Understanding Mast Cells, MCAS (Mast Cell Activation Syndrome) & Histamine

Mast cells play a crucial role in the immune system, but when they act up, they can cause a range of health issues.

This post explains what mast cells are, and what happens when mast cells become over reactive. Possible causes of this over reactivity are canvassed.

Microscopic close-up of mast cells

What Are Mast Cells?

Every body has mast cells. They are a type of white blood cell involved in the body’s immune system.

Mast cells were first described as early as 1863. Mast cells are a type of white blood cell located all through the body, but are generally higher in tissues that serve as the barrier between your body and the outside world: the skin, lungs, and intestines. Mast cells have normal functions to keep your body in balance and healthy. They have major roles in keeping your body processes in balance (homeostasis), repair body tissues there is a 'tear' and have a very fundamental role in the immune system, both the acquired immune system and the innate immune system. When mast cells are working as they should, they are monitoring for threats to the body's health such as allergens and any injury. Mast cells are part of the cell group called granulocytes, which are cells that contain granules with several types of chemicals within them- think of little water balloons. Overall, mast cells contain 50 – 200 granules. Mast cells can degranulate quickly — releasing various inflammatory molecules (histamine, heparin, cytokines, leukotriens and growth factors) into the surrounding tissue. This is called 'degranulation' of the mast cells.

This release of these mediators causes inflammation, swelling, and other defence mechanisms to protect the body. These cells are essential for fighting infections and healing wounds.

In normal conditions, mast cells help maintain balance and protect the body.

Mast cells in different tissues act differently — secreting different chemicals when activated. For example, some release only tryptase, and others only chymase (both along with histamine, IL-6, TNF-alpha, prostaglandins, etc.). Mast cells are immune cells and are primed to react to any pathogens, such as viruses, parasites, and bacteria, as part of their role in protecting the body. Mast cells, normally, will degranulate (trigger) in the presence of:

• allergens, in a typical IgE reaction. Common allergens include pollen, cats, dust mites, nuts, dairy, and fish

• Pathogens (Lyme disease, lipopolysaccharides from bacteria, certain viruses, and mould spores)

• parasites (worms)

• Various drugs, environmental toxins (MRGPRX2 receptor, details below)

• Peptides (including endorphin, leptin, PTH, and more)

• Physical conditions (cold, heat, pressure, stress, and vibration).
  

Mast Cell Issues

Mast cells become a problem when they are activated when they should not be.

There are 3 main conditions where this happens.

1. Mastocytosis – occurs when the body produces too many mast cells. These cells can continue growing and tend to be overly sensitive to activation and releasing mediators. If the cells build up (accumulate) in organ tissues, this can result in symptoms that affect multiple organ systems.

2. Mast Cell Activation Syndrome (MCAS) – occurs when people have normal amounts of mast cells but there is an abnormal amount of mediators (including histamine) released.

3. Hereditary Alpha Tryptasemia (HAT) - an inherited genetic trait where a person has one or more extra copies of the tryptase gene. Tryptase is one of the mediators released by activated mast cells, and people with HAT are known to have higher tryptase levels than normal, even when they are well.
   

MCAS

In MCAS, the behaviour of mast cells is not due to abnormal mast cell production (ie there is not an increase in the number of mast cells) but to ongoing abnormal activation of the mast cells (ie the mast cells become too active or 'twitchy').

Consequently, the mast cells trigger too easily, they degranulate and release large amounts of histamine, heparin, prostaglandins, tryptase, and cytokines into the body excessively and/or too frequently.

"While more severe forms are not all that common, some research estimates that MCAS could “affect up to 17% of the population on a spectrum from very mild to debilitating symptoms.” Others include very mild symptoms such as allergic rhinitis in the mast cell activation spectrum, which includes up to 30% of the population.[ref]. Basically, it depends on how you define it. In general, clinicians tend to diagnose mast cell activation syndrome in people with more severe symptoms, and patients often see multiple doctors in search of a diagnosis. A survey of people with a mast cell activation syndrome diagnosis found that 94% had abdominal pain, and 89% had skin-related issues (dermatographism and flushing). Other common symptoms included headache, diarrhea, and memory or concentration difficulties." There seems to be different groups of MCAS, with one of these groups being peole who are sensitiv to amines (including ghistamines) in foods and drinks. Having a high load of histamine in the diet can exacerbate the symptoms. MCAS Triggers

With MCAS, the following may result in triggering or degranulation of the mast cells.

