The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 32

39. How are mast cell disease, Ehlers Danlos Syndrome and POTS connected? (Continued)

I’m answering this question in two parts because there is a lot of information to relay and it’s important that it is done clearly. This is the second part.

Mast cells are found throughout the body. There is no record of a person living without mast cells. They perform many essential functions. This is the reason why killing off all of a person’s mast cells is not a viable treatment for mast cell disease. While mast cells cause so many symptoms and problems for patients with mast cell disease, life is unsustainable without mast cells.

Let’s specifically consider just a few of the mast cell’s essential functions here and how they relate to POTS and EDS.

Mast cells help the body to regulate blood pressure and heart rate. Many of the mast cell’s chemicals do this so it happens in many different ways all stemming from mast cells. This means that when mast cells are not behaving appropriately, there are many ways in which this dysfunction can lead to not regulating blood pressure and heart rate correctly.

  • Histamine can affect blood pressure and heart rate differently depending upon how it acts on the body. If it uses the H1 receptors, it can cause low blood pressure. If it uses the H2 receptors, it elevates blood pressure. If it uses the H3 receptor, it can cause low blood pressure. When it does this at the H3 receptor, it’s because it tells the body not to release norepinephrine. Not releasing as much norepinephrine lowers heart rate and making the heart beat more weakly.
  • Prostaglandin D2 lowers blood pressure and causes fast heart beat. However, the molecule made by breaking down PGD2, called 9a,11b-PGF2 increases blood pressure.
  • Vasoactive intestinal peptide lowers blood pressure.
  • Heparin, chymase and tryptase can decrease blood pressure. They do this by helping to make a molecule called bradykinin. When this happens, a lot of fluid falls out of the blood stream and gets stuck in the tissues, causing swelling.
  • Thromboxane A2 increases blood pressure.
  • Many mast cell molecules affect the amount of angiotensin II. This molecule strongly drives the body toward high blood pressure. Some mast cell molecules that affect blood pressure this way include chymase and renin.

Another very essential function of mast cells is to make connective tissue. Mast cells help the body to shape itself correctly and to make tissue to heal wounds. When mast cells are not behaving appropriately, their dysfunction can interfere with making connective tissue and wound healing. It can cause wounds to heal very slowly or for there to be too much scar tissue. It can also cause the connective tissue to be too weak or too strong.

The interaction between POTS and mast cell disease

In POTS, the body is already predisposed toward not regulating blood pressure and heart rate correctly. When a person with POTS stands up, their body quickly causes the heart to beat very fast. When your body does this, it takes steps that cause mast cells to become activated. In turn, the mast cells release chemicals to try and regulate the heart rate. However, if you have mast cell disease, the mast cell may release the wrong chemicals, or too many chemicals, failing to regulate the heart rate. This in turn results in a situation where the body becomes very stressed. Stress activates mast cells, which results in more release of chemicals. Patients can very easily become trapped in a cycle where POTS and mast cell disease irritate each other.

POTS can be exacerbated by the use of medications that affect blood vessels. Medications that are vasodilators (that make the blood vessels bigger) are taken by many people, including mast cell patients. In some people, using medications that blocks the action of histamine or prostaglandins can help to improve symptoms of both POTS and mast cell disease. Conversely, some of the medications used to manage POTS, like beta blockers, can trigger mast cell reactions and raise the risk of anaphylaxis. However, some POTS treatments can also help alleviate mast cell symptoms, specifically the use of IV fluids.

A paper published in 2005 found that hyperadrenergic POTS was sometimes found in patients with mast cell activation disorders.

The interaction between EDS and POTS

POTS is a form of dysautonomia. Dysautonomia means dysfunction of the autonomic nervous system. This is the part of your nervous system that helps to control automatic functions like heart rate, blood pressure and digestion.

In EDS patients, the body does not make collagen correctly. Collagen is the most common connective tissue protein in the body. This can cause vascular laxity. Blood vessels change size depending upon how much blood they need to move through them. If they get larger, it is called vasodilation. When they get smaller, it is called vasoconstriction. When a person has vascular laxity, their vessels can get larger than they should and they can stay that way longer.

