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Posted by on May 10, 2013 in The Basics |

What is Mastocytosis?

What is Mastocytosis?

Do you have any questions about mastocytosis? Then please head for the “Why Is It All So Confusing?” forum and we'll try and help.

A Comprehensive Video Summary

Let's get  started with this comprehensive video summary (7:23)  from the Mayo clinic.

As there is so much information in the video summary, we've also included a transcript at the bottom of this post, after our own brief introductory overview. It would be useful for you to read the transcript once at your own pace, and then proceed with the posts in this site, as we will be clarifying many of the concepts talked about in the video.

If this is your first encounter with mastocytosis, the amount of information contained in the video transcript may overwhelm you a bit. Once again, don't worry, throughout this site, we intend to take you through the detail bit-by-bit.

Pierre Noel, M.D., hematologist at Mayo Clinic in Arizona, discusses the diagnosis and treatment of systemic mastocytosis or mast cell disease.

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Let’s Summarise The “Comprehensive Video Summary”

Mastocytosis is a disease that is characterized by abnormal growth and accumulation of white blood cells called mast cells in

  1. the skin,
  2. in internal organs, or
  3. in both skin and internal organs.

Therefore, mastocytosis is a disorder caused by the presence of too many mast cells (overabundant, superfluous mast cells) in a person's body. Both children and adults can develop mastocytosis.

A mast cell is a type of blood cell made in the bone marrow that is involved in allergic reactions as well as fighting parasitic infections. In a mastocytosis patient, in addition to being overabundant, these mast cells cells may also be misshapen or malformed, further contributing to their dysfunction.

Mast cells, sitting next to all major organs, contain packets (or granules) of chemicals, including histamine, which are released outside the mast cell when the body feels it is under attack by germs.  This chemical release is a normal reaction of our immune system if indeed we are under attack.

As the released chemicals are a bit of a toxic affair, our body is usually very good at releasing those chemicals only in the case of an obvious attack, and the amount of chemicals released is in proportion to the perceived attack.  However, in mastocytosis patients, the release of those chemicals can happen for no real reason, even when there is no attack. And if there is an attack, the release is also out-of-proportion and too many chemicals are spilled out.

That would be bad enough if you had the right number of mast cells, but paired with the fact that mastocytosis patients have an over-abundance of mast cells, it is easy to understand why their bodies behave as if they were under constant, incessant and  massive attack.

This chemical release can lead to symptoms such as flushes, indigestion (dyspepsia), abdominal pain, muscle/bone pain, changes in blood pressure (usually a fall known as hypotension), generalised fatigue and in extreme cases, anaphylactic shock, which can be fatal.

The severity of the symptoms will depend on the site or organ affected and the extent to which the mast cells have built up in that organ, as well as how trigger-happy the mast cells are to release their chemically-loaded granules.

Mastocytosis  is a rare disorder. The true incidence of mastocytosis is unknown, but the available evidence suggests that it is a rare disease, with a prevalence of no more than 0.3 per 10,000, which qualifies it as an orphan disease.

In medical terms, mastocytosis is called a “myeloproliferative neoplasm characterized by infiltration of clonally derived mast cells in different tissues”. Quite a mouthful, but as you learn about the disease, you'll get used to these terms.

Mastocytosis has many forms, and we will learn the detail of these different forms in the “Diagnosis” section of this site. But, in broad terms, there are two general forms of mastocytosis: cutaneous and systemic.

Cutaneous Mastocytosis

Cutaneous mastocytosis is an increase of mast cells in the skin and accounts for about 90% of mastocytosis cases.

There are various sub-types of the cutaneous version, which we will discuss in another section of the site. But, by and large, Urticaria pigmentosa  is the most common version of Cutaneous Mastocytosis. It is characterized by tan or red-brown spots (lesions) on the skin. These spots generally appear first on the midsection of the body, and then can spread throughout the body. Symptoms such as nausea, vomiting, and diarrhea may also be present with urticaria pigmentosa.

If you are an adult, I am afraid you are stuck with those spots for life. However, if you are a child, there is a high likelihood that you'll get rid of it.

Cutaneous mastocytosis usually develops in early childhood. Most pediatric patients with CM have a benign and often self-limited clinical course. The disease often regresses spontaneously during puberty.

Systemic Mastocytosis

Systemic mastocytosis involves internal organs throughout the body, including the gastrointestinal tract, bone marrow, liver, spleen, and lymph nodes.

In 85% of people with systemic mastocytosis, the cutaneous mastocytosis sub-type of urticaria pigmentosa developed first.

