Mast cell activation syndrome

Mast cell activation syndrome (MCAS) is a term referring to one of two types of mast cell activation disorder (MCAD); the other type is idiopathic MCAD.^[1] MCAS is an immunological condition in which mast cells inappropriately and excessively release chemical mediators, resulting in a range of chronic symptoms, sometimes including anaphylaxis or near-anaphylaxis attacks.^[2][3][4] Primary symptoms include cardiovascular, dermatological, gastrointestinal, neurological and respiratory problems.^[3]

MCAS is an umbrella term that describes a set of symptoms; it is not a specific diagnosis.^[1][5] Multiple diagnostic schemes for MCAS have been proposed. MCAS has been increasingly over-diagnosed or misdiagnosed.^[6][7]

Signs and symptoms[edit]

MCAS can present with a wide range of symptoms in multiple body systems, these symptoms may range from digestive discomfort to chronic pain, mental issues as well as an anaphylactic reaction. Symptoms typically wax and wane over time, varying in severity and duration. Many signs and symptoms are the same as those for mastocytosis, because both conditions result in too many mediators released by mast cells.^[8] It has many overlapping characteristics with recurrent idiopathic anaphylaxis, although there are distinguishing symptoms, specifically hives and angioedema.^[9] The condition may be mild until exacerbated by stressful life events, or symptoms may develop and slowly trend worse with time. MCAS symptoms are common in long COVID.^[10]

Common symptoms include:^[11]

• Dermatological
  • flushing
  • hives
  • easy bruising
  • either a reddish or a pale complexion
  • itchiness
  • burning feeling
  • dermatographism
• Cardiovascular
  • lightheadedness, dizziness, non-cardiac chestpain, presyncope, syncope, arrhythmia, tachycardia
• Gastrointestinal
  • diarrhea and/or constipation, cramping, intestinal discomfort
  • nausea, vomiting, acid reflux
  • swallowing difficulty, throat tightness
• Neuropsychiatric
  • brain fog
  • headache
  • fatigue/lethargy
  • lack of concentration
  • mild cognitive problems
  • sleep disturbances
• Respiratory
  • congestion, coughing, wheezing
• Systemic
  • Anaphylaxis

Causes[edit]

There are many causes of mast cell activation, including allergy. Genetics may play a role. In particular, Mutations of the KIT gene (which codes for the KIT protein that regulates cell growth and specifically ), specifically around codon 816 with the common one being asp816val, have been suspected to be associated with MCAS and is also associated to most systemic mastocytosis patients.^[12][13] It has been found that MCAS patients tend to have a wider range of KIT mutations around all domains of the protein and multiple at the same time rather than a single one, which could be a potential cause of the heterogeneity of the presenting symptoms of MCAS. Symptoms of MCAS are caused by excessive chemical mediators released by mast cells.^[14] Mediators include leukotrienes, histamines, prostaglandin, and tryptase.^[15]

Pathophysiology[edit]

Mast cell activation can be localized or systemic, but a diagnosis of MCAS requires systemic symptoms.^[16][17] Some examples of tissue specific consequences of mast cell activation include urticaria, allergic rhinitis, and wheezing. Systemic mast cell activation presents with symptoms involving two or more organ systems (skin: urticaria, angioedema, and flushing; gastrointestinal: nausea, vomiting, diarrhea, and abdominal cramping; cardiovascular: hypotensive syncope or near syncope and tachycardia; respiratory: wheezing; naso-ocular: conjunctival injection, pruritus, and nasal stuffiness). This can result from the release of mediators from a specific site, such as the skin or mucosal tissue, or activation of mast cells around the vasculature.^[18]

Diagnosis[edit]

MCAS is often difficult to identify due to the heterogeneity of symptoms and the "lack of flagrant acute presentation".^[11] Many of the numerous symptoms are non-specific in nature. Diagnostic criteria were proposed in 2010^[3] and revised in 2019.^[17] Mast cell activation was assigned an ICD-10 code (D89.40, along with subtype codes D89.41-43 and D89.49) in October 2016.^[19]

According to the American Academy of Allergy, Asthma, and Immunology (AAAI), the most precise method of diagnosing MCAS is through a bone marrow biopsy and aspirate.^[17] This method is commonly used to diagnose systemic mastocytosis, and the presence of SM increases the possibility of subsequently having MCAS. In addition, other common laboratory tests including KIT-D816X mutational analysis and flow cytometry analysis seeking co-expression of CD117 and CD25 are also commended for diagnosing clonal MCAS.^[20]

Although different diagnostic criteria are published, a commonly used strategy to diagnose patients is to use all three of the following:^{[citation needed]}

1. Symptoms consistent with chronic/recurrent mast cell release:
   Recurrent abdominal pain, diarrhea, flushing, itching, nasal congestion, coughing, chest tightness, wheezing, lightheadedness (usually a combination of some of these symptoms is present)
2. Laboratory evidence of mast cell mediator (elevated serum tryptase, N-methyl histamine, prostaglandin D2 or 11-beta- prostaglandin F2 alpha, leukotriene E4 and others)
3. Improvement in symptoms with the use of medications that block or treat elevations in these mediators

According to the British Medical Journal Best Practices, a diagnosis of MCAS is confirmed by evidence of a significant rise in a mast cell marker (e.g., serum tryptase) during acute episodes and a positive clinical response to a medication that targets a mast cell mediator. It is important to then evaluate the MCAS subtype: primary (clonal), secondary (usually associated with IgE-dependent allergy), or idiopathic.^[21] For a diagnosis of MCAS to be confirmed:

1. There must be recurrent, acute episodes of symptoms/signs associated with secreted mast cell mediators that affect two or more organ systems at the same time
2. A transient rise in a mast cell mediator (e.g., tryptase) must be confirmed during these acute episodes
3. The symptoms must respond to drugs that either target released mast cell mediators or suppress mast cell activation (e.g., antihistamine, H2 antagonist, leukotriene receptor antagonist, cromolyn).

In most cases, MCAS presents with recurrent episodes of anaphylaxis.

The World Health Organization has not published diagnostic criteria.

Treatment[edit]

Pharmacological treatments include:

• Mast cell stabilizers,^[9][22] including cromolyn sodium and natural stabilizers such as quercetin^[23]
• H1-antihistamines,^[9][22] such as cetirizine or ketotifen or fexofenadine or loratadine
• H2-antihistamines,^[9][22] such as ranitidine or famotidine
• Antileukotrienes,^[9][22] such as montelukast or zileuton as well as natural products (e.g., curcumin or St. John's wort extracts)
• Nonsteroidal anti-inflammatory drugs, including aspirin,^[22] can be very helpful in reducing inflammation in some patients, while other patients can have dangerous reactions to these drugs^[8]
• Monoclonal antibodies, such as omalizumab^[9]
• Corticosteroids^[22]

Prognosis[edit]

The prognosis of MCAS is uncertain.^[17]

History[edit]

The condition was hypothesized by the pharmacologists Oates and Roberts of Vanderbilt University in 1991, and named in 2007, following a build-up of evidence featured in papers by Sonneck et al.^[24] and Akin et al.^[25][8]

See also[edit]

• FcεRI
• Histamine intolerance
• Immunoglobulin E

References[edit]