POTS is the most common form of orthostatic intolerance in HEDS. Orthostatic intolerance is when a patient has symptoms specifically as the result of standing up. All EDS patients have more autonomic symptoms than healthy people. Among patients with EDS, autonomic symptoms are more common and more severe in HEDS. 94% of HEDS patients have orthostatic symptoms, including lightheadedness, dizziness, palpitations, nausea, blurred vision, and anxiety. Dysautonomia is much worse in HEDS compared to CEDS and VEDS patients.

Patients with HEDS were found overall to have overactive sympathetic nervous systems. However, when their body needed to activate in response to regulate heart rate and blood pressure in response to changing position, their responses were not strong enough.

In EDS patients, the connective tissue does not support blood vessels enough. This makes the harder for the blood vessels to get the blood back to the right places when you stand up, exacerbating POTS.

The interaction between EDS and mast cell disease

Mast cells are involved in making and repairing connective tissue, which involves collagen. For this reason, there are many mast cells living in connective tissues. Mast cells are stimulated when the body is making or trying to make collagen. Because EDS causes the body to make collagen incorrectly, mast cells can become activated to try and make collagen and other connective tissue correctly. When mast cells in one place are activated a lot over a long time, they can activate other mast cells elsewhere, resulting in systemic symptoms.

The interactions among mast cell disease, POTS and EDS

It is undeniable that there is an association among mast cell disease, EDS and POTS. However, there is not much data published on this topic. There was a poster presented in 2015 that found some combination of EDS, POTS and MCAS in a group of 15 patients. This is a very small population and we need larger studies to understand incidence. There is ongoing work to tie this group of conditions to specific genetic markers. However, this also requires further investigation and more patients. In the absence of hard data, we are forced to use some early data and understanding of similar conditions to try and figure out exactly what happens. As more data comes out, this understanding may change.

This is very much a chicken and egg situation where it’s not clear exactly what begets what. EDS is a genetic disorder and considered primary. However, that does not necessarily mean POTS or mast cell disease is secondary in this scenario.

Regardless of which is the initiating condition, the relationship seems to be something like the following:

1. A patient has EDS. They make defective connective tissue. These defective tissues do not support the bodily organs and vessels properly.

2. A patient stands up. Blood quickly moves from the torso into the legs.

3. The blood vessels in the legs try become more narrow and more able to keep fluid in the bloodstream. However, in an EDS patient, the blood vessels are stretched out and not held in the right place because the connective tissue is too weak.

4. The blood vessels in the legs are not able to pump blood back to the heart quickly enough. The body interprets this as having low blood pressure.

5. The nervous system sends signals to increase heart rate to compensate for the “low” blood pressure.

6. The signals sent to increase heart rate activate mast cells.

7. Mast cells activate release mediators to try and regulate blood pressure and heart rate.

8. Mast cell mediators activate other mast cells, eventually affecting other parts of the body.

9. The molecules released by mast cells make blood vessels bigger and more leaky.

10. As fluid leaves the bloodstream and gets stuck in places where it can’t work (third spacing), blood pressure decreases and heart rate increases. This exacerbates POTS symptoms. The cycle repeats.

For more detailed reading, please visit these posts:

Cardiovascular manifestations of mast cell disease: Part 1 of 5

Cardiovascular manifestations of mast cell disease: Part 2 of 5

Cardiovascular manifestations of mast cell disease: Part 3 of 5

Cardiovascular manifestations of mast cell disease: Part 4 of 5

Cardiovascular manifestations of mast cell disease: Part 5 of 5

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part 1)

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part 2)

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part 3)

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part 4)

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part 5)

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 1

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 2

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 3

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 4

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 5

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 6

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 7

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part Five)

HEDS patients showed overactivity of sympathetic nervous system (part of autonomic nervous system) at risk.  Conversely, when presented with a trigger that should activate the sympathetic nervous system, they show a lower response than they should.  In response to Valsalva maneuvers, their blood pressure dropped more than it should. In tilt table testing, the diastolic blood pressure increases less than it should.  Hypermobility was associated with worsened dysautonomic symptoms.  POTS is the most common subtype of dysautonomia found in HEDS patients.

