Mast Cell Acti­va­tion Syndrome (MCAS) Explained: Media­tors and Related Symptoms

In recent years the science commu­nity has deve­loped an incre­a­sing inte­rest in the under­lying cause of dise­ases that are related to mast cells and their patho­phy­sio­lo­gical effects because our under­stan­ding of these has been sketchy at best.

Some of the more widely known examples include Irri­table Bowel Disease and Chronic Fatigue Syndrome / Myalgic Ence­pha­lo­mye­litis or diffi­cult to explain allergic symptoms. Given this new inte­rest, there is hope that an improved under­stan­ding of the under­lying processes will lead to new treat­ment options for those affected by these dise­ases. But let’s start with the basics:

What exactly are mast cells?

Mast cells are part of our immune system, more speci­fi­cally, they are a subset of our white blood cells (Leuko­cytes) which repre­sent the cellular defense of our body. However, only a small part of these cells is actually found in our blood and the vast majo­rity can be found in the mucous membrane, where they are involved in a variety of meta­bolic processes, predo­mi­nantly related to inflamma­tory conditions.

It is important to under­stand that contrary to common belief, not all inflamma­tory processes are nega­tive. In fact, they are part of a normal immune response and are as such part of the defen­sive mecha­nisms our body can employ to protect itself from harm. A foreign body for example will either be elimi­nated if possible or – if that is impos­sible – surrounded by specia­lized immune cells that ulti­mately create a capsule, a kind of wall, which effec­tively sepa­rates the foreign body from the rest of our body.

What is meant when we speak of mast cells degranulating?

When mast cells are involved in inflamma­tory processes, they release certain trans­mitter subs­tances. This happens in the form of tiny vesi­cles, which can only be seen with a micro­scope. These vesi­cles are called granules and the process of releasing those is there­fore called degranulation.

What is Mast Cell Acti­va­tion Syndrome? (MCAS)

Mast cells release a subs­tance called hist­amine when they become acti­vated through contact with certain viruses, bacteria, or aller­gens. Heat, cold as well as physical or psycho­lo­gical stress can also lead to mast cell acti­va­tion. Hence the name of the disease – mast cell acti­va­tion syndrome (MCAS).11

What kind of media­tors (trans­mitter subs­tances) are released by mast cells?

Upon acti­va­tion, mast cells can release quite a variety of diffe­rent subs­tances. These include cyto­kines like TNF-alpha, interleukin‑1 or ‑6 which have a rele­vant role in inflamma­tory dise­ases like rheu­ma­toid arthritis. But it is predo­mi­nantly the effect of hist­amine and leuko­trienes which affected pati­ents expe­ri­ence as symptoms.2

Hist­amine as a word should sound fami­liar if you happen to suffer from aller­gies. The class of drugs coun­te­ring those symptoms is called anti­hist­amines (anti = against, those drugs are directed against the effect of hist­amine, which causes most of the allergic symptoms). The release of hist­amine is the reason for the great simi­la­rity of symptoms between aller­gies and mast cell acti­va­tion syndrome.

Other subs­tances released by mast cells include heparin, which inhi­bits the clot­ting of blood, and sero­tonin.2,3

Histamine, Leukotrienes, & Prostaglandins create a wide variety of symptoms
MCAS Media­tors and Related Symptoms

Symptoms of Mast Cell Acti­va­tion Syndrome (MCAS)

Symptoms caused by „hyper­ac­tive“ mast cells are largely defined by the chemical media­tors released in the indi­vi­dual patient. Which systems are prima­rily involved depends on the extent to which the indi­vi­dual patient is affected, other highly indi­vi­dual factors, and can be diffi­cult to predict. However, hist­amine appears to be the single most rele­vant subs­tance for most of the observed symptoms.

