to many symptoms including immune system reactions. Leaky gut is not recognized by all physicians, but according to the gastroenterology literature us most likely in an inflamed bowel.

Small intestinal bacterial overgrowth (SIBO) and its cousin small intestinal fungal overgrowth (SIFO) occur more frequently in hypermobile patients with gut problems. The reason for this is not clear, but these overgrowths can lead to symptoms such as belching, bloating, abdominal pain, diarrhea, flatulence, and indigestion.

Gluten sensitivity, and it’s more severe form Celiac disease, are more common in patients with hypermobility.

Finally, medications can have a strong effect on the gut. Opiates are famous for causing painful constipation. Patients with hypermobility, especially those with MCAS, may be sensitive to or even allergic to some medications. And being on multiple medications may cause drug interactions or have conflicting effects on the body (This is sometimes called “Poly pharmacy” in the medical community.)

In the next post in this short series, we will explore treatment approaches for the gut problems we have talked about here.

Until then – cheers!

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

References:

1. Wong, S., et. al, The Gastrointestinal Effects Amongst Ehlers-Danlos Syndrome, Mast Cell Activation Syndrome and Postural Orthostatic Tachycardia Syndrome. AIMS Allergy and Immunology, 6(2): 19-24, DOI: 10.3934/Allergy.2022004
2. Beckers, A.B., et. al., Gastrointestinal Disorders in Joint Hypermobility Syndrome/ Ehlers-Danlos Syndrome Hypermobility Type: A Review for the Gastroenterologist. Neurogastroenterology & Motility 2017; 29:e13013: 1-10; doi.org/10.1111/nmo.13013
3. Castori, M., et. al., Gastrointestinal and Nutritional Issues in Joint Hypermobility Syndrome/ Ehlers-Danlos Syndrome, Hypermobility Type. American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 169C: 54-75 (2015); doi 10.1002/ajmg.c.31431.
4. Thwaites, P, et. al., Hypermobile Ehlers-Danlos Syndrome and Disorders of the Gastrointestinal Tract: What the Gastroenterologist Needs to Know. Journal of Gastroenterology and Hepatology 37 (2022) 1693-1709; doi:10.1111/jgh.15927
5. Farmer, A.D. & Aziz, Q., Visceral Pain Hypersensitivity in Functional Gastrointestinal Disorders. British Medical bulletin 2009; 91: 123-136; doi:10.1093/bmb/ldp026.
6. Camilleri, M., The Leaky Gut: Mechanisms, Measurement and Clinical Implications in Humans. Gut 2019 August; 68(8): 1516-1526. Doi:10.1136/gutjnl-2019-318427
7. Freiling, T., et. al., Evidence for Mast Cell Activation in Patients with Therapy Resistant Irritable Bowel Disease. Z. Gastroenterol 2011; 49:191-194. http://dx.doi.org/10.1055/s-0029-1245707.
8. Gottfried-Blackmore, A., et. al., Open Label Pilot Study: Non-Invasive Vagal Nerve Stimulation Improves Symptoms and Gastric Emptying in Patients with Idiopathic Gastroparesis. Neurogastroenterol Motil. 2020 April; 32(4): e13769.doi:10.1111/nmo.13769
9. Frokjaer, J.B., et. al., Modulation of Vagal Tone enhances Gastroduodenal Motility and Reduces Somatic Pain Sensitivity. Neurogastroenterol Motil (2016) 28, 592-598; doi:10.1111/nmo.12760
10. Cirillo, G., et. al., Vagus Nerve Stimulation: A Personalized Therapeutic Approach for Crohn’s and Other Inflammatory Bowel Disease. Cells 2022, 11, 4103; https://doi.org/10.3390/cells11244103
11. 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.
12. Uy, P., et. al, SIBO and SIFO Prevalence in Patients with Ehlers-Danlos Syndrome Based on duodenal Aspirates/ Culture. The American Journal of Gastroenterology 116, PS218-S219, October 2021; doi:10.14309/01.ajg.0000774444.60980.27
13. Danese, C., et. al., Screening for Celiac Disease in Joint Hypermobility Syndrome/ Ehlers-Danlos Syndrome Hypermobility Type. American Journal of Medical Genetics Part A 9999:1-3.
14. Torres, J., et. al., Crohn’s Disease. Lancet 2017; 389: 1741-1755; http://dx.doi.org/10.1016/S0140-6736(16)31711-1.
15. Alomari, M., et. al., Prevalence and Predictors of Gastrointestinal Dysmotility in Patients with Hypermobile Ehlers-Danlos Syndrome: A Tertiary Care Center Experience. Cureus, 2020, 12(4): e7881; doi.10.7794/cureus.7881

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

Zeborah Dazzle, PT here spokes-zebra for Good Health Physical Therapy and Wellness.

June is Pride month in the US. Happy Pride month!

