A large number of mast cell activation disorder patients carry a concurrent diagnosis of Dysautonomia, a collection of conditions associated with dysfunction of the Autonomic Nervous System (ANS).

During a physician-patient small group discussion at last year’s Mastocytosis Society Conference, the question was raised, “How many of you have been diagnosed with POTS?” (Postural OrthostaticTachycardia Syndrome). Surprisingly, approximately half of the group, approximately 20 out of 40 patients raised their hands. POTS is a chronic form of dysautonomia characterized by tachycardia in response to orthostatic stress such as going from a sitting position to standing and may involved multiple organ systems. The symptoms can range in severity from mild to disabling. Interestingly, the co-existing conditions of dysautonomia did not stop with POTS. Patient participants reported diagnoses with other forms of dysautonomia including Neurally Mediated Syncope (NMS, also known as Neurocardiogenic Syncope or Vasovagal Syncope), and Orthostatic Hypotension. Interestingly, the coexisting mast cell disorders included patients with disorders along the mast cell activation disorder spectrum (MCAD) including IgE-mediated Anaphylaxis, Cutaneous Mastocytosis, Systemic Mastocytosis, and Mast Cell Activation Syndrome (MCAS). Clearly, there appears to be a connection between dysautonomia and mast cell activation (MCA), but what? The presence of gastrointestinal (GI) symptoms may be prominent in both of these disorders but in general, the involvement of mast cell mediator activity and its association with ANS dysfunction is a topic that has been given little attention. Further study in this area may provide clues about the pathophysiology of both dysautonomia and MCADs.

OBSERVATIONS
It is known that mast cells interact closely with nerves. Mast cells have been observed degranulating adjacent to nerve synapses and increased numbers of activated mast cells have been documented in the mucosal tissues in “functional” gastrointestinal (GI) disorders that often coexist with dysautonomia. It therefore makes sense that abnormal mast cell mediator release may be a driving force behind nervous system disorders that involve the ANS and that may lead to GI symptoms. The ANS is made up of three parts: the sympathetic nervous system, the parasympathetic nervous system and the enteric nervous system (ENS). Much of the current study of dysautonomia focuses on the roles of the sympathetic and parasympathetic nervous systems, however there has been little emphasis on the ENS. The ENS is comprised of a fabric-like system of neurons that are located in the smooth muscle linings of the intestines (see figure below) and plays an important role in many GI functions. It stands to reason that dysautonomia affecting the ENS leads to GI symptoms.

This cutout view of the small intestine illustrates the location of the nerves that make up the ENS.
Basic structure of the alimentary canal, including its four basic layers. Digital illustration. © 2012 Pearson Education, Inc.
www.anatomyandphysiologyi.com/digestive-system-histology-alimentary-canal/

Not enough is known about MCA. However, it may be one of the more important medical findings of our time. There are many theories about the basic mechanisms of MCA that may contribute to GI symptoms including diarrhea and abdominal pain. For example, mast cells may activate near the nerve synapses in the smooth muscle walls surrounding the lining layers of the GI tract possibly changing the “leakiness” of the gut. At this time there is not enough clinical evidence to understand the full relationship between GI problems and MCA. We know that mast cells have the capacity to release chemical inflammatory mediators including; histamine, leukotrienes, prostaglandins, proteases and cytokines. In the GI tract, it is possible that these mediators may be affecting smooth muscle contraction (to increase or slow the propulsion of food through the GI tract) and may increase leakiness and mucus secretion (to cause more watery-type diarrhea). But understanding how MCA works in patients to cause symptoms requires further research.

An improved understanding of MCA is critical because it appears to be more common than initially thought. MCA is now implicated in many chronic medical conditions such as Irritable Bowel Syndrome (IBS), Fibromyalgia and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS). Overlapping symptoms in these disorders may be attributable to MCA because of the diverse array of mast cell mediators that may be involved and that act on multiple organ systems. Although it will be hard to determine how many patients suffer from disorders due to abnormal MCA, it is likely that all physicians see at least a handful of these patients in their practices. MCA may be playing a role in as much as 15-20% of the patient population who have chronic, multi-system symptoms. This is hypothesized based on what we know about mast cell biology in relation to inflammatory disorders.