Symptoms of MCAS are:

  • Runny nose, sneezing
  • Swel­ling, e. g. facial (angio­e­dema)
  • Itching, Rashes
  • Migraine-like headache
  • Severe allergic reactions
  • Diar­rhea, Nausea, and Vomiting
  • Asthma
  • Flush (red colou­ring of the body)
  • Migra­ting joint pain and inflamma­tory condi­tions2

This list only contains some of the more frequently observed symptoms and is far from being complete. A single mast cell can release more than a hundred diffe­rent trans­mitter subs­tances (media­tors) of which only a small part is curr­ently well rese­ar­ched and unders­tood.4

Some of the subs­tances of which we have a rela­tively good under­stan­ding include hist­amine, leuko­trienes, prosta­glandins, tryp­tase, and heparin and it is, there­fore, worth taking a closer look at their effects.

This article is about a health issue. It is important that you have your symptoms examined and treated by medical profes­sio­nals. This article is not intended to be, and cannot be, a substi­tute for the care and advice of medical profes­sio­nals that may be avail­able to you.

Symptoms Caused by Exces­sive Hist­amine Release

Swel­ling & Rashes

Hist­amine is probably the trans­mitter subs­tance with the most reco­gniz­able effects. On our skin, it causes an itchy rash called urti­caria. In places where the skin is parti­cu­larly thin like lips or eyelids, it causes swel­ling by incre­a­sing the permea­bi­lity of blood vessels for liquid- The tech­nical term for this is angio­e­dema (the word angio indi­ca­ting the connec­tion to blood vessels; edema is incre­ased water reten­tion in a tissue).

In older lite­ra­ture some­times the term Quincke’s edema is used, after the German physi­cian who first described this condi­tion, Hein­rich Irenaeus Quincke (1842–1922).


Auch die mitunter beob­ach­teten, migrä­ne­ar­tigen Kopf­schmerzen sind vermut­lich auf die gestei­gerte The migraine-like headache some­times observed in affected pati­ents is probably caused by an incre­ased permea­bi­lity of intra­cra­nial blood vessels. Unlike in other places, the brain tissue has no room to expand inside the skull, and the increase of water in that tissue results in an incre­ased pres­sure which in turn results in pain.


Diar­rhea is a symptom again based on a very similar patho­phy­sio­lo­gical mecha­nism. Only this time the water going out of the blood vessels in the gut tissue is not staying there but is pulled into the gut lumen, following an osmotic gradient, where it incre­ases the water content of the stool.

Histamine mediated symptoms in mast cell diseases like rashes, nausea, runny nose, sneezing, diarrhea
Hist­amine mediated symptoms in mast cell diseases


Severe allergic reac­tions which can even become life-threa­tening when the respi­ra­tory pathways become blocked (when edema deve­lops in the tissue) or the circu­la­tory system fails are caused by hist­amine. Experts call this an anaphyl­actic reac­tion or just anaphy­laxis.5

This life-threa­tening condi­tion is asso­ciated with short­ness of breath and a drop in blood pres­sure (because blood volume is decre­ased by water being shifted from inside blood vessels into the surroun­ding tissue and vaso­dila­tion) which results in an incre­ased heart frequency and often profound anxiety.

Diffe­rence between anaphy­laxis and anaphyl­ac­toid reactions

While anaphy­laxis is an allergic reac­tion caused by an overly strong immune response to the contact with an antigen (that is the subs­tance to which the body reacts allergic) there is also a kind of pseudo-allergy, that is not mediated through IgE.

Without labo­ra­tory studies, the symptoms are pretty much indis­tin­guis­hable from those of a real allergy and even the same media­tors are released. On a bioche­mical level, however, the under­lying immune reac­tion between antigen and anti­body (mostly IgE) is not present.

To diffe­ren­tiate between those two, the term used is not anaphyl­actic but anaphyl­ac­toid, where the part ‑oid means as much as “alike”.

A typical example for such a pseudo-allergy is the reac­tion to non-stero­idal anti-inflamma­tory drugs (NSAID) in pati­ents with NSAID into­le­rance (AERD, sali­cylate sensitivity).