• Inflammatory cytokines (IL-1B, IL-33), which cause the release of IL-6, TNF, IL-8, and VEGF

• Heavy metals (aluminum, cadmium, mercury)

• Herbicides (atrazine, glyphosate)

• Pathogens (Lyme disease, lipopolysaccharides from bacteria, certain viruses, and mould spores)

A receptor, called MRGPRX2, has been found on mast cells that reacts to protein fragments, such as in a viral infection, as well as drugs such as fluoroquinolone, opioids, and more. This receptor seems to be the key to drug hypersensitivity reactions, such as to contrast media for CT scans.

• Extremes in temperature: heat, cold and also sudden changes in temperature

• Stress- emotional, physical, including pain, or environmental (i.e., weather changes, pollution, pollen, pet dander, etc.)

• Exercise

• Fatigue

• Food or drinks, including most alcohol

• Some additives including azo dyes, found in some medications and constrast dyes used in x-rays

• Drugs (opioids, NSAIDs, antibiotics and some local anesthetics)

• Natural odors, chemical odors, perfumes and scents

• Venoms (bee, wasp, mixed vespids, spiders, fire ants, jelly fish, snakes, biting insects, such as flies, mosquitos and fleas, etc.)

• Infections (viral, bacterial or fungal)

• Mould

• Mechanical irritation, friction, vibration

• Sun/sunlight

In addition, the following have been shown in studies to cause mast cells to degranulate. The majority of the studies are in cell cultures or animals, so it may not apply completely to individuals. Likely, many more not uncovered by research.

• Chemicals in the environment: PFOAs, off-gassing | BPA | Herbicide (RoundUp) | Preservative in toiletries/cosmetics | Pesticide, wood preservative | Plastics; prenatal exposure effects | Teflon, food wrappers, stain-resistant carpet

• Chemicals in the body: Mercury, silver fillings | Dental amalgams

• Chemicals in food: Food preservatives | Sodium benzoate (a preservative found in food and some medications) |

• Psychological stress

• Other: Methylisothiazolinone | Glyphosate | Endosulfan | Methylisothiazolinone
  

Sometimes/often there is no trigger found. This is called idiopathic mast cell activation syndrome.

Common MCAS Issues

When mast cells over react, they cause symptoms that range from mild to severe to life-threatening (anaphylaxis).

MCAS involves different systems and organs in the body such as the cardiovasucalar system, the skin, the gut, and commonly many systems are involved. This results in different clinical symptoms. Because of the complex pattern of symptoms, no two people are likely to experience MCAS in exactly the same way. Symptoms can also vary over time, often waxing and waning.  The severity of the symptoms depends on a number of independent factors and correlates with the amount and type of mediators released from mast cells during an mast cell release event. The different mediators released can lead to different symptoms of mast cell activation syndrome:

• Histamine leads to headaches, migraines, low blood pressure, itching, stomach acid release (and much more)

• Tryptase causes inflammation .

• Prostaglandin E2 also produces inflammation and pain. It can manifest itself in a variety of ways. For example, animal studies show mast cells in the colon release prostaglandin E2, causing pain and hypersensitivity in IBS (irritable bowel syndrome). Colon biopsies from IBS-D patients also showed increased levels of prostaglandin E2. Using either a mast cell stabilizer or a medication to reduce prostaglandin E2 synthesis (e.g., a COX2 inhibitor) stopped the hypersensitivity in the animal model of IBS.

The following sets out the systems that can be affected in MCAS. Most people will have some, but not all of the following symptoms:

Cardiovascular system & MCAS

• Hypotension

• tachycardia

• syncope or near syncope

• blood pressure changes

• chest pain.

• Postural orthostatic tachycardia syndrome (POTS) has some similar clinical symptoms as in MCAS.

