Understanding Mast Cell Activation Syndrome

Mast cell activation syndrome (MCAS) is a syndrome – a collection of signs and symptoms that fit together – characterised by non-specific inflammatory symptoms. This release of mediators can impact the reproductive and urinary tract, causing unpleasant or painful symptoms.

It’s important to note that MCAS can affect any part of the body, and each person presents a little differently. If you suspect MCAS, talk to a practitioner experienced in treating and managing this condition.

How MCAS affects the urogenital tract

Some common issues that could be related to mast cell activation include interstitial cystitis (IC) or vulvodynia.

Urinary tract symptoms of MCAS

Increased urinary frequency
Difficulty starting urination
Incomplete bladder emptying
Painful urination
Flank or abdominal pain from kidney stones
Blood in the urine (rare)
Signs of infection, but a test comes back clear

Vaginal/reproductive tract symptoms of MCAS

Inflamed vulva or vagina
Vaginitis
Itchy vulva or vagina
Spotting between periods, dysfunctional uterine bleeding
Painful sex (dyspareunia)
Endometriosis is common
Often mistaken as bacterial or yeast infection
Signs of infection, but the test comes back clear

Luteinising hormone activates mast cells, which then release histamine to stimulate ovarian contractility, ovulation, and progesterone released by follicles. Thus, antihistamines can prevent ovulation.

Mast cells are abundant in endometrial lesions, while they are not activated in normal endometrium. The tissue and fluids around endometrial lesions contain inflammatory mast cell mediators.

Pregnancy symptoms in MCAS

Decreased libido
Infertility
Early miscarriage
Severe, excessive or prolonged vomiting
Pre-eclampsia
Pre-term labour
Poor response to anaesthetics

Hormonal symptoms of MCAS

Delayed or premature puberty
Extremely painful periods
Irregular periods
Heavy periods
Weak bones
Thyroid abnormalities
High cholesterol or triglycerides
Blood sugar dysregulation, type II diabetes, hypoglycaemia
Issues transporting nutrients

MCAS and vulvodynia

In vulvodynia, there appears to be a disruption to the regulation of the inflammatory response related to activation of the hypothalamic-pituitary (HPA) axis.

Biopsies show that vulvodynia sufferers have increased mast cell degranulation and infiltration compared with controls. Mast cell mediator heparanase was identified specifically in the vestibule of vulvodynia patients.

In the vestibule, heparanase degrades a component of basement membranes, heparin sulfate, and the extracellular matrix, which allows leukocyte infiltration.

Mast cell activation is increased in those with postmenopausal vulvodynia when compared with premenopausal subjects, despite oestrogen receptor α and neural hyperplasia being about even in the two groups. The discrepancy suggests that further regulatory processes may contribute to the age-related incongruence.

Mast cell activation releases preformed mediators and causes the synthesis and release of other active molecules involved in inflammation, such as cytokines, eicosanoids and chemokines. After stimulation, mast cells produce proinflammatory cytokines and tumour necrosis factor-α, as found in vulvodynia biopsy samples.

MCAS and interstitial cystitis

Mast cells set off inflammation that causes pain. Interstitial cystitis (IC) is a bladder condition resulting in severe pelvic pain that has no known cause and without consistent inflammation. IC symptoms correlate with elevated mast cell counts.

The cause of MCAS symptoms

The symptoms are caused by the inappropriate release of mast cell-produced compounds, but when there is no identified excess of mast cells (mastocytosis).

MCAS appears as unexplainable, chronic multi-system, multi-symptom health problems. These health problems can become known in infancy, childhood, adolescence or later after a trigger event such as a tick bite resulting in Lyme disease or an infection.

What is a mast cell?

A mast cell is an immune cell found in all human tissue but is more concentrated in the skin and mucous membranes. Mast cells hold special mediators, such as histamine, tryptase, synthesised chemokines and cytokines, which are released when activated by the immune system. One main mediator is immunoglobulin E (IgE). If you’ve ever had an allergy test, this is a mediator that is tested for.

Non-immune triggers for mast cells to secrete these mediators include stress and chronic pain.

Mast cell activation causes the mast cell to burst, known as degranulation, and it releases its contents. It’s this process of degranulation that is responsible for a variety of reactive, allergic or inflammatory symptoms. The mediators stored inside the mast cell vary widely depending on the location in organs and tissue (where the cell ‘belongs’ in the body); thus, when the mast cell bursts, what reaction occurs will depend on where the cell lives.