Dysfunction of sympathetic nervous system is common in HEDS.  Laxity of connective tissue and use of medications that affect blood vessels aggrevate dysautonomia. Autonomic dysfunction in HEDS patients is associated with poor disease prognosis, decreased quality of life, unstable blood pressure, increased risk of cardiac disease and death as a result of it, particularly under anesthesia.

Deconditioning has a complicated relationship to orthostatic intolerance and dysautonomia.  Deconditioning lowers blood volume and alters response to adrenalin, contributing to orthostatic symptoms.

However, a study on the relationship between HEDS and dysautonomia found that decreased physical activity was not linked to worsened orthostatic symptoms.  As a result, it is thought that deconditioning in this group is probably not the primary cause of orthostatic intolerance, but a secondary contributor.

References:

de Wandele I, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism 2014, 44: 93-100.

de Wandele I, et al. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism 2014, 44: 353-361.

Wallman D, et al. Ehlers-Danlos Syndrome and Postural Tachycardia Syndrome: A relationship study. Journal of Neurological Sciences 2014, 340: 99-102.

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part Four)

The relationship between Ehlers Danlos Syndrome and dysautonomia, the dysfunction of autonomic nervous system, is currently being elucidated.  There is a correlation between hypermobility and autonomic symptoms. One study found that in patients with autonomic dysfunction, 18% had EDS, compared to the control group, in which only 4% had EDS.

Ehlers Danlos Syndrome alters collagen structure throughout the body. In HEDS, this usually affects the skin less than in other types of EDS.  In the cardiovascular system, this contributes to vascular laxity, which allows excessive dilation of the blood vessels, causing orthostatic intolerance. Importantly, you do not see the spontaneous rupture of blood vessels seen in VEDS.

In HEDS, connective tissue defects in the GI tract lead to dysfunctional peristalsis (contraction of GI tract to move food through it), excessive stretching or swelling, dysregulation of intestinal permeability and damage to the epithelial cells of the GI tract. Without proper connective tissue support, the bladder can become distended or impinge on other structures, as in cystocele.  HEDS frequently causes weakness in the pelvic floor and can lead to prolapse of pelvic organs.

Pain and fatigue are often attributed to dysautonomia in EDS patients, but it could also be caused by HEDS. Peripheral neuropathy is prevalent in HEDS and can drive pain in this population.  Many HEDS patients have sensory pain, such as tingling, pins and needles, numbness, radiating or burning pain. If the autonomic nervous system is responsible for the pain signals, it could provide a link between dysautonomia and pain. Chronic pain and inflammation can change the structure and behavior of the nervous system, making it easier to transmit pain signals.  Orthostatic intolerance can activate the sympathetic nervous system, part of the autonomic nervous system, contributing to these types of symptoms.

By contrast, many HEDS patients are known to frequently have anxiety, palpitations, dizziness, shortness of breath and high affective distress.  Rather than being from HEDS directly, these are likely from dysautonomia.

References:

de Wandele I, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism 2014, 44: 93-100.

de Wandele I, et al. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism 2014, 44: 353-361.

Wallman D, et al. Ehlers-Danlos Syndrome and Postural Tachycardia Syndrome: A relationship study. Journal of Neurological Sciences 2014, 340: 99-102.

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part Three)

Autonomic dysfunction can present in many ways.  Patients complained of orthostatic symptoms like fatigue, difficulty concentrating, brain fog, chest pain, palpitations, headache, visual disturbances, shortness of breath and feeling “absent.” Common GI symptoms were early satiety, bloating, nausea and vomiting (particularly after a meal), colonic spasms, constipation and diarrhea.  Sweating too much or too little and dry eyes and mouth were reported.  Raynaud’s phenomenon and purple limbs upon standing affected many HEDS patients.  Sensitivity to light and difficulty focusing vision occurred due to dysregulation of pupils. Urine retention, failure to empty bladder while urinating, and incontinence of urine were also common.

