Mast Cell Activation Syndrome (MCAS)

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Introduction/Definition

Mast Cell Activation Syndrome (MCAS) is one of several Mast Cell diseases (MCD) . It is particularly hard to identify and is often misdiagnosed or left unreckogonized for many years. It prenests with a wide range of differing symptoms and can be the result of many different triggers that are not always consistent across the population of these infected and can be inconsistent even within the individual who suffers from MCAS.

Mast cell activation is a normal response in our bodies to the introduction of potentially harmful triggers. The activation of the mast cells can be a result of an IgE mediated response or a non- IgE mediated response the reactions of which, in both cases can vary from mild to severe and include a wide range of varied symptoms. Mast cell Activation Syndrome occurs when there is an over-reaction and/or inappropriate reaction of the mast cells to a stimuli, known or unrecognized, that can not be explained by any other disease.

3 types of mat cell activation:

1. Monoclonal (primary):
   • This is a rare form of the dysfunction.
   • It is the result of over-profiletarion of mast cells and usually involves mutations in the KIT gene or aberrant expression of the CD25 or CD2.
   • Monoclonal mast cell activation syndrome can also be a result of mastocytosis.
2. Secondary (non-clonal):
   • There is a normal level of mast cell production in the tissues.
   • Mast cells are inappropriately activated as an allergic reaction to typically harmful triggers creating either a heightened IgE or non-IgE mediated response.
3. Idiopathic:
   • No defined allergic or autoimmune cause has been identified for the diagnosis of idiopathic mast cell activation syndrome.
   • It is a non-clonal/secondary idiopathic MCAS.
   • This is likely more prevalent than the other forms ( 1 and 2 above) of mast cell activation syndrome.

While these categories have been set, many people suffer from more than one type of mast cell activation which can lead to severe life threatening reactions and anaphylaxis.

MCAS also has correlations with other orthopedic diseases. While MCAS has been recognized for many decades, there is still much research needed in order to understand the causes, triggers, and the many potential systemic effects.

Clinically Relevant Anatomy

Mast cells are granular cells that originate from bone marrow and are distributed throughout the body residing in a wide variety of tissues including but not limited to skin and connective tissues, the GI system, and the respiratory system. They are most commonly located near blood vessels, mucosa, and lymph. Mediators are found in the membranes surrounding the granules and are released into the environment as a response to allergens. This release results in an inflammatory response that also recruits other immune cells to be released in the region.

For a mast cell to survive, it first binds onto a stem cell factor in the bone marrow, KIT (a transmembrane tyrosine kinase receptor) , and then it adapts using environmental cues to the cell’s phenotype where it resides becoming a mature mast cell. They are influenced by many factors including: Interleukin-3, 4, 9 and transforming growth factor beta1.

There are 2 types of mast cells:

1. MCT  - connective tissue, skin, peritoneal cavity (T for tryptase in the granules). They express interleukin-5 and 6.
2. MCTC- gut and respiratory mucosa (TC for tryptase and chymase). They express interleukin-4.

Common mediators released in the mast cell response:

• Histamine
• Leukotrines
• Prostaglandins
• Tryptase
• Interleukins
• Heparin
• Tumor necrosis factor
  

Mechanism / Pathological Proces

Mast cells coordinate an immune response to pathogens through surface receptors, receptors for adenosine phosphate, estrogen, and immunoglobulins, physical stimuli (pressure and temperature), and toxins.

Mast cells main role of creating an immune response to potentially harmful stimuli and pathogens is initiated when surface receptors for adenosine phosphate, estrogen, and immunoglobulins, physical stimuli (pressure and temperature), and toxins become active. This leads to the synthesis of an increased number of mediators and the release histamine and proteases. This, in turn, leads to an increased production of prostaglandins and leukotrienes (lipid-derived mediators) and many pro and anti-inflammatory cytokines and chemokines. The result of mast cell response can vary greatly intensity. It can be as small as the red bump around a mosquito bite or a full anaphylactic reaction.

Mast cells, in addition to the allergic response, have many other functions in the cell. They are responsible for homeostasis, phagocytosis, cytokine and chemokine production, and the immediate release of vasoactive substances. Mast cells are found within tissues as opposed to other immune cells which are located outside of cells. They are surrounded by nerves, blood vessels, and lymphatic vessels.

Clinical Presentation

There are a wide variety of clinical symptoms associated with Mast Cell Activation Syndrome. Some of the variation in symptoms and clinical presentation are due to the different mediators that may be released by the mast cell in response to a noxious stimulus. In addition, for people who have MCAS, the body’s response to a specific stimulus is unpredictable and the level of immune reaction that occurs may change with recurrent exposures. Often, because of the amount of mast cells in the Gastrointestinal tract, there are a host of GI symptoms present.