The risk of developing systemic mastocytosis increases with age.

Depending on the number of mast cells in the different organ parts, it is classified as either indolent (slow-growing) or aggressive mastocytosis.

As the number of mast cells build up in an organ, symptoms of the disease may worsen. Currently, there is no known cure and no known cases of spontaneous remission.

Prognosis

The prognosis of mastocytosis depends on the specific classification of the disease.

In general, the prognosis of childhood mastocytosis is very good.

In adults, the prognosis for cutaneous mastocytosis and indolent mastocytosis is good. Occasionally, a patient with indolent mastocytosis progresses to a more severe classification, but this is unusual, especially if the diagnosis has been made for several years and the progression has not been rapid.

Most patients with indolent mastocytosis will have what is probably a normal life span. However, they should expect the quality and predictability of their life to be affected, sometimes significantly. No doctor will be able to tell you the measure of that your quality of life deterioration : while the symptom manifestation is generally broadly similar for a mastocytosis patient population, every patient is affected differently.

The prognosis for aggressive mastocytosis is guarded and relies on supportive care and response to cytoreductive therapy.

In spite of the generally good prognosis, managing anaphylaxis events is paramount, as these can, in extreme conditions,  be fatal.

Video Transcript

I'm Pierre Noel, I am an hematologist in the division of hematology / oncology at Mayo Scottsdale. I'd like to speak today with you about systemic mastocytosis.

Systemic mastocytosis is a rare disease and it's a disease involving myeloid cells which are part of the cells in the bone marrow.

The organ which is most frequently involved in mast cell disease is the skin. Over ninety percent of the patients with systemic mast cell disease have skin involvement.

How do you know if you have mast cell disease? Well, mast cells are cells which are present in our body, in different parts of our body, below our skin, gastrointestinal tract and bone marrow. Patients with systemic mast cell disease, for the large majority, approximately ninety-five percent, have a mutation in their mast cells, when we collect mast cells from the bone marrow. Over ninety-five percent of patients with systemic mast cell disease have a c-KIT mutation, which is a mutation we can analyze when we do a bone marrow biopsy, and this confirms the diagnosis of systemic mastocytosis, especially if it's done in conjunction with other tests.

Some of the other tests, when we look at the bone marrow, we look at the number of mast cells and the presence of mast cell aggregates. We require over fifteen mast cells as part of an aggregate and if we have a significant number of aggregates in conjunction with the presence of a mutation, we feel more comfortable in making a diagnosis of systemic mastocytosis.

Other factors, which are important, is something we can measure in the peripheral blood, which is called tryptase. Tryptase is, or the level of tryptase, correlates with the total mast cell burden in your body. So when we evaluate someone with systemic mastocytosis, we do a tryptase to try to evaluate how many mast cells are present.

The other thing we look at, when we look at mast cells, we look at what they look like morphologically, under a microscope and patients with systemic mastocytosis frequently have mast cells which have an unusual shape. Frequently, they have a spindle shape, and we look at the proportion of mast cells which have spindle shape.

Other organs which can be involved in systemic mastocytosis include the gastrointestinal tract, the spleen, the liver, the lymph nodes and when we evaluate patients in clinical we try to evaluate what organs are involved and the extent of the involvement. We stage patients with systemic mastocytosis based on their organ involvement, as well as the side-effects which occur from the systemic mastocytosis.

Some of these side effects can include fractures of bones, can include a spleen which is enlarged and kind of captures or traps a lot of the normal blood cells, it could be involvement of the liver which increases pressure on the liver and accumulation of fluid in the abdomen or it could be involvement of the gastrointestinal tract with problems of absorption and weight loss.

One other important thing in systemic mastocytosis is there's a proportion of patients who have a phenomenon called anaphylaxis and anaphylaxis is a severe allergic reaction which can occasionally result in death. Most patients do not die, but have problems breathing and problems with your blood pressure. This can occur following bee stings, snake bites, insect stings, but also, very commonly, it can be associated with medications. Apart from medications, symptoms of an anaphylaxis can occasionally occur in patients who do very strenuous exercise.

So, we see patients coming to us because they had an episode of hypotension with respiratory compromise and your physician thought about mast cell disease and did a tryptase and found that the tryptase was significantly increased, or someone had a severe reaction to an insect bite and that's a source of referral to an oncologist for evaluation for systemic mastocytosis.

What we do in patients with systemic mastocytosis, from a treatment standpoint, there are patients who have indolent systemic mastocytosis and these patients have an excellent prognosis and what we try to do is to minimize your symptoms and this minimization of symptoms can be done through the use of different forms of antihistamines, to block the histamine release from mast cells.

