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 left unreckogonized 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 and also within an individual.

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.

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 the many potential systemic connections.

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. They can also be found around blood vessels and lymphoid organs. Mediators such are found in the membranes surrounding the mast cell and are released into the environment causing an inflammatory response and recruiting other immune cells to be released in the region. The eventual release of cytokines and chemokines then mediate the inflammatory response.

The survival of the mast cell is dependent initially on the binding of a stem cell factor to KIT (a transmembrane tyrosine kinase receptor) and then on its ability to adapt using signals in its environment to the specific phenotype for the tissue where they reside. They are influenced by many factors including: Interleukin-3, 4, 9 and transforming growth factor beta1.

Mechanism of Injury / Pathological Process

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 which are lipid-derived mediators and many pro and anti-inflammatory cytokines and chemo lines. 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**

dd text here relating to the mechanism of injury and/or pathology of the condition

Clinical Presentation

MC can also be the cause of other disorders such as headaches, irritable bowel syndrome, gluten intolerances, osteoporosis, autoimmune disorders, neuropsychiatric disorders, and interstitial cystitis (Theoharides et al., 2015)

Hypotension(1)

Mast cell mediators: (TMS chart)

Histamine: flushing, itching, diarrhea, hypotension

Leukotrienes: Shortness of breath

Prostaglandins: flushing, bone pain, brain fog, cramping

Tryptase: Osteoporosis, skin lesions

Interleukins: Fatigue, weight loss, enlarged lymph nodes

Heparin: Osteoporosis, problems with clotting/bleeding

Tumor Necrosis factor-(inset alpha): Fatigue, Headaches, body aches

Activators: food, stress, exercise, environmental allergens, infection, medication( opioids, NSAIDS, local anesthetics), module, changes in body temperature, venoms (bee/wasp, snake, spider, fire ant, etc), friction, vibration,

Difficulty to ID triggers

Range of severity of triggers can change over time and in the same individual leading to episodic triggers and unpredictable

Lead to multi system, wides prepared symptoms:

Gastric, chronic pain, throat swelling and itching, flushing, purities, hives, angioedema, bladder conditions, respiratory complications including wheezing and shortness of breath, fatigue, cognitive dysfunctions, anaphylaxis, angioedema(swelling), low blood pressure, rapid heart rate (TMS)

Non-specific symptoms that are currently not recommended to be included:

-nasal congestion, neurological symptoms, and fatigue, fibromyalgia like pain, demographischen, rashes of many sorts, psychiatric and neurological disorders, Elhers-Danlos syndrome and postural Orthostatic tachycardia syndrome (POTS) (4)

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

Diagnostic Procedures

add text here relating to diagnostic tests for the condition
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

text here relating to the differential diagnosis of this condition

Relevance in Physiotherapy

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

Mast cells and 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),

Clinically relevant anatomy

What is a mast cell:  a mast cell is a granule dense cell that lives near the blood vessels in the mucosa and in the connective tissues. Bone marrow, GI tract skin, lining of the airway.the granules fontina mediators which respond to allergens and are responsible for the reactions and anaphylaxis responses. (TMS) the granules all have membranes surrounding them or sacs where mediators are contained (https://tmsforacure.org/overview/)

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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