Mast Cell Activation Syndrome (MCAS)

Mast Cell Activation Syndrome (MCAS) is a condition in which mast cells, a type of white blood cell involved in the immune system, release excessive amounts of chemicals such as histamine, prostaglandins, and other inflammatory substances inappropriately or excessively. This abnormal activation leads to symptoms affecting multiple organs and systems.  Mast cells are part of the immune system and are found in tissues throughout the body, especially near the skin, lungs, gastrointestinal tract, and blood vessels.

Histamine is a compound involved in local immune responses and regulating physiological functions in the gut. It is released by mast cells and basophils and plays a pivotal role in allergic reactions, causing symptoms such as itching, swelling, and vasodilation.

Causes of MCAS

In MCAS, these mast cells become overactive and release mediators too often or at the wrong times, causing a wide variety of symptoms. The causes of MCAS can include:

• Genetic factors: Some individuals may have genetic predispositions that make their mast cells hyper-responsive.
• Environmental triggers: Infections, mold exposure, stress, allergens, and certain medications or foods can activate mast cells inappropriately.
• Idiopathic: In many cases, the exact cause is unknown.

MCAS is different from mastocytosis, where there is an abnormal increase in the number of mast cells. In MCAS, the problem is that the existing mast cells release too many mediators rather than there being too many mast cells.

Symptoms of MCAS

The symptoms of MCAS are highly variable, as mast cells are present throughout the body and can affect multiple organs and systems. Symptoms are typically episodic.  Common symptoms include:

1. Skin Symptoms:  flushing, hives, itching, swelling
2. Gastrointestinal Symptoms:  nausea, vomiting, diarrhea or constipation, abdominal pain, heartburn
3. Cardiovascular Symptoms:  low blood pressure, dizziness, rapid or irregular heartbeat
4. Respiratory Symptoms:  wheezing, shortness of breath, nasal congestion
5. Neurological Symptoms:  headaches, brain fog, fatigue
6. Other Symptoms:  anaphylaxis, joint or muscle pain, difficulty regulating body temperature

Histamine Blockers

• OTC H1 Blocker, eg Zyrtec, Claritin, Allegra, Benadryl, Ketotifen
• OTC H2 Blockers, eg Pepcid, Tagamet, Zantac
• Rx H1 Blockers, Ketotifen 0.5mg PO QHS

Mast Cell Stabilizers

• Cromolyn solution 100mg/5mL 200mg 4x/day before meals and at bedtime
• Ketotifen 0.5 – 2 mg 2x/day

Leukotriene Inhibitors

• Montelukast (brand name Singulair) 10mg daily (selectively binds to cysteinyl leukotriene receptors)
  • Montelukast Black Box Warnings:  Serious Neuropsychiatric Events
• Zafirlukast (Accolate) 20mg bid (antagonizes leukotriene D4 and E4 receptors)

Midodrine

Midodrine can help patients with mast cell activation syndrome by stabilizing blood pressure, improving blood flow, and reducing orthostatic stress, which can indirectly help to reduce mast cell activation and associated symptoms of flushing and hives.  It is particularly useful for managing symptoms related to orthostatic hypotension, which is a common issue in MCAS.  However, midodrine is typically part of a broader treatment plan that includes other medications targeting mast cell activity directly.

Black Box Warnings:  Midodrine can cause marked supine blood pressure elevations, use in patients whose lives are considerably impaired despite standard clinical care

Low Dose Naltrexone (LDN) 0.5-4.5 mg per day

Mechanisms of Low-Dose Naltrexone (LDN)

1. Immune Modulation:
   • LDN is thought to exert its effects by modulating the immune system. It temporarily blocks opioid receptors, leading to a rebound increase in the production of endorphins and enkephalins, which are natural opioids produced by the body. These endogenous opioids can modulate the immune response, potentially leading to reduced inflammation and mast cell stabilization.
2. Reduction in Pro-Inflammatory Cytokines:
   • LDN has been shown to reduce the production of pro-inflammatory cytokines, which are signaling molecules that can activate mast cells and promote histamine release. By lowering these cytokines, LDN might help to reduce the activation and degranulation of mast cells.
3. Regulation of TLR4 (Toll-Like Receptor 4):
   • LDN might exert some of its effects through the modulation of Toll-Like Receptor 4 (TLR4), which plays a role in the immune system’s response to pathogens. TLR4 is involved in the activation of mast cells. By modulating TLR4, LDN could potentially reduce inappropriate mast cell activation and histamine release.

Supplements

Supplements including luteolin, quercetin, vitamin C, local raw honey, bromelain, probiotics, astragalus, butterbur, D-HIST, PEA may reduce microglial activation

Luteolin calms/inhibits the mast cell response; has anti- inflammatory, anti-carcinogenic, and anti-viral properties; “inhibits interleukin (IL)-6, IL-8 and VEGF

Low Histamine Diet

A histamine avoidance diet can help reduce the amount of histamine the body needs to deal with.

Testing for Mast Cell Activation Syndrome (MCAS)

Testing for Mast Cell Activation Syndrome is best approached as supportive evidence rather than a single confirmatory result. Laboratory evaluation is most useful when timed to symptom flares and interpreted alongside a baseline value.

Serum Tryptase

Serum tryptase remains the most widely used marker of mast cell activation. It should be drawn as soon as possible during a flare, ideally within 1–4 hours, and compared to a baseline level obtained when the patient is stable. A clinically meaningful rise is defined as an increase of at least 20% above baseline plus 2 ng/mL. In practice, many patients with suspected MCAS have normal tryptase levels, so a normal result does not exclude the diagnosis.

Urinary Mast Cell Mediators

Twenty-four-hour urine testing often provides more useful information than serum markers. The most commonly measured mediators include N-methylhistamine, prostaglandin D2 (or its metabolite 11-beta-PGF2α), and leukotriene E4. These tests are ideally collected during or immediately following a symptomatic episode. Proper handling, often including refrigeration during collection, is important for accuracy. Even under optimal conditions, results can be variable and occasionally normal despite active symptoms.

Plasma Histamine

Plasma histamine can be measured but is limited by its short half-life and rapid fluctuation. Levels rise quickly during activation and fall just as quickly, making timing critical and false negatives common. For this reason, it is generally considered a less reliable marker.

Baseline vs Flare Testing Strategy

A practical approach is to establish a baseline tryptase level, then repeat testing during a flare when feasible. Pairing this with urine mediator testing during symptomatic periods increases the likelihood of capturing objective evidence of mast cell activation. The comparison between baseline and flare values is often more informative than any single measurement.

Excluding Clonal Mast Cell Disorders

Testing should also consider the possibility of Systemic Mastocytosis, particularly in patients with persistently elevated baseline tryptase. In those cases, additional evaluation such as KIT mutation testing or referral to hematology may be appropriate.

Bottom Line on Testing

Laboratory testing for MCAS is supportive rather than definitive. The highest yield comes from correctly timed measurements—especially tryptase and urinary mediators—interpreted in relation to baseline values. Normal results do not rule out mast cell activation, and testing is most useful when it captures the physiology of an active flare rather than a quiet baseline state.  At the end of the day, due to testing hassle and imperfection, we don’t bother with testing unless there is some compelling reason or doubt in the diagnosis.