The other thing we do is, we give patients EpiPens, which are pens containing epinephrine, that they can use if they are unfortunate and have an anaphylactic reaction. They can react to this reaction by injecting, self-injecting or having a family member inject the epinephrine and help to resolve this episode of anaphylaxis.

The other thing we do with these patients is we evaluate them for osteoporosis because osteoporosis and fractures are complications which can be associated with systemic mastocytosis.

There are forms of systemic mastocytosis which are more aggressive. There is a sub-type called aggressive mastocytosis and the other one is mast-cell leukemia. These sub-types of mastocytosis need to be treated more aggressively and the standard of care for at these disorders has been to use alpha-interferon, as well as other chemotherapeutic drugs.

There's a small proportion of patients in which we do not have to c-KIT mutation and within that small sub-population  there are patients who are responsive to a drug called imatinib and we have used this with success in a small proportion of patients.

Mayo participates in investigational trials with different agents for patients to have aggressive systemic mastocytosis, and we are involved in Mayo in providing a complete evaluation of patients and offering them both the standard of care or in patients which fail the standard of care we evaluate their eligibility for investigational treatment.

Thank you very much for your attention.

 

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Posted by on May 10, 2013 in The Basics |

What Are Mast Cells?

What Are Mast Cells?

Do you have any questions about mast cells? Then please head for the “Why Is It All So Confusing?” forum and we'll try and help.

Discovery

In 1878, medical student Paul Ehrlich, who was later to be awarded the Nobel Prize, discovered numerous cells filled with granules under the light microscope using new staining methods. Because they looked well-fed to him, Ehrlich named these cells “Mastzellen” (from German ”Mast”– fattening, feeding).

It was not until a century later that scientists found out that mast cells in tissues arise from stem cells in the bone marrow and, therefore, are cells of the immune system.

Mast cells are found in lower invertebrates as well as vertebrates, suggesting that they serve a fundamental role within the immune system. We now believe these may have been some of our first lines of defense to evolve against the toxins in our environment.

Role

Mast cells are ubiquitous throughout the tissues of the human body and play numerous roles, both beneficial and destructive. We know they are important in our army of immunity warrior cells, which defend us against viruses, bacteria and parasitic invaders.

They are also very well known for the havoc they wreak, causing uncomfortable symptoms due to their release of histamine and other mediators which cause the all too familiar itching, sneezing, urticaria and rhinorrhea of allergic responses.

Mast cell activities are diverse and include painful inflammatory reactions in autoimmune conditions such as rheumatoid arthritis. In the gastrointestinal system, mast cells are implicated in diverse actions such as increased gastric acid secretion, polyp formation and uncomfortable conditions such as Irritable Bowel Syndrome.

Mast cells have long been recognized for their participation in allergic disease, including asthma, rhinitis, conjunctivitis, atopic dermatitis, urticaria, and anaphylaxis. However, they also have a variety of protective and regenerative roles throughout the body

Mast cells have been noted for many years to be present within human atherosclerotic lesions although their function within these lesions is unclear .

Lifecycle

Mast cells are white blood cells which originate in the bone marrow, where they only spend around 4 days. They comprise a very small proportion of the marrow cells. They leave the bone marrow in a relatively immature state. They circulate only briefly in the blood vessels.  They rapidly leave the circulation and enter the peripheral tissues, where they mature. They are present in every peripheral tissue in the body, where they are relatively immobile and tend to live as long as the patient lives.

Mast cells are found in varying quantities in virtually all tissues of the human body and are stationed much like sentinel cells of the immune system at bodily portals of entry. The numbers of mast cells are highest at locations where they can respond to foreign organisms and antigens, thereby concentrating heavily in the skin, intestines, the inside of the eyelids, lungs and airways.

They are even present in the atrial appendage of the heart. Mast cells are also found in the brain, and in low numbers in the kidneys and bone marrow. They are often located closely to blood vessels, nerves and lymphatics.

A unique feature of mast cells is that they do not die after degranulation. In some circumstances, some of the cells withstand the exhaustive degranulation process, survive, are reloaded with new granules, and during the next few weeks can  be activated again. These are long lived cells that are hard to kill.

Mast cell numbers increase significantly at multiple areas in mastocytosis.

Function

From their vantage point surrounding blood vessels, their actions can influence the function of vascular structures, monitor blood for inflammatory and infectious changes and distribute mediators, which they release in response to a specific stimulus.