Common Complaints

Some of the most common complaints and symptoms include but are not limited to:

• Flushing, itching, and skin rash, skin lesions, and/ or redness
• Fatigue , headaches, body aches
• Osteoporosis, bone pain
• Gastrointestinal symptoms including
  • bloating, pain, nausea, diarrhea, GERD, IBS symptoms
• Throat swelling, shortness of breath
• Cramping
• Weight loss and enlarged lymph nodes
• Problems with clotting and bleeding

Correlates

There have also been many non-specific correlates to MCAS, and while there is mounting evidence in favor of correlations between these issues and MCAS, more research is necessary to fully understand how mast cell activation directly causes them.

• Nasal congestion
• Neurological symptoms
• Fatigue and Fibromyalgia like pain
• Rashes
• Psychiatric and neurological disorders
• Elhers-Danlos syndrome
• Postural Orthostatic tachycardia syndrome (POTS)
• Celiac disease and gluten intolerances
• Autoimmune disorders
• Hypotension

Because MCAS is episodic and unpredictable and the range of severity of triggers can change over time and in the same individual, the identification of these correlates in the diagnosis of MCAS is not recommended.

Diagnostic Procedures

MCAS can be difficult to diagnose. There are three specific criteria, of which all must be met, to have a true diagnosis of MCAS.

1. Systemic symptoms (involving a minimum of 2 organ systems) of mast cell activation that are severe and recurrent
2. Noted activation or elevated mast cells
3. A response to treatment with mast cell stabilizer or mast cell mediator therapy, mast cell blockers like histamine receptor blockers

Organ systems commonly recognized for diagnosis are as follows:

• Ear, nose, throat

• Gastrointestinal
• Cardiovascular: light-headed, disregulated heart rate, inflammation
• Skeletal: bone pain, osteoporosis
• Cutaneous: hives, flushing
• Urinary: bladder irritation

Testing and Measures

1. Serum testing:
   • Primary testing for MCAS is based on values found of the Tryptase release through serum testing. The threshold for serum Tryptase is 20% above baseline plus 2ng/ml. The blood sample needs to be collected within 4 hours of symptomatic episode, and then compared to baseline. If there is no already known baseline levels, testing for baseline must be done 24-48 hours after the activation episode. While this is the best test to rule in MCAS, a negative result does not necessarily rule out MCAS because so much of the test relies on timing of the sample collection during the reaction process.
2. Urinary testing:
   • Urinary testing has been done to in order to identify mediators from a mast cell response in the urine within 24 hours of the reaction taking place. The test must also correspond to the case story and historical symptoms. Testing is checking the levels of N-methylhsitamine and prostaglandins D2, metabolyte 11β , prostaglandin F2α,DM, leukotrienes E4 or MIAA.
3. Test by treatment:
   • While not as objectively measurable, this method offers a diagnosis for MCAS if treatment for it is successful (As in the 3rd diagnostic requirement).
4. Endoscopy:
   • An endoscopy may show elevated or mast cell numbers in the GI tract but is much more invasive and not commonly used as a diagnostic procedure.

Management / Interventions

Management interventions

Treatments:

Medications:

-H1 antihistamines: (1st generation H1 antihistamines- hydroxyzine hydrochloride, diphenhydramine, chloroheniramine, doxepin hydrochloride, ketotifen, 2nd generation H1 antihistamines (usually cuase less drowsiness-fexofenadine, loratidine, desloratidine, levocetirixine, cetirizine) may stabilize the mat cells and reduce the acute symptoms of allergy: itching, rashes, flushing and headaches, brain fog

-H2 antihistamines (nizatadine, famotidine, cimetidine: also for general mast cell stability but may also help with GI symptoms

-mast cell stabilizers (oral chromodynamics sodium, ketotifen, Quercetin and luteolin) and: GI symptoms and brain fog

-Leukotrienes inhibitors (montelukast, zafirlukast, zileuton)- mast cell stability and respiratory symptoms

-aspirin therapy for elevated prostaglandins and will help with brain fog, bone pain and flushing

-anti IgE therapy (omalizumab and others) for overall stability and asthma, anaphylaxis (TMS chart)

Range of triggers can be reduced when the rage of sxs has been decreased

PPI have been helpful

Treatment for severe presentations of MCAS may need lifelong immunotherapy omalizumab (anti- IgE) therapy or pharmacological therapy (1)

