The Many Co-Morbidities of MCAS

A frequent question that I get from newly diagnosed patients is “What conditions go hand-in-hand with MCAS?”

The short answer is: Research in this area is in it’s infancy. The disease itself has only been coined for a decade, so there’s a scarcity of high quality evidence to evaluate in this area, and none of the research concludes causality – so far, it’s more about potential associations.

In terms of the conditions that appear to have the greatest amount of research among the MCAS patient population, Postural Orthostatic Tachycardia Syndrome (POTS) and Ehlers-Danlos Syndrome (EDS) are two conditions that consistently report findings and associations with MCAS. In fact, MCAS, EDS and POTS have been coined the “terrible triad” due to the sense that the three conditions seem to gang up on certain patients all at once.

When it comes to the more all-encompassing umbrella of MCAD (which includes Systemic Mastocytosis), the list of potential co-morbidities is much more varied. For the purposes of this article, I’ll stick to focusing on what conditions tend to be associated specifically with Mast Cell Activation Syndrome.

A handful of research currently exists that has attempted to evaluate the prevalence of the following conditions specifically in relation to MCAS:

• EHLERS-DANLOS SYNDROME (EDS)
• POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME (POTS)
• CANCER
• IRRITABLE BOWEL SYNDROME (IBS)
• FIBROMYALGIA SYNDROME (FMS)

MCAS, EDS and POTS

EDS and POTS are the clear front-runners in terms of conditions that have been specifically studied in the MCAS patient population. (They are both so common that they will have a future in-depth blog post of their own soon!)

The hypermobile type of EDS (the only type without an identified genetic mutation) appears to be more commonly associated with MCAS, though some patients do test positive genetically for the other types. It’s important that patients with suspected EDS are tested and have specialist-monitored care, as a number of more serious complications can occur with the disease, including Chiari malformation, idiopathic intracranial hypertension, cerebrospinal fluid leaks, tethered cord syndrome, and others.

There are also several types of POTS, and the hyperadrenergic type is rare in the general population but has been reported to be more commonly associated with MCAS.^1,2 An overactive sympathetic nervous system and an underactive Vagus nerve have been theorized to contribute to POTS.  It’s also plausible that some patients suffer from neuropathic POTS, where the issue may be more tied to the circulatory system; a drop in blood pressure due to blood pooling in the lower extremities may trigger a compensation in heart rate.

A 2015 study found that 66% of patients with POTS also had EDS and validated signs of MCAS. The authors concluded that collagen disorders, dysautonomia seen with POTS, and mast cell activation appeared to “co-segregate” together. However, this study had a small (15 patient) female-only sample size.³

A separate 2015 study evaluated a larger group of patients 117 patients with POTS, 74% of which were female. Of these patients, 20% had laboratory evidence of MCAD (specifically, elevated urinary prostaglandins or elevated urinary histamine levels).⁴

A 2016 study evaluated 41 patients with POTS and found that 63% had a co-existing joint hypermobility syndrome (JHS). Thirty-five percent of patients in the POTS + JHS group had a positive family history for JHS, and 27% of these patients had laboratory evidence of MCAD.⁵

While the literature indicates that the three conditions go hand-in-hand, there are certainly discrepancies in study results as well as the methods used in the studies to determine the diagnosis of EDS vs. JHS, and “MCAS.”

Here are some links to more information on these conditions:

Ehlers-Danlos Society website: https://www.ehlers-danlos.com/

Dysautonomia International website about POTS: http://www.dysautonomiainternational.org/page.php?ID=30

Cancer

Research has made connections between mast cells and different types of cancer including thyroid tumors, pancreatic cancer, multiple myeloma and Hodgkins lymphoma. Many theoretical associations have been shared and are quite plausible.