In addition, it has long been appreciated that there are tissue-specific differences in mast cells. Therefore, the specific contribution of a mast cell may depend on its location and the location of the nearby target cells, the type of the activating signals it receives, the intensity of the signals and the genetic background of the individual.

 

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Posted by on May 10, 2013 in The Basics |

What is Degranulation?

What is Degranulation?

Do you have any questions about mast cell degranulation? Then please head for the “Why Is It All So Confusing?” forum and we'll try and help.

Watch Out For My Granules!

Each mast cell holds hundreds of little granules that contain chemicals. In normal circumstances, mast cells release these chemicals when they perceive that the body is under attack from invading germs, viruses or parasites. These chemicals have a toxic effect on the invader and usually kill them, which is really what we want.

However, these chemicals also have a moderate negative impact on healthy tissues. So, although mast cells are good for us as they protect us from foreign invasion, there is a bit of collateral damage when mast cells perform their normal, everyday duty. Nothing that we can't tolerate, but some damage nevertheless.

The release of the chemical granules by the mast cell when it receives a signal that we are invaded by nasties is called degranulation'.

Too Much Of A Good Thing

Now, in mastocytosis, we have a mast cell “population explosion”. Due to a genetic defect, our body keeps creating mast cells and disregards the signal to stop when enough mast cells have been produced. So, we have an overabundance of these critters. And since mast cells are very difficult to kill, that overabundance increases day by day.

Mast cells are good, in normal circumstances. But you know what they say about too much of a good thing …

If a normal amount of mast cell causes a certain level of collateral damage on our tissues and nerves, imagine what happens when we have an oversupply of mast cells degranulating.

Show Me!

OK, then. Watch this short video and see an animation of a mast cell degranulating.

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Mast cells have like little antennas on their surface, called receptors. These receptors are waiting for a signal that tells the mast cell that our bodies are under attack. You can see the Y-shaped receptors (in blue) on the cell membrane (the thin envelope which separates the inside of the cell from the outside world) in light green.

These Y-shaped receptors, which in this case are called antibodies, tunnel through the cell membrane into the cytoplasm (the cell innards) and and are able to transmit signals from the outside of the cell to the inside of the cell. They are like the mast cell ‘detonators'.

Through the transparent cell membrane, you can see the nucleus of the cell (in purple) and the chemical granules (mediators) in red. In the video, these granules contain histamine. But be aware that the cell contains around 200 other chemical mediators which are also dispersed on activation of the mast cell receptors. The other more frequently quoted mediators are tryptase, heparin, prostaglandin D2, serotonin, leukotrienes and proteinases … loads of heavy duty, sometimes toxic material to assist in the killing of the invader.

  1. at 00:01 here comes the antigen (the bad guy with bad intentions, in bright green)
  2. at 00:12 the antigen binds with the antibody and the antibody signals to the cell that it's under attack and it is time to degranulate
  3. at 00:15 degranulation starts
  4. at 00:17 the cell membrane disintegrates, releasing the payload of mediators
  5. at 00:20 the cell has dispersed the mediators, the cytoplasm debris and the nucleus will be eaten up by garbage collectors later

Also, while the video depicts a total degranulation, mast cells can also selectively secrete some biochemical mediators and retain others within the cell. And most importantly, in the case of mastocytosis, the mast cell often degranulates spontaneously without being ‘detonated' by an antigen.

Here's a video of a real mast cell degranulating.

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If you read the uploader's comments on Youtube, you'll find their answer the following question about mast cell death after degranulation:

Do mast cells apoptose after degranulation? (Apoptosis means the cell committing programmed suicide)

Mast cells did not apoptosis after degranulation. Cells were alive and restored the granules again. We have observed these phenomena before.

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Posted by on May 10, 2013 in The Basics |

What Are Receptors?

What Are Receptors?

Confused about Receptors? Who wouldn’t be? Please head for the “Why Is It All So Confusing?” forum and we’ll try and explain.

Two Antennas Got Married …

The ceremony wasn't much, but the reception was excellent.

Sorry, I couldn't resist. It's just that, as it happens, we're going to talk about two ‘antennas'.

OK, you read in the degranulation post that mast cells have like little antennas on their surface, called receptors. These receptors are waiting for a signal that tells the mast cell that our bodies are under attack. And you saw the video which showed little blue Y-shaped poles sticking out of the cell membrane. I'll spare you the details, but just know that in that Y-shaped pole, there is a receptor.