Note re: POTS: although the etiology is not fully known, suggesting that there may be a relationship between them and they may have a common pathogenesis The first likely pathophysiologic mechanism is incomplete sympathetic neuropathy.

Skin & MCAS

• Flushing caused by the vasodilating effects of histamine and other mediators. Flushing may be caused by exercise, alcohol, temperature, and emotional changes.

• Angioedema may occur especially on the lips and tongue.

The flushing seen in mast cell disorders is episodic, lasts longer, and it is usually not accompanied by sweating.

• Nonspecific urticaria, pruritus, etc. may occur.

Respiratory System & MCAS

Upper and lower respiratory tract symptoms are common in patients with MCAS.

This includes:

• nasal congestion

• nasal itching

• shortness of breath

• wheezing

• bronchoconstriction

• bronchospastic cough

• throat swelling

• rhinorrhea

• Angioedema of the upper respiratory tract may also be seen, but it is rare.

Gut & MCAS

Often, because of the amount of mast cells in the gut, there are a host of gut symptoms present.

General effects of MCAS on the gastrointestinal tract include:

• nausea

• vomiting

• wandering abdominal pain

• abdominal tenderness

• Gut cramps

• bloating

• malabsorption

• gastroparesis

• mouth sores/ulcers

• gastroesophageal reflux

• dysphagia

• diarrhea

• constipation

• angioedema

Irritable Bowel Syndrome and MCAS

Irritable bowel syndrome (IBS) may be observed in some patients in association with MCAS. Irritable Bowel Syndrome is a common gastrointestinal disorder. It is characterized by abdominal pain, alternating constipation, and diarrhea. Impaired intestinal barrier function in IBS is caused by mast cell activation due to stress response. One of these stress responses is due to certain components in the food ingested, such as plant-derived substances. These components regulate mast cell activation Mast cell numbers have been shown to increase in the terminal ileum, jejunum, and colon of patients with IBS.

Mast cell numbers were found to be directly realted to how severe the gut pain was and it is thought that it is the mast cell mediators released from the mast cell causing these symptoms.

SIBO & MCAS

The severity of the pain is associated with the number of mast cell cells located close to where the nerves are located (enteric nerves). The mast cells release mediators which activate or trigger these enteric nerves and this causes pain to be felt.

Small intestinal bacterial overgrowth (SIBO) is common in MCAS. SIBO is a condition in which colon bacteria overgrow in the small intestine. It occurs as a result of anatomical abnormalities as well as motility, and metabolic, systemic, and immune system disorders. MCAS, in theory, may well set up a situation where SIBO is more likely. SIBO, in turn, causes activation of mast cells and increase in T lymphocytes. T lymphocytes in turn secrete microparticles that again activate mast cells. Activated mast cells and T lymphocytes release cytokines that increase intestinal permeability.

This leads to a vicious cycle in which intestinal permeability is constantly impaired and inflammation is constantly increased

Neuropsychiatric symptoms and disorders & MCAS

Common symptoms:

• Headache

• fatigue

• weakness

• lethargy

• lack of attention

• feelings of exhaustion,

• mild impairment of cognitive activity
  

Migraines & MCAS

According to various studies and investigations, mast cells are considered to make a significant contribution to the pathophysiology of migraine.

Mast cells are found in the meninges and are thought to be included in the pathophysiology of migraine through events such as sequential neuropeptide release and vasodilation leading to mast cell degranulation.

Mast cells discharge hundreds of various mediators such as histamine, tryptase, and leukotrienes, and degranulation of meningeal mast cells contributes to the activation of the trigeminal vascular afferent pathway.

This is assumed to be one of the underlying mechanisms of migraine and pain.

Long Term COVD & MCAS

People with long-term COVID-19 disease have major cardiac, neuropsychiatric, and pulmonary complaints. Multi-system disorders such as myocardial inflammation, POTS, dystonia, and myalgic encephalomyelitis/chronic fatigue syndrome can develop. Immune system effects include recurrent infection, autoimmunity, urticaria, allergic rhinitis, and asthma. MCAS is thought to be the possible mechanism underlying these effects.