Symptoms Caused by Prosta­glandins: Flushes & Brain Fog

Prosta­glandins can be released in rela­tively large amounts by mast cells. Depen­ding on the specific type of prosta­glandin, the effects can vary and even appear to be the exact oppo­site of each other. Some prosta­glandins inhibit inflamma­tory processes, others increase exactly those processes.

Prosta­glandins come into exis­tence following compli­cated bioche­mical reac­tions in our body for which certain enzymes called cycloo­xy­ge­nases are needed to faci­li­tate important steps in those reac­tions. Two of those are known and can be diffe­ren­tiated, COX‑1 and COX‑2.

If those enzymes are inhi­bited – for example by taking so-called non-stero­idal anti-inflamma­tory drugs (NSAID) like Ibuprofen, Aspirin (acetyl­sa­li­cylic acid) or Diclo­fenac, the body can produce less prosta­glandins and symptoms like headache and inflamma­tory reac­tions are supressed.

Nausea and abdo­minal pain as well as flushes are also related to prosta­glandins and it is suspected, that they also have a role in the infa­mous brain fog.2


Symptoms Caused by Leuko­trienes: Asthma Attacks & Runny Nose

Next to the afore­men­tioned hist­amine, it is espe­cially leuko­trienes which are respon­sible for an increase in mucous produc­tion and narro­wing of respi­ra­tory pathways and bron­chia. In sensi­tive pati­ents, they are known to cause asthma attacks and bronchospasms.

Leuko­trienes do not only have an important role in MCAS but they are also asso­ciated with other dise­ases like samter’s disease. Affected pati­ents frequently suffer from severe asthma attacks, nasal polyps, and into­le­rance to NSAIDs.2,6 Some pati­ents with MCAS show incre­ased leuko­triene levels for the same reason.

The complex effects caused by these media­tors are known to cause not only asthma but also inflamma­tions of the nasal sinuses (sinu­sitis) and a runny nose (rhinitis) without the presence of a viral infec­tion which most frequently is asso­ciated with these symptoms.2,5

More Media­tors: Tryp­tase, Sero­tonin, Heparin & Cytokines


Another subs­tance released by mast cells is the protein tryp­tase. It is almost enti­rely released by mast cells only. The first way is in conti­nuous low doses. The second way is upon acti­va­tion and degra­nu­la­tion of mast cells when larger amounts of tryp­tase are actively pushed into the bloo­d­stream, resul­ting in massi­vely incre­ased blood levels.

It then takes hours for the level to return to the base value. This makes tryp­tase a valu­able diagnostic marker to esti­mate the poten­tial seve­rity of a mast cell response when acti­vating factors are present and there­fore appro­xi­mate the risk of a severe anaphyl­actic reac­tion. 2,4


Media­tors like heparin are among those which can be released by mast cells. Heparin is well known and widely used as an anti­coagu­la­tory agent, a subs­tance that prevents blood from clotting.

For many years it has been used and is still used by doctors around the globe in various forms and varia­tions to prevent throm­bosis, espe­cially in pati­ents with limited mobi­lity (e. g. after operations).

In pati­ents with MCAS, however, the large amount of heparin can lead to an incre­ased risk of blee­ding in various parts of the body. Most obvious are those affec­ting the skin, where they impose a blue or dark spot, so-called hematoma.4

Sero­tonin in MCAS: Respon­sible for slee­ping trou­bles and brain fog?

Sero­tonin does not only affect our emotions but is also involved in the regu­la­tion of our sleep-wake-cycle through its meta­bo­lite Mela­tonin. The slee­pi­ness and fatigue/brain fog asso­ciated with aller­gies and MCAS is most likely caused by a combi­na­tion of diffe­rent factors. However, an invol­ve­ment of sero­tonin as part of this mecha­nism appears to be enti­rely possible. 3

Here again, the close rela­ti­onship between nerve messen­gers (neuro­trans­mit­ters) and the immune system and vice versa becomes appa­rent, which can also be used thera­peu­ti­cally, for example.

