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 diagnose and is often misdiagnosed, left undiagnosed for many years due to the difficulty in identifying specific triggers of the disease and the wide range of symptoms that can present across different people, but also within an individual.

Mast cell activation is a normal response in our bodies to the introduction of potentially harmful triggers and in a normal state. The activation 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 offer 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.

MCAS 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 its connections to other illnesses.

Mast cells are white blood cells that are well known for IgE mediated allergies. They are also commonly seen in food allergies, venom allergies from insect bites, asthma, and at its extreme, anaphylaxis.

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.

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. When the cells are activated they synthesize more mediators and release histamine and proteases which leads to an increased production of prostaglandins and leukotrienes (lipid-derived mediators) and many pro and anti-inflammatory cytokines and chemo lines.

2 types of MC:

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 **ADD REFERENCE**

Clinically Relevant Anatomy

Mast cells are granular cells that originate from the bone marrow and are distributed throughout the body. They reside in a wide variety of tissues including but not limited to skin and connective tissues, the Gi system, and the respiratory system. Mediators can are found in the membranes surrounding the mast cell

through stem cell factor binding to KIT (a transmembrane tyrosine kinase receptor) the propagation , differentiation, migration  and survival of the Mast cell happens. They evolve into the specific phenotype for the tissue based on signals that they receive from that environment. They are influenced by many factors including: Interleukin-3, 4, 9 and transforming growth factor beta1 (Gali et al 2011)

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.

When the cells are activated they synthesize more mediators and release histamine and proteases which leads to o increased production of prostaglandins and leukotrienes which are lipid-derived mediators and many pro and anti-inflammatory cytokines and chemo lines. text here relating to clinically relevant anatomy of the condition

Mechanism of Injury / Pathological Process

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Clinical Presentation

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Diagnostic Procedures

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Diagnosis

3 criterion for dx: (1, 3, 4)

1. Systemic symptoms (involving a minimum of 2 organ systems) of mast cell activation that are severe and recurrent (1)
2. Noted activation or elevated mast cells

Thresholds for diagnosis are a rise in cell mediators to the following values:

-serum Tryptase: 20% above baseline plus 2ng/ml (1)

-or 24 hour urine test:

urinary n-methyl histamine or other histamine metabolites

-    prostaglandin D2  or its metabolite 11 (beta)-prostaglandin F2(alpha)

-     leukotrienes E4 or MIAA

1. -a response to treatment with mast cell stabilizer or mast cell mediator therapy, mast cell blockers like histamine receptor blockers

1. -monoclonal (primary)- abnormal mast cells are identified and but systemic mastocytosis criteria have not been met.  The mutation detected is: KIT D816V and mast cells aberrantly display CD25 in most cases. (1,3,4)
   1. Confirmed mastocytosis with the mutation
   2. Or with only 2 minor SM criteria???  (1)
2. Secondary- MCAS occurs as an indirect response to another disease process as in an infection or autoimmune disease wtih an IgE mediated allergy or other hypersensitivity reaction
   1. There is another immunological disease present
   2. There is no mutation KIT D816V (CD25+)or neoplasticism (1,3) Mast cells
      1. IN this case treatment would need to focus on both the underlying disease and the MCAS
3. Idiopathic-MCAS reactions are clearly present abut htere ie no known cause and any secondary criteria: (1)
   1. No disease related
   2. No neoplasticism MCs
   3. No IgE allergy
      1. Treatment is aimed at controlling MCA and anaphylaxis

While these categories have been set, many people suffer from mre than one type of mast cell activation which can lead to severe life threatening reactions and anaphalyxis (1)

DX MCAS:

• challenging to dx:

4 criteria most commonly used:

1. Clinical symptoms commonly associated with MCAS: (https://tmsforacure.org/wp-content/uploads/MCD-Symptoms-Infographic.pdf)
   1. Ear/nose/ throat
   2. GI
   3. Skeletal: bone/Musica pain, osteoporosis and osteopenia,
   4. cutaneous: hives, flushing of the face/neck/chest, skin rashes, itching without rash
   5. Cardiovascular:
      1. Lightheadedness, syncope, rapid heart rate, chast pain, low BP, HBO at the start of a reaction, blood pressure instability
   6. Gynecological:
      1. Uterine cramps
      2. Bleeding
   7. Urinary
      1. Bladder irrationality
      2. Frequent urination
   8. Anaphylaxis
   9. Angiodema (swelling)

Testing and Measures

1. Testing for mediator release
   1. Tryptase serum testing: only diagnostic mediator tests for MCAS with a specified increase from baseline to dx. Sample Needs to be collected within 4 hours of symptomatic episode, and then compared to baseline 24-48 hours after. A negative result does not rule out MCAS
   2. Urinary tests:
      1. N-methylhsitamine and prostaglandins D2, DM, F2a (5)
2. Test by treatment
   1. The theory that if someone responds to a treatment for MCAS that the person actually has it

Urine testing for

Testing: timing needs to be during flare, 24 urine histamine prostaglandins with case stories and historical sxs

Endoscopy 

(see Outcome Measures Database)

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

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Relevance in Physiotherapy

Relevance for PT

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.

• Co morbid clinical manifestations with GI disorders
  • Functional GI disorders (Fikree et al 2015)
  • Eosinophilia GI disorders (Adonis et al. 2013)
  • Increased Asthma (Morgan et al 2017)
  • Neuropsychiatric conditions (sinibaldi et al 2015)
  • Osteoporosis (deodar and Woolf 1994)
  • Orthostatic intolerance (garland et al 2015)
  • Increased number of chymase positive MC in eyelid skin of people with CTDs in the eyelid skin: (joint hypermobility, skin hyper-elasticity), spinal deformities, thumb and wrist sign, vascular, fragility, varicose veins, telangiectasias

Resources

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