The mediators have different impacts, interacting with receptors in the tissue. Just about everything is affected, including the nervous system, cardiovascular system, skin, respiratory tract, uterus, digestive tract, bone marrow, and white blood cells. Thus, mast cell activation could affect any part of you.

Mast cells may be activated selectively or non-selectively. Non-selective activation of a mast cell means the whole cell is degranulated, while selective activation results in the release of patterns of mediators, known as differential degranulation.

Mast cell activation syndrome is difficult to identify, with the diagnosis made by identifying the pattern of symptoms and case history. The patterns tend to escalate in severity after stress, for example, puberty, trauma and infections.

MCAS is a mast cell activation disorder (MCAD), and other conditions, including cutaneous (skin) and systemic (whole-body) mastocytosis (mast cell proliferation), have been identified.

Systemic mastocytosis (an excess of mast cells) is reasonably rare, occurring in one in every 364,000 people. MCAS is much more common, occurring in 5-10 per cent of the population. MCAS means overactive or sensitive mast cells.

MCAS tends to be familial, with 75 per cent of diagnosed people having a close relative also diagnosed. About half of those diagnosed with MCAS have children who are affected to varying degrees.

How to identify MCAS

The most common signs and symptoms of MCAS include:

Abdominal pain 48%
Alternating diarrhoea and constipation 36%
Anxiety/panic 16%
Asthma 15%
Chills 56%
Cognitive dysfunction 49%
Constipation 14%
Cough 16%
Depression 13%
Diarrhoea 27%
Difficulty swallowing 35%
Dizziness/fainting 71%
Easy bleeding/ bruising 39%
Environmental allergies 40%
Eye irritation 53%
Fatigue 83%
Fever 40%
Fibromyalgia symptoms 75%
Flushing 31%
Frequent infections 27%
Gastroesophageal reflux 50%
Hair loss 15%
Headache 63%
Heart palpitations/dysrhythmia 47%
Heat and cold intolerance 13%
Insomnia 35%
Itching/rash 63%
Multiple/odd drug reactions 16%
Nail changes 13%
Nausea and vomiting 57%
Non-angina chest pain 40%
Oral irritation/sores 30%
Period pain 16%
Poor wound healing 23%
Rashes 49%
Sinusitis 17%
Shortness of breath/laboured breathing 53%
Sweats 47%
Swelling that moves around the body 56%
Swollen lymph nodes 28%
Tingling/prickling skin 58%
Throat irritation 48%
Tooth/gum/dental deterioration 17%
Tremor 13%
Urinary symptoms (excluding interstitial cystitis) 27%
Visual anomalies 30%
Weight gain/obesity 17%
Weight loss 16%

The most common physical findings in MCAS

Abdominal pain (any location, any type, any severity) 32%
Achy/pained appearance 28%
Anxious demeanour 11%
Back tenderness (one or more points) 11%
Brain fog 12%
Bruising 22%
Cardiac murmur 11%
Chronically ill appearance 42%
Dental deterioration 21%
Depressed demeanour 11%
Dermatographism 76%
Epigastric tenderness (just below ribs) 19%
Flushing 12%
Mild diastolic hypertension (90-199 mm/Hg) 14%
Mild systolic hypertension (140-159 mm/Hg) 32%
Moderate systolic hypertension (160-179 mm/Hg) 12%
Obesity 37%
Pallor (paleness) 13%
Rash (any type) 34%
Right lower abdominal tenderness 19%
Right upper abdominal tenderness 15%
Soft tissue tenderness 16%
Swelling 39%
Tachycardia (fast heartbeat) 28%
Tingling/prickling 20%
Tired appearance 46%
Use of mobility-assisting devices 12%
Weakness 12%

Other conditions often found with MCAS include:

Gastroesophageal reflux disease (GORD or GERD) 35%
Hypothyroidism (underactive thyroid gland) 17%
Blood clots 13%
High blood pressure 29%
Headaches 17%
Frequent or atypical infections 13%
Multiple/atypical drug reactions 23%
Depression 16%
Obesity 13%
Abdominal pain 22%
Sinusitis 16%
Osteoarthritis 13%
Hysterectomy 21%
Fibromyalgia 16%
Anxiety or panic 12%
Hyperlipidaemia 20%
Anaemia of chronic inflammation 15%
Cardiovascular malformations 12%
Cholecystectomy 20%
Sleep apnoea 15%
Dermatitides (inflammatory skin conditions) 11%
Environmental allergies 19%
Frequent upper respiratory tract infections 15%
Pre-syncope or syncope 11%
Tobacco abuse 18%
Miscarriage 15%
Interstitial cystitis (IC) 11%
Asthma 18%
Pharyngitis of tonsillitis 14%
Chronic kidney disease 10%
Type 2 Diabetes 17%
Dysmenorrhea (period pain) 14%
Postural orthostatic tachycardia syndrome (POTS) 10%

Diagnosis of MCAS

You may be diagnosed via a combination of personal health history information and one or more of the following:

Functional testing for evidence of mast cell activation – urinary N-methyl histamine (a practical and stable marker), tested when symptoms are present
Plasma histamine and plasma heparin (though N-methyl histamine tends to provide greater accuracy)
A 24-hour urinary histamine metabolite of prostaglandin D2 (PGD2) or its metabolite may be supportive of an MCAS diagnosis

What drives MCAS?

There are several key drivers for MCAS:

Chronic stress
Gut dysbiosis and intestinal permeability (‘leaky gut’)
Sleep problems and insomnia
Chronic infections and chronic inflammatory response syndrome
Chronic pain
Oestrogen activity/exogenous oestrogen exposure

How chronic stress drives MCAS

Mental, emotional, metabolic, traumatic or physical stress may trigger the body’s innate stress response. In turn, the hypothalamus releases corticotropin-releasing hormone (CRH). CRH then stimulates the pituitary to release adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal glands to produce the stress hormone cortisol.

CRH causes the synthesis and release of mast cell mediators such as tumour necrosis factor-alpha (TNFα), proteases, tryptase, chymase, histamine, leukotrienes (LTs) and PGD2 from mast cells.

Over time, this response may result in the perpetual cycle of chronic mast cell activation and CRH activity.

How gut dysbiosis and intestinal permeability drive MCAS

Gut dysbiosis is the state whereby the digestive tract flora has become unbalanced. Intestinal permeability is the state whereby the intestine has become prone to letting much larger particles through than it should, also known as leaky gut. This leakage can cause an immune response.

Gut dysbiosis and intestinal permeability can contribute to MCAS via inflammatory compounds stimulating mast cell activation by aggravating toll-like receptors found on mast cells.

An imbalanced gut microbiome may mean the enzyme that metabolises dietary histamine is lacking. Histamine, therefore, may continue to circulate, exacerbating mast cell activation.

Short-chain fatty acids produced by some gut bacteria may reduce the expression of genes associated with mast cell activation, the inflammatory response, and cytokine signally, thus reducing the frequency of MCAS symptoms. Dysbiosis may reduce colonies of such bacteria.

Antigens may enter the mucosa, causing mucosal mast cell activation, an inflammatory response, and altered mast cell-enteric nerve interaction when the intestinal barrier is not performing well.

How sleep disturbances and insomnia drive MCAS

Melatonin, the hormone that regulates our sleep-wake cycle (circadian rhythm), directly prevents mast cell degranulation, infiltration, and activation. When melatonin production is interrupted, MCAS symptoms can occur.

How chronic infection or CIRS drive MCAS

Pathogenic bacteria, fungi, and viruses produce toxins and proteins which can activate mast cells through pattern recognition receptors on mast cell surfaces, resulting in Chronic Inflammatory Response Syndrome (CIRS). Receptors recognise and respond to molecular patterns produced by pathogens.

Some specific pathogens are known to activate mast cell receptors:

Staphylococcus aureus
Escherichia coli
Cholera
Pertussis
Clostridium difficile
Mycoplasma
Respiratory syncytial virus (RSV)
Rhinovirus
Reovirus
Dengue fever virus
Human immunodeficiency virus (HIV)
Influenza
Candida albicans
Cryptococcus neoformans
Aspergillus fumigatus

How chronic pain drives MCAS

Pain receptors, when activated by inflammatory mast cell mediators, may activate the release of pain-signalling neuropeptides, which in turn can stimulate mast cell activation.