You'll remember we called this Y-pole the antibody and that the ‘signal' the ‘antenna' or receptor received was called the antigen. The result of the antigen touching (called ‘binding') the antibody had the effect of triggering a degranulation event.

Don’t Touch My Antenna, Or Else …

All “antennas” (receptors) belong to one of many families of antennas (receptors) and each receptor does have its own name. That antigen antenna? Its scientific name is IgE, which stands for Immunoglobulin E.

One of the roles of receptors is to do precisely what the antigen (aka. IgE receptor) did in the degranulation event. A receptor just sits there atop the cell membrane, minding its own business sensing the outside world, and when something touches the receptor, it transmits a signal to the inside of the cell and the cell acts on that signal.

The receptor only reacts to things that it likes, though. It only connects (binds) with things (ligands) that have a shape matching the shape of the receptor. It's like a space ship docking to a space station. Both the ship and the station need to have matching docking pieces for that connection to happen.

Let's pause a bit and watch a receptor (in this case, interleukin 1 receptor) bind with its corresponding interleukin1 signalling molecule.

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The whole (simplified) process above is called cell signalling. It's a quite bit more elaborate than that, but you get the picture : an external stimuli signals the receptor, which in turn signals the cell, which in turn processes the signal and does something as a result. That “doing something” could be to manufacture yet another ‘something' using machinery within the cell or to create a clone of the cell or to commit cell suicide, among numerous other things. Or, in the case of a mast cell … to degranulate!

Receptors, Receptors Everywhere …

So you've met your first receptor, IgE, the one that causes mast cell degranulation.

But, truth be told, there are many receptor types and a cell's surface is covered with hundreds of receptors of each of the different receptor types. You've briefly met the Interleukin 1 (Il1) receptor in the video above, which was useful just to show you the binding process.

However, forget Il1 for a moment, because the second receptor I'd like to draw your attention on is the infamous c-KIT. It is infamous because it is the cause of all the mastocytosis problems.

The c-KIT  is the receptor that causes mast cells to proliferate in an uncontrolled fashion.

The c-KIT is the ‘antenna' which receives the signal which tells the mast cell that it must reproduce itself. When the c-KIT antenna receives that signal (which is called Stem Cell Factor), the c-KIT switches on some machinery inside the cell which causes it to split and ‘give birth' to one more incarnation of a mast cell.

The Ninja Mutant Mastos.

But here's the rub. In some people, the c-KIT receptor is broken. When the c-KIT was manufactured, one piece was incorrectly mounted. Either that, or during time, the c-KIT machinery broke in one particular place. That break, that defect is called a mutation.

The c-KIT mutation is a defect in the receptor, which has the effect of leaving the mast cell production machinery switch on all the time. That means that the mast cell reproduces itself, even though no signal was received to do so. That causes abnormal mast cell proliferation, which is the hallmark of mastocytosis.

As you will learn later in “The Diagnosis” section of this site, the c-KIT mutation is only a minor factor in the diagnosis of mastocytosis. 80 to 90% of mastocytosis sufferers exhibit what is commonly called ‘the D816V' c-KIT mutation. But absence of ‘the D816V' mutation does not preclude having mastocytosis. The reason is that there are 100's of c-KIT mutations which are likely to have the same aberrant proliferation effect, but only very few of those mutations can be effectively tested and detected.

For example, my partner Ann does not have ‘the D816V c-KIT mutation they are testing for. But she still has been diagnosed with mastocytosis. Which means she probably has ‘an XYZ' mutation in the c-KIT, but it cannot be detected by currently available tests.

Knowledge is Power

So, there you have it. You now know the source of mastocytosis (your c-KIT having a mutation) and, although we have not yet reached the section of this site which talks about the symptoms,  the reason why you experience mastocytosis symptoms (an antigen hitting IgE receptor and causing mast cell degranulation).

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Posted by on May 10, 2013 in The Basics |

What Are Triggers?

What Are Triggers?

What are your specific triggers? Head for the Triggers forum to discuss.

Please, Don’t Pull The Trigger …”

A trigger is something that can set off a mast cell response and bring on symptoms of mastocytosis.

Not all mastocytosis patients have the same triggers. What is a problem for one person will be OK for someone else. You may have several triggers, but triggers will vary in intensity of their evoked symptoms. It may take a while for you to work out which triggers are a problem for you.

It will be impossible to avoid all of your triggers, but once you have identified them, there are things you can do or avoid to reduce symptoms and control your mastocytosis.