Some symptoms were strongly associated with others.  Fatigue and difficulty in concentrating was most often seen in association with symptoms that affected blood vessels changing size, symptoms that affected secretion by glands, and GI or sleep symptoms.  An overall large burden of autonomic symptoms was also seen in patients with fatigue and difficulty concentration.  Greater concentration difficulties also correlated with worse orthostatic symptoms, bladder symptoms, gastroparesis, dysregulation of pupil motion and an overall large burden of autonomic symptoms.

Many autonomic symptoms (but not those affecting motion of blood vessels or fainting) were correlated to neuropathic pain.  Orthostatic, GI, bladder, pupil and gland secretion symptoms, sleep dysfunction, and overall high autonomic burden were linked to pain severity. Tachycardia when upright and dysautonomia generally were related to severity of pain.

Dysautonomia symptoms were often seen in HEDS, particularly orthostatic and GI symptoms.  Dysautonomia symptoms greatly impacted quality of life and were associated with more fatigue and pain. Dysautonomia was much worse in HEDS than in CEDS, VEDS or fibromyalgia. In particular, orthostatic intolerance dramatically affected quality f life.  The physical limitations observed in POTS patients, the most common form of orthostatic intolerance for HEDS patients, were comparable to those seen in people with congestive heart failure or COPD.  These symptoms contribute to the lower quality of life seen in HEDS patients when compared to other EDS patients.

References:

de Wandele I, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism 2014, 44: 93-100.

de Wandele I, et al. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism 2014, 44: 353-361.

Wallman D, et al. Ehlers-Danlos Syndrome and Postural Tachycardia Syndrome: A relationship study. Journal of Neurological Sciences 2014, 340: 99-102.

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part Two)

The Autonomic Symptom Profile (ASP) is a questionnaire that assesses symptoms in functional areas controlled by the autonomic nervous system.  The autonomic nervous system regulates many involuntary functions, such as heart rate, blood pressure, urination and digestion.  Dysfunction of the autonomic nervous system can affect many organ systems.

One study evaluated Ehlers Danlos patients for autonomic symptoms using the ASP.  The patients in this study had classic Ehlers Danlos (cEDS), vascular Ehlers Danlos (vEDS) or hypermobility type Ehlers Danlos (HEDS).  Symptom burden was compared among these different presentations of EDS and to healthy controls.

Patients with HEDS had the highest total burden of autonomic symptoms among EDS patients.  All EDS patients had more autonomic symptoms than healthy controls.  HEDS caused more orthostatic symptoms (symptoms that happen when standing up) than in other EDS forms.  94% of HEDS patients had orthostatic symptoms, including lightheadedness, dizziness, palpitations, nausea, blurred vision and anxiety.  Though many patients said they often “felt faint”, true fainting was not common.  These symptoms could be provoked or worsened with physical activity, heat, meals, or change in position.

Patients with HEDS also had the highest burden of GI symptoms compared to other types of EDS.  73% had gastroparesis, 66% had chronic constipation, and 64% had regular diarrhea.  Diarrhea was found to be the most impairing GI symptom.

HEDS patients had a larger impact of orthostatic symptoms and bladder dysfunction than either CEDS or VEDS.  Compared to just CEDS, HEDS showed more GI, secretomotor (release of fluid by glands) and pupillomotor (motion of pupil) symptoms.  Compared to just VEDS, HEDS patients had more vasomotor burden (symptoms related to the dilation of blood vessels).  HEDS autonomic burden was similar to those seen in fibromyalgia patients, with more bladder dysfunction and less sleep dysfunction.