Inflamma­tory Cyto­kines: Interleukin‑6, Interleukin‑1 and TNF-alpha

Another class of subs­tances released from mast cells are cyto­kines, among those interleukin‑6, interleukin‑1 and TNF-alpha. All of these have the poten­tial to cause and main­tain inflamma­tory processes.

They become espe­cially rele­vant in the context of addi­tional dise­ases like rheu­ma­toid arthritis, auto­im­mune connec­tive tissue disease, or vascu­litis (inflamma­tory dise­ases of blood vessels) because they are respon­sible for the inflamma­tory processes asso­ciated with these diseases.

But migra­tory joint inflamma­tion and fever are also seen in pati­ents with MCAS.4,5 Some of these subs­tances can also trigger the acti­va­tion of other mast cells, resul­ting in a vicious circle of self-sustai­ning symptoms which can be diffi­cult to break.

Diagnosis is difficult

The symptoms discussed above can only be a subset of the whole range of symptoms asso­ciated with MCAS because mast cells release such a wide variety of subs­tances that trigger effects in many diffe­rent loca­tions in our bodies.

Consi­de­ring the wide range of poten­tial symptoms and their overlap with symptoms of other, some­times acute condi­tions, medical profes­sio­nals find it often chal­len­ging to find the link between isolated symptoms and arrive at the correct diagnosis, espe­cially as the defi­ni­tion of diagnostic criteria for MCAS has not been finalized.


  1. Kritas SK, Saggini A, Cerulli G, et al. Asthma and Mast Cell Biology. Eur J Inflamm. 2014;12(2):261–265. doi:10.1177/1721727X1401200205
  2. Lee MJ, Akin C. Mast cell acti­va­tion syndromes. Ann Allergy Asthma Immunol. 2013;111(1):5–8. doi:10.1016/j.anai.2013.02.008
  3. Meeusen R, Watson P, Hase­gawa H, Roelands B, Piacen­tini MF. Central fatigue: the sero­tonin hypo­thesis and beyond. Sports Med Auckl NZ. 2006;36(10):881–909. doi:10.2165/00007256–200636100-00006
  4. Afrin LB, Self S, Menk J, Lazar­chick J. Charac­te­riz­a­tion of Mast Cell Acti­va­tion Syndrome. Am J Med Sci. 2017;353(3):207–215. doi:10.1016/j.amjms.2016.12.013
  5. Molde­rings GJ, Brettner S, Homann J, Afrin LB. Mast cell acti­va­tion disease: a concise prac­tical guide for diagnostic workup and thera­peutic options. Accessed June 19, 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069946/
  6. Celik G, Bavbek S, Misir­ligil Z, Melli M. Release of cysteinyl leuko­trienes with aspirin stimu­la­tion and the effect of prosta­glandin E(2) on this release from peri­pheral blood leucocytes in aspirin-induced asth­matic pati­ents. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2001;31(10):1615–1622. doi:10.1046/j.1365–2222.2001.01074.x
  7. Valent P, Akin C, Metcalfe DD. Masto­cy­tosis: 2016 updated WHO clas­si­fi­ca­tion and novel emer­ging treat­ment concepts. Blood. 2017;129(11):1420. doi:10.1182/blood-2016–09-731893
  8. Valent P, Akin C, Bona­donna P, et al. Mast cell acti­va­tion syndrome: Impor­t­ance of consensus criteria and call for rese­arch. J Allergy Clin Immunol. 2018;142(3):1008–1010. doi:10.1016/j.jaci.2018.06.004

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Natur­o­path, hypno­the­ra­pist, owner of an immune system gone crazy with various auto­im­mune special effects. She likes reading through medical papers and is an avid learner of all things regar­ding the human immune system. When her joints and body allow it: enthu­si­astic do-it-your­selfer around the house.

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Physi­cian, entre­pre­neur and behind-the-scenes advisor with wide-ranging inte­rests from health manage­ment and public health to photo­graphy and Japa­nese martial arts

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