DIAGNOSIS
Although we would like to think that physicians at the local level increasingly recognize MCAD, the reality is that many do not consider these disorders when confronted with a patient presenting with multiple seemingly unrelated complaints. Like dysautonomia patients, mast cell patients present heterogeneously with complaints that may differ from patient to patient. This makes it difficult for doctors to recognize and diagnose such conditions. For this reason, it is important that patients be proactive and educate physicians about their suspected condition(s) and even help them understand which tests are needed to make a diagnosis. A wealth of information is available on The Mastocytosis Society website (www.tmsforacure.org). In the case of MCAS, much of the diagnosis still relies on the physician’s ability to elicit the key signs and symptoms of MCA and to ensure that there is no other condition that better explains the patient’s symptom profile. The physician must also determine whether a patient has adequately responded to anti-mast cell mediator medications, which support the mast cell activation diagnosis. Lab tests are used to confirm the diagnosis. Since some lab tests are more or less specific for detecting abnormal mast cell activation and many variables have the potential to interfere with consistent findings more research is needed to improve and standardize laboratory tests. Most tests are sent out to various labs in the country such as Mayo Clinic so any physician can order them. Common screening tests used at Brigham and Women’s Hospital for MCAS are a serum tryptase, a 24 hour urine for N-methyl histamine, prostaglandin D2 or its metabolite 11-beta prostaglandin-F2α. Although urine samples must be kept refrigerated until submitted to the laboratory (unless your lab provides collection bottles with chemicals added to stabilize the sample without refrigeration) these metabolites are thought to be relatively stable. These tests are ideally performed when the patient is at their “baseline” and then repeated during a flare of symptoms or during the acute onset of symptoms. If a clonal mast cell disorder such as systemic mastocytosis is suspected because of an elevated tryptase, characteristic urticaria pigmentosa rash, a history of unexplained anaphylaxis, or other clinical features, then a KIT D816V mutation can be screened for with a blood test. It is recommended that a specialist with knowledge of these disorders sees the patient with a strongly suspected or confirmed MCAD. Consultation with an experienced specialist will help confirm the diagnosis, characterize it among the spectrum of mast cell disorders and determine whether a patient will need additional testing such as a bone marrow examination, colonoscopy with biopsies, or a bone DEXA scan.

GASTROINTESTINAL FINDINGS
The three most common GI symptoms that accompany MCAD and dysautonomia are:

1. Abdominal Pain (Some component of this is seen in nearly all MCAD patients. Note: this is also common in many primary GI disorders such as IBS).
2. Diarrhea
3. Bloating and gas

Additional GI complaints include: constipation, gastroparesis (slow emptying of the stomach), nausea, vomiting, and gastroesophageal reflux disease (aka “GERD”) that may result in heartburn and occasional swallowing difficulties.

When patients are evaluated for the above GI symptoms, health care providers often consider and rule out other inflammatory conditions such as celiac disease, inflammatory bowel disease (ulcerative colitis, Crohn’s disease, microscopic colitis), chronic infections (such as Giardia), malignancy (colon cancer), and functional GI disorders such as IBS where there is no obvious abnormality detected on testing. It is important to note that many of these disorders may present with similar symptoms so specific testing may be required to differentiate them.

A key clue that a patient may have a mast cell disorder is the presence of complaints and ongoing symptoms in many organ systems (GI tract, skin, lungs) of varying severity and intensity.

These other symptoms outside of the GI tract may include fatigue, flushing, dermatographism, memory/concentration difficulties, headaches, itching and respiratory problems. Symptoms tend to wax and wane and may be triggered by various environmental factors such as certain foods, temperature changes, bites/stings, stress and strong inhaled scents. When present with dysautonomia it is common to have orthostatic issues (symptoms such as light-headedness and palpitations upon standing), peripheral neuropathies (numbness and tingling in the feet and/or hands), GI issues that sometimes include the upper GI tract including gastroparesis, reflux, and nausea. These complaints associated with MCA appear to be fairly prevalent in the dysautonomia population and especially in patients with POTS.

Since many Gastroenterologists would likely not consider dysautonomia and/or MCAD when assessing a patient’s GI symptoms, two-way communication between patient and physician is often a crucial element in the diagnostic process. Ultimately, the process of diagnosing MCAD may be lengthy and time consuming. It is important that both patient and physician are diligent and that patients strive towards the detection of objective findings that can validate the suspected condition. Although this diagnostic process may be frustrating to the patient, having a high suspicion for a mast cell disorder is a valuable first step.

RECOMMENDATIONS

Rule Out Dysautonomia
Once a mast cell disorder has been identified, it may be helpful to evaluate for the co-existence of dysautonomia due to the observed possible association of these disorders. This can be done initially in the clinic by assessing the orthostatic vital signs of the patient. If abnormal vital signs (such as a 30 beats per minute or more increase in heart rate or a drop in blood pressure of 20/10 mmHG (millimeters of mercury) after three to five minutes of standing) are identified in response to orthostatic stress, a full autonomic workup by a knowledgeable dysautonomia specialist may be warranted. A number of reputable autonomic specialists can be found on the www.DysautonomiaInternational.org or DINET.org websites. It is important to recognize the presence of dysfunction of the ANS in order to provide a complete set of treatment options for the patient.

Find an Effective Local Doctor
Perhaps in no other medical condition is it more important to have good two-way communication between the patient and physician than in the case of MCAD. This is because the medical community is still learning about the pathophysiology of MCA and associated disorders. Further, the dissemination of clinical research findings often do not make their way down the chain quickly to the local treating physician. Finding an effective local doctor means finding a physician who is willing to work with an out of town specialist, refer to appropriate specialists and learn about MCAD and/or dysautonomia themselves. Effective continuity and communication between the local physician, specialist, and patient is necessary for optimal clinical outcomes.