Higher autonomic symptom burden was associated with more physical impairment, pain and decreased vitality.  More hypermobility was associated with higher burden of orthostatic symptoms, GI symptoms generally, gastroparesis, diarrhea, vasomotor symptoms and overall autonomic symptom burden.

References:

de Wandele I, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism 2014, 44: 93-100.

de Wandele I, et al. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism 2014, 44: 353-361.

Wallman D, et al. Ehlers-Danlos Syndrome and Postural Tachycardia Syndrome: A relationship study. Journal of Neurological Sciences 2014, 340: 99-102.

Gastroparesis: Autonomic nervous system and vagus nerve (Part Six)

Gastric emptying is facilitated by neurologic signals through the autonomic nervous system.  The autonomic nervous system controls many of the involuntary functions of the body, such as digestion.  The autonomic nervous system has two components: the parasympathetic nervous system, which manages activities pertaining to digestion, among other things; and the sympathetic nervous system, which mediates the fight-or-flight response.  Normally, upper GI function receives parasympathetic neurologic signals from the vagus nerve.  Sympathetic control is maintained by nerves originating at spinal T5-T10.

The vagus nerve sends signals the enteric neurons, nerve cells in the GI tract, to increase gastric motility.  The vagus nerve does not directly stimulate smooth muscle in the GI tract.  Signals from the vagus nerve help to relax the stomach to allow room for food, contract to move the food to the pyloric sphincter, and relax the pyloric sphincter to pass stomach contents to the small intestine.  These actions occur by coordinating the signals among the enteric neurons (GI nerve cells), interstitial cells of Cajal (which control smooth muscle contraction) and smooth muscle cells.

Normally, food passes through the esophagus and into the portion of the stomach closest to the esophagus.  The pressure of the food in this area causes other parts of the stomach to relax and allow food.  The stomach then contracts to break up food and push it towards the small intestine.

At any part of this process, dysfunction of the autonomic nervous system can inhibit proper digestion and gastric emptying.  Gastroparesis is a frequent complication of conditions affecting autonomic function, like orthostatic intolerance.  In some cases, treatment of the orthostatic intolerance can improve gastroparesis symptoms.

Vagotomy, an outmoded surgical treatment for ulcers that severs the vagus nerve, prevents the stomach from being able to relax to accept food.  It can trigger rapid movement of liquids through the stomach, while not allowing solids to be emptied.   Unintentional damage to the vagus nerve can be occur for a number of other reasons, including surgery or persistent high blood sugar, as in some diabetics.

The tone of the stomach and how much food can fit is controlled by enteric nerve cells that release nitric oxide (NO.)  NO keeps the stomach relaxed.  Interfering with cholinergic signaling can also keep the stomach relaxed, to fit more food.  Medications like opiates and anticholinergics have this effect.

In GP patients, stomach biopsies show that the enteric neurons are not shaped correctly. There are far fewer interstitial cells of Cajal than normal, and those that remain look damaged.  There are less nerve fibers than normal.  83% of GP patients have abnormalities in their stomach biopsies.

References:

Sarosiek, Irene, et al. Surgical approaches to treatment of gastroparesis: Gastric electrical stimulation, pyloroplasty, total gastrectomy and enteral feeding tubes.  Gastroenterol Clin N Am 44 (2015) 151-167.

Pasricha, Pankaj Jay, Parkman, Henry P. Gastroparesis: Definitions and Diagnosis. Gastroenterol Clin N Am 44 (2015) 1-7.

Parkman, H. P. Idiopathic Gastroparesis. Gastroenterol Clin N Am 44 (2015) 59-68.

Nguyen, Linda Anh, Snape Jr., William J. Clinical presentation and pathophysiology of gastroparesis.  Gastroenterol Clin N Am 44 (2015) 21-30.

Bharucha, Adil E. Epidemiology and natural history of gastroparesis. Gastroenterol Clin N Am 44 (2015) 9-19.

Camilleri, Michael, et al. Clinical guideline: Management of gastroparesis. Am J Gastroenterol 2013; 108: 18-37.