One of the puzzles of working with a special focus on hypermobility spectrum disorder (HSD) and hypermobile Ehlers-Danlos (hEDS) syndrome is the number of patients who come for care who are gay, lesbian, transgender, bi, queer and/or non-binary – a higher percentage of our patient population than most experienced clinicians have seen in other clinical settings. While we feel lucky and privileged to be serving so many amazing, strong, gentle people, as clinical scientists, we do puzzle about whether there is a physiologic relationship between HSD/hEDS and identifying as LGBTQ.

We will tell you up front that there is as yet no answer to this and almost no literature overall looking at it. No literature was found on EDS and diversity of sexuality. What literature we have found looks at the prevalence of EDS among patients who have what is called in the medical world “gender dysphoria.” Gender dysphoria is the medical term used for individuals who experience incongruence, or mismatch, between the sex they were assigned at birth and their gender identity. During this month, we thought it might be a service to look at what is out there, and specifically three recent journal articles.

The first article {1} comes out of Oregon Health Sciences University from the plastic and general surgery department. The study looks at 1363 patients who came for gender reassignment surgery between 2016 and 2020. They looked at two things: how common EDS was in that group of patients and how those patients healed after their surgery. (Since EDS is a connective tissue disorder, the study authors wanted to know if there were healing problems.)

Out of the 1363 patients, 36 had a diagnosis of Ehlers-Danlos syndrome (EDS). Looking at this number and comparing it to the different estimates of how often EDS occurs in the general population, the study authors concluded:

Our investigation revealed the prevalence of Ehlers-Danlos syndrome in patients seeking gender-affirming surgery at our institution to be 132 times the highest reported prevalence in the general population. (pg. 5)

This is pretty astounding. And the study left us with a question. Reading this paper closely, they only looked for EDS as a diagnosis. They did not look at HSD. This makes us wonder how much higher the number of patients and the prevalence would have been if they had looked at all patients on the hypermobility spectrum.

Oh, by the way, they did not find any difference in surgical complications when matched against a control group of their patients who did not have EDS. So, it does not appear that individuals with hypermobility who seek gender affirming surgery are at higher risk of complications than non-hypermobile patients.

The second article {2} comes from Kansas City, Missouri. The authors looked at 166 adolescent patients seen in a multi-disciplinary EDS clinic between January 2020 and May of 2022. Specifically, they looked at how many of these patients were experiencing gender dysphoria based on their self-reports. This study did include both hEDS and HSD in their definition of an EDS patient.  They identified 28 patients out of the 166 which is 17%. Since the high-end estimate of adolescents with gender dysphoria in the general population is 1.3% {2, pg. 2} this means the prevalence of gender dysphoria in this EDS population was 13 times higher than the general population.

This study also looked at a number of interesting characteristics of this group of 28 patients:

89% were assigned female at birth, 12% male, with gender identity as follows: > Cisgender 4% T > Transgender 61% > Nonbinary 14% > Gender Fluid 11% > Agender 7% > Unsure 3% Reported pronouns: > He/Him 47% > She/Her 14% > They/ Them 39% The most common health problems for the 28 patients were: > Joint pain 79% / Muscle pain 36% > Mast Cell Activation Disorder 21% > Anxiety 75% > Attention deficit hyperactivity disorder (ADHD) 21% > PTSD 18% > Dysautonomia 61% / Postural Orthostatic Tachycardia Syndrome (POTS) 29% > GI/ Digestive Issues 68% > Headaches 75%

The third study {3} we looked at for this blog post came out of Children’s Hospital of Philadelphia which some who read this will recognize as one of the leading places in the country for the treatment of dysautonomia and POTS. This was a case series, meaning a journal article looking at three different cases they treated. All three of the cases were transgender men. All three patients had POTS. (If you are not familiar with POTS, please see the blog series on dysautonomia and POTS posted earlier this year). All three patients transitioned with the assistance of testosterone hormone therapy and all three had some relief of their POTS symptoms with introduction of the hormone therapy.

So, as the study authors point out, while the patients did have some decreased symptoms with the introduction of testosterone, this does not mean that testosterone should be tried for POTS. It does however lead to a recommendation that for transgender patients with POTS undergoing gender affirming therapy with hormonal treatments, further study is merited to see if and how their symptoms are affected. Why might this be important? In the Kansas study {2}, the majority of gender dysphoric hypermobile patients were transgender and almost a third had POTS.

So, if you are still reading after all these nerdy facts and figures, what are we to conclude?

We think this confirms a suspicion that we have had. While certainly not all gender diverse patients have HSD/hEDS the incidence is much higher than in the general population, and we can say too that the available literature suggests that the incidence of gender dysphoria among patients with HSD/hEDS is higher than the general population as well. Is there any hint in the literature as to why this might be? None at all that we have found so far. It is a puzzle.

We do believe though that there is an important takeaway from this information.  Increased awareness within the LGTBQ+ community of hypermobility spectrum disorders and the related health problems could help many make sense of seemingly mysterious, often chronic, health concerns and pains. When in doubt, screening for hypermobility by a physician or physical therapist might be of great benefit.