I have added a list of triggers I have found from several sources. Now, please be careful with this information:

  1. Believe me, if anything is variable and individual in mastocytosis patients, degranulation triggers are at the top of the list.
  2. You will not experience all the triggers in the list. You may never experience some of them at all.
  3. You will experience triggers that are not on this list, or any list available on any site, or on any list yet to be compiled.
  4. The fact you have reacted once to a trigger does not mean you will react to the same trigger again, although it is quite probable you will.
  5. The fact that you never reacted to a potential trigger is no guarantee that you will never react to it.
  6. The fact that you usually react to a trigger but you now no longer react to it does not mean that you never will react to it again. You may hear about de-sensitization, but it does not mean de-sensitization applies to you.
  7. The intensity of the symptoms is usually dose/time/intensity dependent, so more of a trigger is usually worse. A little of a trigger may not affect you at all.
  8. Symptoms related to triggers may be immediate, delayed by a few minutes, hours or even days. So, figuring out your specific triggers will require strong investigative skills.
  9. If you experience more that a dozen triggers, you'll never get to the bottom of your specific triggers unless you keep a journal.
  10. Don't expect to eradicate all the possible triggers. You stand no chance. Work towards minimizing the impact of the triggers.
  11. When you'll think you have got to the bottom of it all, things will change.

I don't wish to come across as glib, insensitive or lacking compassion. Heck, would I have spent so much time  and effort building this site if I didn't care? What I am saying is that you literally  need to do all the hard work for yourself. Giving you a list of triggers will only provide you with a few pointers for guidance.

If You Really Want A List, Here’s One (For What It’s Worth)

Please note this is not an exhaustive list.

Physical Agents

  • Mold (Causes airway symptoms. Sources: old tents, anything remaining damp, garages, basements)
  • Temperature (Cold, heat, sudden change in temperature, feeling cold in association with menstruation and infection)
  • Pressure
  • Bacteria or fungi
  • Environmental toxins
  • Exercise or exertion
  • Friction (also of clothing, particularly underwear)
  • Room freshener sprays
  • Smells
  • Sunlight, direct or indirect
  • Hot baths/showers
  • Fever
  • Emotional stress
  • Water
  • Vibration
  • Insect bites (Wasp, Hornet, Bee, Mosquito
  • Snake venoms
  • Biological compounds released by intestinal worms, jellyfish (on contact), crayfish and lobster.
  • Ascaris species (intestinal roundworms)
  • Portuguese man-of-war
  • Spines & hairs of Caterpillars
  • Nettles
  • Moths
  • Infections
  • Inhalants
  • Scents/Odors, Smoke (wood burning, cigarette, marijuana)
  • Scented products
  • Perfume
  • Man-made materials
  • Chemicals
  • Latex
  • Cosmetics/Creams containing salicylates
  • Preservatives,  Additives, Dyes,  Artificial flavours/colouring
  • Vasculitis
  • Internal diseases
  • Biologic polypeptides
  • Wool
  • Pesticides – contain aldehyde -wether this is in high enough levels within foods is not testable currently . But reactions to otherwise safe commercially produced – non organic foods could contain aldehyde
  • Detergents
  • Animal Dander
  • Cat and Dog Saliva
  • Exotic woods
  • Formaldehyde
  • Hair sprays
  • Horse serum
  • Lindane
  • Monoamylamine
  • Nail polish
  • Perfumes
  • Silk
  • Acrylic monomer
  • Aminothiazole
  • Ammonia
  • Arthropods
  • Benzophenone
  • Benzoyl peroxide
  • Cephalosporins
  • Cetyl alcohol
  • Chlorpromazine
  • Cobalt chloride
  • Diethyltoluamide
  • Estrogenic creams
  • Phenylmercuric propionate
  • Platinum salts
  • Sodium sulfide

Foods

  • Foods high in Histamine or Tyramine, Gluten, Soy, Salicylates
  • Foods containing preservatives and colorings
  • Spices, spicy foods
  • Acohol
  • Vinegars : made of malt, spirit, balsamic, white wine, red wine, rice, cider
  • Sulphytes
  • MSG
  • Salicylates
  • Shellfish, Any fish not fresh
  • Strawberries
  • Egg Whites
  • Tomatoes
  • Potatoes
  • Nuts (peanuts, walnuts etc.)
  • Wheat
  • Carrots
  • Castor beans
  • Cod liver oil
  • Flour

Drugs (Do NOT assume your doctor will know not to prescribe these for you!)