However, the first bit of research specific to the MCAS patient community was published in 2017 by Dr. Molderings and colleagues in Germany. The researchers retrospectively evaluated the prevalence of solid tumor forms of cancer reported in the past medical history of 828 European (German) and American MCAS patients. 68 patients (8.2%) of patients reported the development of a solid tumor prior to their diagnosis with MCAS.⁶

As a whole, MCAS patients presented with a higher prevalence of lung, thyroid, bladder, breast and reproductive organ (cervical, ovarian, testicular, uterine) cancers and melanoma than the general population. The German group had a higher rate of melanoma, testicular cancer and breast cancer than the American MCAS patients. The U.S. MCAS study population had a higher prevalence of ovarian and thyroid cancer when compared to the German MCAS population. Both MCAS groups had higher than average rates of lung cancer and cancer of the urinary bladder when compared to the general population.⁶

Irritable Bowel Syndrome

A 2011 study found that 19 out of 20 patients diagnosed with irritable bowel syndrome (IBS) had signs and symptoms of pathological mast cell activation disease.⁷ According to a 2017 publication by researchers Wirz and Molderings, “a majority of MCAD patients complain about abdominal pain and/or cramping usually accompanied by bloating-gassiness of the bowel, diarrhea, constipation, thereby fulfilling the diagnostic criteria for IBS. A bulk of results suggest roles of mast cell infiltration and activation in IBS-related pain pathology.”⁸

Fibromyalgia Syndrome

A study in 2016 concluded that the presence of elevated inflammatory mast cell mediators noted in 84 patients with fibromyalgia syndrome (FMS) could potentially be connected to the etiology of the condition.⁹ A 2017 review article noted that pain is one of the most severe symptoms in patients with MCAD, and concluded that a subset of patients with FMS may be the clinical manifestation of MCAD.⁸

Other Conditions

The literature also has noted that the following conditions may be more commonly encountered in this patient population and therefore may be associated with MCAS:

• COMPLEX REGIONAL PAIN SYNDROME (CRPS)
• MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS)
• NEUROPSYCHOLOGICAL CONDITIONS: ANXIETY, DEPRESSION & AUTISM SPECTRUM DISORDERS
• (and much more)

Mast cells themselves have been implicated to play a role in dozens (if not hundreds!) of conditions. For example, a 2004 study noted significantly higher levels of mast cell mediators in the limbs of patient with Type I complex regional pain syndrome (CRPS) compared to the unaffected limbs. They also found a significant correlation between pain and tryptase levels in CRPS patients.¹⁰

This type of research presents the conundrum: does this mean that patients with CRPS may have underlying MCAS, or rather is it that the inflammatory process occurring recruits extra mast cells to the area? Thus, at best, we have a lot of literature that indicates preliminary associations based on the measurement of mast cells, their mediators, and responses to medications and natural supplements that target mast cells.

Mast cells have been theorized to be associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) by Dr. Theoharides and colleagues. Specifically, mast cells in the diencephalon area of the brain could be responsible for some of the physiological pathways responsible for ME/CFS symptoms.¹¹

Dr. Theoharides is also leading the way with research regarding autism spectrum disorders (ASD) and their potential connection to MCAS. According to Dr. Theoharides, “Perinatal mast cell activation by infectious, stress-related, environmental or allergic triggers can lead to release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in a subgroup of ASD patients.”¹²

A 2016 study evaluated co-morbid conditions in patients diagnosed with MCAS based on their medical records/history. A number of conditions including gastroesophageal reflux disease (GERD), asthma, and interstitial cystitis (to name a few) also appear to be common in the MCAS patient population. Certain clinical findings such as anemia, elevated liver enzymes, blood pressure abnormalities, and fainting or near-fainting episodes are also frequently reported.¹³

And lastly, expert opinions in the functional medicine/naturopathic world note clinical trends in the overlap of MCAS with conditions such as:

• MOLD ILLNESS/TOXICITY
• LYME DISEASE/VECTOR-BORN ILLNESS
• EPSTEIN-BARR VIRUS (EBV)
• THYROID DISEASE
• MULTIPLE CHEMICAL SENSITIVITY
• PARASITIC INFECTION
• CELIAC DISEASE
• SMALL INTESTINAL BACTERIAL OVERGROWTH
• (and much more)

The Chicken or the Egg?