Mast cells are the key producers of the inflammatory cytokines of COVID-19. A persistent inflammatory state with prolonged COVID-19 causes abnormal mast cell activation. It is thought that symptomatic improvement will be achieved with the treatment of MCAS in long-term COVID-19 cases. It is thought that stabilization of mast cells and reduction in related symptoms will be achieved by histamine blockade

Causes of MCAS

Causes of MCAS are currently not known. However, the following is worth noting.

THYROID FUNCTION: thyroid function may affect mast cells, and that mast cell degranulation could affect thyroid function.

GENETIC PREDISPOSITION:  can make some individuals more susceptible to MCAS: The problem may be linked to the KIT gene, particularly the D816V mutation.

DYSREGULATION of the NERVOUS SYSTEM

Autonomic nervous system - which controls involuntary bodily functions like heart rate, digestion, and breathing - has a direct impact on mast cell behaviour. When the nervous system is dysregulated, mast cells become more reactive, leading to increased inflammation and symptoms.

ENVIRONMENTAL TOXINS: Environmental toxins may trigger mast cell activation and worsen symptoms.

AUTOIMMUNE DISORDERS: Autoimmune disorders contirbute to chronic inflammation that can overactivate mast cells.

CHRONIC INFECTIONS: Chronic infections overstimulate the immune system, leading to mast cell dysfunction.

HORMONAL FLUCTAUATIONS (exacerbate MCAS): Hormonal fluctuations can intensify MCAS symptoms, especially in women. Mast cells are highly sensitive to hormonal fluctuations, particulary oestrogen and progesterone. Oestorgen enhances masrtcell activation, increasing the realeaseof histamine and other mediators. Progesterone fluctuations can affect the stability of mast cells, leading to unpredicatble flare ups. This explains why many people with MCAS experience worsened syrmptoms during menstrual cycles, menapause and hormonal replacement therapy.

POOR GUT FUNCTION

Gut inflammation leads to increased histamine levels contributing to MCAS symptoms. Improving gut health can be very useful, but if there is sensitivity to naturally occurring histamine (amines), salicylate, glutamate/additive in foods then reducing these in the diet/environment is part of regaining normal gut function.

Recognizing Symptoms and Seeking Help

People with these conditions often experience symptoms that affect multiple systems, making diagnosis challenging. For example, someone with MCAS might have unexplained stomach cramps, skin rashes, and dizziness all linked to mast cell activity. MCAS is episodic and unpredictable and the range of severity of triggers can change over time and in the same individual.

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, or mast cell blockers like histamine receptor blockers

Managing Mast Cell-Related Conditions

Treatment focuses on controlling symptoms and preventing triggers.

Some common approaches include:

• Antihistamines: To block histamine effects and reduce allergic symptoms

• Mast cell stabilizers: Medications that prevent mast cells from releasing chemicals

• Avoiding known triggers: Such as certain foods, medications, or environmental factors

• Emergency plans: For severe reactions, carrying epinephrine auto-injectors may be necessary

Lifestyle Changes can include: low-histamine diets have been shown in studies to be helpful to some people (and potentially salicylates/ glutamates)

Lifestyle adjustments and working closely with a GP and Specialised Dietitian (if diet is involded as a trigger) may help better manage these conditions.

REFERENCES

Özdemir Ö, Kasımoğlu G, Bak A, Sütlüoğlu H, Savaşan S. Mast cell activation syndrome: An up-to-date review of literature. World J Clin Pediatr. 2024 Jun 9;13(2):92813. doi: 10.5409/wjcp.v13.i2.92813. PMID: 38948000; PMCID: PMC11212760. https://www.allergy.org.au/patients/allergy-testing/mastocytosis, accessed 2/3/2026. Valent P, Akin C, Nedoszytko B, Bonadonna P, Hartmann K, Niedoszytko M, Brockow K, Siebenhaar F, Triggiani M, Arock M, Romantowski J, Górska A, Schwartz LB, Metcalfe DD. Diagnosis, Classification and Management of Mast Cell Activation Syndromes (MCAS) in the Era of Personalized Medicine. Int J Mol Sci. 2020 Nov 27;21(23):9030. doi: 10.3390/ijms21239030. PMID: 33261124; PMCID: PMC7731385.