  • Aspirin and other non- steroidal anti-inflammatory drugs such as Naproxen and Ibuprofen.
  • Anything which the individual is known to be allergic
  • Coloring & flavoring in medications
  • Cextran (used in some IV solutions and eye drops)
  • Compound 48/80
  • Dipyridamole
  • Iodine- containing radioactive dyes
  • Scopolamine
  • Papaverine
  • Thiamine
  • Trimethaphan
  • Narcotic containing analgesics:
    • Codeine, Morphine, Pethidine,  Meperidine, Demerol
  • Neuromuscular blocking agents:
    • D-tubocurarine,
    • Decamethonium,
    • Gallamine,
    • Metocurine,
    • Pancuronium
    • Sympathomimetics (isoproterenol, amphetamine, ephedrine, phenylephrine)
  • Polymyxin B
  • Penicillin
  • Quinine
  • Dextromethorphan
  • Local anesthetics:
    • Lidocaine,
    • Tetracacaine,
    • Procaine,
    • Methylparaben
  • Occlusive dressings
  • Antibiotics – Mycin antibiotics
  • Plasma expanders (dextran)
  • CT contrast
  • Metroclopamide
  • Tricyclic antidepressants : Patients on tricyclic antidepressants needing an EpiPen have a risk of high blood pressure and/or arrythmia (heart arythmias which are outside the normal), so these should not be given to patients with a known need for an EpiPen.
  • Beta blockers :  A patient on beta blockers needing an EpiPen must be very careful, as the epinephrine will have the OPPOSITE effect to the one required!
  • Adrenaline can work on 2 types of receptors:
  • Alpha : Lowers blood pressure and pulse
  • Beta : Increase blood pressure and pulse
  • If the beta receptors are blocked by the use of  Beta Blockers, epinephrine which is needed to increase the pulse and blood pressure during anaphylaxis will be redirected  to the alpha receptors – further lowering pulse and blood pressure.
  • Narcotics – Morphine and opiates
  • Mycin antibiotics – Erythromycin , Vancomycin, Streptomycin
  • CT contrast
  • Iodine, as in many brands of salt
  • MRI contrast is safer (with pre-medication cover)
  • Stearyl alcohol
  • Streptomycin
  • Sulfur dioxide
  • Taliphatic polyamide
  • Tetanus antitoxin

Seriously?

You might be wondering what is left that is NOT a trigger.

And you are right. There's NOTHING that should be considered as unlikely to be a trigger.

To stress the point, let me quote from a guidance paper produced by The Mastocytosis Society for the benefit of emergency room personnel:

Triggers are unique to each patient. If a patient tells you that a certain drug, substance or environmental factor is a mast cell trigger for them, believe the patient even if it does not seem plausible.

And lastly, here's a quote from Dr. Afrin at a conference in Canada in 2011. Understand that Dr. Afrin is one of the most eminent doctors in the world dealing with Mast Cell Disease patients EVERY SINGLE DAY! :

With virtually every passing month, I am seeing, or hearing about, patients with ever odder physical stimuli for their disease.

So, in spite of Dr. Afrin's extensive exposure to MCAS patients, he is still astonished by what can reportedly constitute a trigger.

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Posted by on May 10, 2013 in The Basics |

What Are Mediators?

What Are Mediators?

Do you have any questions about mediators? Then please head for the “Why Is It All So Confusing?” forum and we'll try and help.

You’d Think a “Mediator” Would Be The Good Guy …

If you check the common, day-to-day definition of “Mediation”, you'll find something along the lines of  “a way of resolving disputes between two or more parties”. However, in medical terms, “Mediators”  is a fancy name for the chemicals that are released by mast cells upon degranulation.

You will often hear that mast cells release histamine and that is what causes the mastocytosis symptoms.

Well, this is partially true.

Potent as histamine is, it would need to be many, many times more potent to account for the variety and intensity of all the symptoms you experience.

Mediators, Mediators Everywhere …

Truth be told, there are actually many more chemical mediators, other than histamine, which are released during degranulation.

How many, do you ask? Well, make sure you're seated before you proceed. Here's what my hero, Dr. Afrin, has to say about numbers:

I refer interested colleagues and interested patients to a website called “COPE With Cytokines”, built and maintained by German biologist Horst Ibelgaufts. Even the COPE list is not a complete list of all known mast cell mediators and receptors, but I refer people interested in this topic to the COPE list because it nevertheless is the “most complete” list I have yet found in one place. Again, I know it’s not a complete list, but if you want to go to just one place to get the best visceral impact as to the full scope of what these cells are capable of doing, this is the site to go to, and when you navigate through this site to get to the entry for “mast cells,” you’ll see a very, very long list of mediators and receptors these cells can express.