Once activated, this can cause a positive feedback loop resulting in ongoing mast cell activation and inflammation that may perpetuate chronic pain.

How oestrogen activity drives MCAS

Oestrogen, both human and exogenous (external/environmental), has been linked with mast cell activation. Oestrogen can bind to oestrogen receptors on mast cells and cause mast cell degranulation.

Mast cells express oestrogen receptors in the upper respiratory tract cells and interstitial bladder epithelium. Mast cell overactivation in these cells may be associated with increased oestrogen levels.

In oestrogen-driven conditions, for example, endometriosis, more oestrogen concentrations were associated with greater mast cell activity in ovarian endometriomas and period pain severity.

Treatment for MCAS

Non-drug treatments include:

Probiotics – Lactobacillus paracasei and Lactobacillus rhamnosus to improve immune function and moderate overactivity (induces T regulatory cell production, dampens inflammation in immune disorders.
Quercetin – stabilises mast cells and basophils and reduces degranulation and histamine release.
Aller-7 – a patented blend of herbs that has antihistamine, antioxidant and anti-inflammatory activity, stabilises mast cells, and down-regulates histamine release.
Fish oils high in omega-3 fatty acids control underlying inflammation, support immune regulation and enhance pathogen clearance. They also encourage the switch of proinflammatory M1 macrophages to anti-inflammatory M2 macrophages, which promotes tissue repair.
Prebiotics and fibre promote intestinal integrity, enhance microbiome composition, enrich commensal species associated with short-chain fatty acid production (especially butyrate, which moderates mast cell overactivity), and stimulate mucin secretion.
Herbal medicine for stress management and treatment of infections.
Low histamine diet to reduce intake of histamine-containing foods.

Pharmaceutical treatments include:

Epinephrine – used for acute anaphylaxis/allergic reactions.
Cromolyn sodium – typical dose is 200mg four times daily to reduce bone pain, abdominal cramping, diarrhoea, headaches and skin symptoms (e.g. allergic rash).
H2 and H1 blockers – both short and long-acting (diphenhydramine, hydroxyzine) for anaphylactic symptoms of MCAS.
Aspirin – blocks prostaglandins
Leukotriene antagonists – such as zafirlukast and montelukast, are prescribed for respiratory spasms, skin reactions and swelling.
Corticosteroids – controls malabsorption, the build-up of fluid in the abdomen (ascites), bone pain and to prevent anaphylaxis.

Diet modifications

Avoid alcohol or limit intake – DAO activity is impaired by alcohol, can increase dietary intake of histamines from food, and may trigger MCAS symptoms.
Opt for a Mediterranean-style diet rich in fibre and prebiotics to improve gut microbiome and increase short-chain fatty acids, which reduce mast cell activation
Try the low-histamine diet

Lifestyle modifications

Get plenty of good quality sleep
Avoid stimulants, drugs, and alcohol, as these substances disturb the hypothalamic-pituitary-adrenal axis and can exacerbate symptoms
Do regular physical activity to mitigate corticotropin-releasing hormone-induced mast cell activation

References

Molecular and Cell Biology of Pain Angela N. Pierce, Julie A. Christianson, in Progress in Molecular Biology and Translational Science, 2015

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Afrin LB. The presentation, diagnosis and treatment of mast cell activation syndrome. Curr Allergy Clin Immun. 2014 Sep 1;27(3):146-60.

Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007 May;85(5):1185-96. PMID: 17490952.

Afrin LB. The presentation, diagnosis and treatment of mast cell activation syndrome. Curr Allergy Clin Immun. 2014 Sep 1;27(3):146-60.

Afrin LB, Khoruts A. Mast cell activation disease and microbiotic interactions. Clin Ther. 2015 May 1;37(5):941-53. doi: 10.1016/j.clinthera.2015.02.008.

Afrin LB, Self S, Menk J, Lazarchick J. Characterization of mast cell activation syndrome. Am J Med Sci. 2017 Mar;353(3):207-215. doi: 10.1016/j.amjms.2016.12.013.

Wang X, Liu W, O’Donnell M, et al. Evidence for the Role of Mast Cells in Cystitis-Associated Lower Urinary Tract Dysfunction: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Animal Model Study. PLoS One. 2016;11(12):e0168772. Published 2016 Dec 21. doi:10.1371/journal.pone.0168772