Thanks for reading! In future posts we hope to look more deeply at Mast Cell Activation Disorder as well as other topics.

Cheers,

Zebbie

Zeborah Dazzle, PT, WWF

Thanks to Dr. Mark Melecki, PT, DPT for his assistance in preparing this post. You know, it’s hard to type when you have hooves and not fingers. You rock Mark!

References:

1. Najafian, A., et. al., Ehlers-Danlos syndrome: prevalence and outcomes in gender affirming surgery – a single institution experience. Plast Aesthet Res 2022; 9:35; DOI: 10.20517/2347-9264.2021.89
2. Jones, J.T., et.al, Gender Dysphoria in Adolescents with Ehlers-Danlos Syndrome. SAGE Open Medicine 10:1-6; DOI: 10.1177/20503121221146074
3. Boris, J.R., et. al., Clinical Course of Transgender Adolescents with Complicated Postural Orthostatic Tachycardia Syndrome Undergoing Hormonal Therapy in Gender Transition: A Case Series. Transgender Health 4: (2019) DOI: 10.1089/trgh.2019.0041

Since it is May, Ehlers-Danlos Awareness month, I thought it might be good to explore just how common HSD and EDS are. Now, there is a reason I went into physical therapy and not mathematics – it is so easy to get lost in the numbers rather than have them tell a story. But let’s see what we can do. First a review.

 Hypermobility spectrum disorder as well as all of the thirteen types of Ehlers-Danlos Syndromes are connective tissue disorders resulting in a constellation of problems first and foremost being hypermobile and painful joints. The earliest references to loose joints may have been by Hippocrates in 400 BC {2}. Diagnostic classifications for the connective tissue disorders have evolved over a long period of time.

Ehlers and Danlos were two physicians in the early 1900s. Edvard Lauritz Ehlers was a Danish Dermatologist who published a comprehensive report on patients with hypermobile joints and fragile elastic skin in 1901. And Henri-Alexandre Danlos was a French dermatologist who consulted on a patient diagnosed by Ehlers and gave a contrasting opinion. {2}

The effort to classify the disorders as they are now diagnosed began in 2012 with the formation of an international consortium of experts which published the current diagnostic criteria in the American Journal of Medical Genetics in 2017 {2}. That was only six years ago.

When trying to determine how common any diagnosis is in the population, the specifics of how that diagnosis is made are very important. In other words, how you define something very much affects how it is counted. Before 2017, rather than classifying Hypermobility Spectrum disorder and Hypermobile Ehlers Danlos Syndrome separately, they were lumped together into one category: joint hypermobility syndrome {1}. So, as you might expect, the conversation about how common HSD, hEDS and each of the twelve other types of EDS are, is an ongoing one.

So, are HSD and EDS common? I have translated the diagram provided by the EDS Society {1}, which gives the best recent estimates of case numbers, into the table below and added a column. Since we are talking about cases per million, and since the population of the US in 2021 was 332,278,200 (according to Siri), the column at the right estimates how many cases there may be in the US.

Condition	Estimated Cases per 1 Million People	Estimated Cases in the US
All EDS and HSD	2000	664,556
hEDS and HSD Only	1900	631,329
hEDS	320	106,329
Classical EDS	50	16,614
Vascular EDS	10	3,323
Other Types of EDS: Arthrocalasia Brittle Cornea Syndrome Classical-Like EDS Dermatospraxis Kyphoscoliotic EDS Musculocontractural EDS Myopathic EDS Periodontal EDS Spondylodysplastic EDS	Less than 1	332

A condition is thought to be rare if it affects less than 1 person in 2,000 which is the same as 500 in a million. As you can see above then, all of EDS types combined and also HSD combined with hEDS are not rare, but each of the other categories of EDS would be considered rare. This assumes that the studies are getting an accurate estimate of numbers. And that is a big assumption. As more doctors learn how to diagnose these conditions, these numbers may change.

We are still thinking about what to write about next in this blog series. Future topics may include mindfulness, digestive issues in HSD and hEDS and others.

Until then, cheers!

Zebbie

Zeborah Dazzle, PT, WWF

Spokes-Zebra and Patient Educator for Good Health Physical Therapy and Wellness.

Thanks to Dr. Mark Melecki, PT for his assistance in preparing this blog. (It is very challenging to type with hooves rather than fingers. Thanks Mark.)

References:

1. Ehlers-Danlos Society, Are the Ehlers-Danlos and Hypermobility Spectrum Disorders Rare or common?   https://www.ehlers-danlos.com/is-eds-rare-or-common/ 2023
2. Stott, P., Purdin, H., Introduction to HSD/EDS: Course Notes. Medbridge Online continuing Education. https://www.medbridgeeducation.com/sign-in 2022
3. Demmler, JC, et. al., Diagnosed Prevalence of Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorder in Wales, UK: A National electronic Cohort Study and Case Control Comparison. BMJ Open 2019; 9:e031365. Doi: 10.1136/bmjopen-2019-031365.