In patients with higher medical complexity who tend to have more than one diagnosis, there is great debate about whether the MCAS pre-dated the other condition or whether the other condition triggered the MCAS.

Some triggers like mold and environmental toxins have ample support in the literature in terms of their potential to activate mast cells, but that still begs the question, is this patient sick because their body was already burdened (perhaps since birth or epi-genetically) from MCAS, and these triggers were merely the tipping point? While the preliminary literature indicates that MCAS may have a genetic component, the consensus is far from clear and universally accepted on this topic.

There are several theories out there that provide plausible explanations for a number of the above-listed overlapping conditions. One such theory is the RCCX Theory by Dr. Sharon Meglathery which I’ll be discussing in the next blog post – stay tuned! Be sure to sign up for the email list to stay in the loop!

References

1. Raj SR. The postural tachycardia syndrome (POTS): pathophysiology, diagnosis & management. Indian pacing and electrophysiology journal. 2006 Apr;6(2):84.
2. Shibao C, Arzubiaga CL, Roberts LJ, et al. Hyperadrenergic Postural Orthostatic Tachycardia Syndrome in Mast Cell Activation Disorders. 2005;45:385-390.
3. Cheung I, Vadas P. A New Disease Cluster: Mast Cell Activation Syndrome, Postural Orthostatic Tachycardia Syndrome, and Ehlers-Danlos Syndrome. Journal of Allergy and Clinical Immunology. 2015;135(2):AB65.
4. Hoffman-Snyder C, Lewis J, Harris L, Dhawan P, Goodman B. Evidence of Mast Cell Activation Disorder in Postural Tachycardia Syndrome (P1. 277). 2015 Apr 6;84(14 Supplement):P1-277.
5. Goodman B, Hoffman-Snyder C, Dhawan P. Joint Hypermobility Syndrome in a Postural Orthostatic Tachycardia Syndrome (POTS) Cohort (P5. 116). 2016 Apr 5;86(16 Supplement):P5-116.
6. Molderings, Gerhard J., Thomas Zienkiewicz, Jürgen Homann, Markus Menzen, and Lawrence B. Afrin. Risk of solid cancer in patients with mast cell activation syndrome: Results from Germany and USA. F1000Research. 2017;6.
7. Frieling T, Meis K, Kolck UW, Homann J, Hülsdonk A, Haars U, Hertfelder HJ, Oldenburg J, Seidel H, Molderings GJ. Evidence for mast cell activation in patients with therapy-resistant irritable bowel syndrome. Z Gastroenterol. 2011; 49:191-194
8. Wirz S, Molderings G. A Practical Guide to the Treatment of Pain in Patients with Mast Cell Activation Disease. Pain Physician. 2017;20:E849-E861.
9. Tsilioni I, Russell IJ, Stewart JM, Gleason RM, Theoharides TC. Neuropeptides CRH, SP, HK-1, and Inflammatory Cytokines IL-6 and TNF Are Increased in Serum of Patients with Fibromyalgia Syndrome, Implicating Mast Cells. J Pharmacol Exp Ther. 2016;356:664-672.
10. Huygen F, Ramdhani N, van Toorenbergen A, et al. Mast cells are involved in inflammatory reactions during Complex Regional Pain Syndrome type I. Immunol Letters. 2004;91:147-154.
11. Theoharides TC, Papaliodis D, Tagen M, et al. Chronic fatigue syndrome, mast cells, and tricyclic antidepressants. J Clin Psychopharmacol. 2005;25:515Y520.E/CFS.
12. Theoharides TC, Asadi S, Panagiotidou S. A case series of luteolin formulation (Neuroprotek) in children with autism spectrum disorders. Int J Immunopathol & Pharmacol. 2012;25(2):317-323.
13. Afrin L, Self S, Menk J, et al. Characterization of Mast Cell Activation Syndrome. Blood. 2016;128;3683.