Differential Diagnosis

1. Differential diagnosis: (1,3)
   1. Infectious diseases
   2. IBS
   3. Adrenal insufficiency
   4. Cardiovascular disorders  and myocardial infarction
   5. Phychological factors
   6. Oncologic disorders
   7. Endocrine dysfunctions
   8. Toxicity

For reference the other mast cell diseases: (3)

-Systemic Mastocytosis (SM)

-cutaneous mastocytosis (CM)

-Smoldering mastocytosis (SSM)

-hereditary alpha tryptasemia (HaT)

Confirmed MCAS cases

Celiac disease testing 87% had +

Dietary changes

Adding to GI list for differential dx

WHy the GI system is so affected:

Mast cells are responsible in the GI tract for:

-immune regulation: adaptive, innate

-epithelial Integrity:ion/water secretion, permeabilty

-endothelial function: vascular permeability, coagulation, blood flow

-Microbial defense: bacterial, viruses, parasites

-tissue remodeling: wound healing, fibrosis

-neurological activity: peristalsis and pain persecption

Adults: bloating, pain, diarrhea, nausea present for many years

Mistaken for IBS 40% dx with IBS

Bloating,

Pain, diarrhea

Nausea

Children:

Pain GERD constipation

Reflux

Dyspepsia

Nausea

Diarrhea

Committing

Dysphasia

Bloating

Pain

Leading to inflammation and allergic type responses

HIgh presence of mast cells in the GI tract and some GI symptoms are commonly activated with MCAS.

Most GI MD do not test for MCAS

Activators: food, stress, exercise, environmental allergens, infection, medication

1. Allergic sxs
2. 2. GI next main set of sxs for med referral

text here relating to the clinical presentation of the condition

text here relating to the differential diagnosis of this condition

Relevance in Physiotherapy

Because there are many possible triggers for MCAS, it is important that the fisioterapist recognize and help those with suspected disease avoid potential triggers both in the clinic and in everyday life.

Some of the most relevant triggers in the rehabilitier facility and scope include: exercise, medication ( opioids, NSAIDS, local anesthetics, changes in body temperature, friction, and vibration.

Other common triggers include: : food, stress, environmental allergens, infection, and venoms (bee/wasp, snake, spider, fire ant, etc).

Elhers-Danlos Syndrome (EDS) and Hypermobility Sprectum disorders (HSD)

Because mast cells are so intertwined in the connective tissues where they reside, there is the possibility that they play a distinct role in autoimmune dysfunctions, although the link between the two is still not clear. In hypermobility dysfunctions the chronic release of mast cell factors may be the link between the hypermobility disorder and the autoimmune disorder. There are many shared clinical features between mast cells disease and hEDS/HSD because of the direct relationship of Mast cells to the connective tissues that there may be a relationship worth noting. (6) this would allow the PT to refer and identify patients sooner.

The connection between MCAS and hEDS/HSD may be due to the presence of tryptase anbd histamine (as well as other mast cell mediators) who also play a role in promoting the proliferation of fibroblasts and collagen production. (6)(7)

Urticaria

prevelant in EDS and MCAS- basophils and mast cells are mostly responsible for the urticaria/flushing (6,8,9) but there is no direct cause found as of yet, and may be just a result of the mast cell disease alone.

There have been concernsections drown between the pathogenicity of Lupus erythematosus (SLE), chronic spontaneous urticaria as a result of Mast cell dysfunction.

There has also been a connection/involvement of Mast cells in multiple sclerosis and rheumatoid arthritis. 10,11,12

Rheumatoid arthritis

   Chronic autoimmune inflammatory arthritis and immune cells contribute to the RA pathogenicity. Inflammatorion ofsynovuim of joints (small more common than large) and synovial hyperplasia with various immune cells in the synovium: T cells, B cells, and innate immune cells including mast cells in RA synovitis. (13)

In a study that showed histologic evidence that increased mast cells were present in the synovium of those who also presented with RA versus a control group. (14) there has also been evidence of different phenotypes of synovitis according to the density of the MC infiltration in the synovium (8) several studies show the increased number of mast cells or IgE mediated  in RA: both in the synoviumleading to degradation of the synovium of the joint as well as cartilage and bone in some cases. All of the studies (16),

Links for PT

• linked to connective disorders especially hEDS (6)
  • Mast cell activation has been shown to play a role in the disruption of connective tissue integerty through the activity of its mediators including histamine and tryptase affecting multiple organ systems which leads to mast cells activitaion disorders.

Resources

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