Here's the link he refers you to, if you're curious:

Horst Ibelgauft’s COPE

This makes the rest of this post a bit futile, but let's discuss what is known and what we, as common mortals, maybe able to deal with.

The most studied mediators, and therefore the more discussed in the medical literature are the following:

Preformed mediators (Which are already stored in the mast-cell granules):

  • histamine
  • heparin (active as anticoagulant)
  • tryptase
  • serotonin

Newly formed lipid mediators (which are created at the time of degranulation):

  • thromboxane
  • prostaglandin D2
  • leukotriene C4
  • platelet-activating factor (PAF)
  • cytokines
  • Eosinophil chemotactic factor

Histamine

A bio-active amine causing vasodilation, erythema, edema, pruritus, urticaria, bronchoconstriction, increased gastric acid, intestinal cramping, further degranulation of mast cells, leukocyte activation.

It is a potent mediator of inflammation causing attraction of other immune cells including white blood cells which eat dead bacteria cells, causes nerves to fire, makes blood vessels porous allowing white blood cells to the tissues to find and remove bacteria and diseased cells. It also influences body temperature.

Heparin

Initiates the production of a hormone called bradykinin, that contributes to swelling, anaphylaxis and inflammatory symptoms. This production of bradykinin causes swelling, low blood pressure (from fluid loss) and white blood cells sticking together (which stimulates the immune system). Prolonged high release of heparin leads to bone density loss, leading to osteoporosis /osteopenia in otherwise low risk patients.

Heparin inhibits localized clotting, thus causing bleeding.

Tryptase

Degrades HDL (good) cholesterol, which compromises its protective role. Leads to clinically high LDL (bad) cholesterol in patients who have good diets. Tryptase is a measure of mast cell numbers not disease severity

Dr. Theoharides calls it meat tenderizer. Enough said …

Serotonin

Serotonin is stored in and released from human mast cells. It is also released from activated platelets.

Serotonin has several roles and effects in the body

  • Regulates bowel movements by increasing smooth muscle tone .
  • Controls appetite (higher concentration of serotonin makes you hungrier )
  • Regulates insulin and growth factor release – so suppresses insulin release from the pancreas
  • Regulates the breathing rate (higher concentration of serotonin increases your breathing rate )
  • Regulates the heart rate (higher concentration of serotonin increases your heart rate )
  • Constricts blood vessels(called vasoconstriction), which means the heart has to pump harder (increased cardiac output ). This increases blood pressure
  • Upregulates any mood – anxiety, depression, happiness, anger – making these moods more intense .
  • Controls sleep, pain and memory
  • Has a role in building and degenerating bone
  • In platelets, serotonin has a role in maintaining our bodily system's balance or in returning these systems to functioning within a normal range (homeostatis) and blood clotting

Mast cells release serotonin as a function of their normal activity. Mast cells in mastocytosis patients release serotonin twice a day. The normal rate is once a day.

Chymase

Causes death of endothelial cells and causes release of IL8, which also activates other mast-cells, causing a chain reaction of degranulation. This highlights one mechanism by which one mast cell being activated leads to further degranulation, releasing chemical contents from other mast cells.

This is noted by patients as a snowball effect: having one reaction makes another more likely. They notice they are becoming more sensitive to triggers. This is known medically as “second phase reactions”, caused by anaphylaxotin produced as part of the activation of the complement system.

Chymase is also known to convert angiotensin I to angiotensin II and thus plays a role in hypertension and atherosclerosis. Inhibition of coagulation locally, bronchoconstriction, osteoporosis

Renin

This also coverts angiotensin I to angiotensin II.

Leukotrienes

Cause bronchoconstriction, increased vascular permeability and contractability

Prostaglandin D2

Cause pruritus, pain, rhinorrhea, hypotension, flushing, osteoporosis

Platelet-activating factor

Cause wheal and flare, pain, pruritus

Tumor necrosis factor

Causes recruitment of inflammatory cells

Interleukins

Attract neutrophils

Multiple, Combined and Mast Cell-Specific Effect

Each mediator doesn't cause just one problem. Each mediator has an entire array, a unique array, of effects – direct effects, indirect effects, local effects, and remote effects – so when you do all the multiplying implicit in all of this biology math, you begin to understand why this disease could present with such extreme variety of symptoms.

The amount and type of mediators released by a mast cell appears to depend on the specific stimulus applied. In addition, different types of mast cells exist, and distinct systemic effects may be caused by different mast cell types.

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