The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 16

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

24. What is degranulation?
• Mast cells make chemicals inside them and often store them in pockets inside themselves. These pockets are called granules. When mast cells turn these pockets out so that the chemicals are dumped out of them into the body, that is called degranulation.
• There are several ways that mast cells release chemicals. These chemicals are commonly called mediators because they mediate many reactions in the body.
• Mast cells have to find certain building blocks from inside the body and whenever they find them, they use them to make mediators they need. Mast cells make some mediators whenever they have the opportunity and save them for later so they are there when they are needed. Often, the way mast cells save these mediators is by placing them inside granules. Mediators that are kept this way are called stored mediators.
• Mast cells have two options for getting those mediators out of their granules into the body. The first is to empty some of the granules entirely, just push everything out into the body at once. They can also release a little at a time. When mast cells are activated in response to an allergic or infectious process, overwhelmingly, they release the contents of a granule all at once.
Frequently, they empty many of the granules at the same time. This can cause an emergency response in your body and can impact your entire body. This is what happens during anaphylaxis but it happens during other processes too, like mast cell attacks, bad infections, or sudden trauma.
When mast cell patients say “I am degranulating”, it means they feel symptoms associated with mast cell mediator release. Histamine is stored in granules in large quantities so this is an offhand way of saying that they are feeling symptoms coming on.
• Mast cells have other ways of releasing mediators. They make some mediators only when they need to use them. These mediators are not stored but the building blocks they need are. A good example of this method is prostaglandin D2.
• Mast cells do not make prostaglandin D2 and stuff it inside granules. Instead, they keep the building blocks to make it inside of themselves. In this case, the building block they store is called arachidonic acid. When mast cells need to make prostaglandin D2, they use some of the arachidonic acid they have stored. But as soon as they use it to make prostaglandin D2, the mast cells secrete it right into the body. It is not stored in a granule.
• Mediators that are made with this kind of process are called “de novo” mediators. This means that the mediators are made “new” on demand when they are needed.

 

 

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 6

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

12. What do these blood and urine tests look for?

• There are a lot of tests ordered for mast cell disease. How they are interpreted can depend upon a lot of factors. Some of the tests are unreliable, a fact that will be addressed in detail later in this series. (And has been addressed in detail elsewhere on this blog). Please keep in mind when reading this post that I am being VERY general and assumed the test was performed correctly on a correctly stored sample.
• The most common test ordered for mast cell disease is serum tryptase. Tryptase is a molecule that mast cells release. While it has lots of functions in the body, and is especially important in healing wounds and tissue growth, the amount present in your body at a given moment should be low.
• Tryptase is special because mast cells release it in two ways. Firstly, they make and release a little bit steadily. This is not related to activation. Mast cells just normally release a little tryptase as they go about their work. So the idea is that if you have more mast cells than you should, and each of those mast cells releases a little tryptase all the time, that you will have a higher than normal serum tryptase.
• Patients with a clonal mast cell disease, in which they have too many broken mast cells, usually have elevated baseline tryptase. This means tryptase that is elevated at least two times when you are NOT having a big reaction or anaphylaxis.
• Mast cells also store lots of tryptase in their pockets. When the mast cell is activated and it empties out its pockets, lots of tryptase comes out at once. This is why tryptase can be higher after a reaction or anaphylaxis, because mast cells release a bunch at once.
• Patients with mast cell activation syndrome or cutaneous mastocytosis do not always have elevated tryptase even with a big reaction or anaphylaxis.
• Mast cells have huge amounts of histamine stored in their pockets inside their cells. Histamine has lots of functions inside the body and is required for normal body functions. In particular, it is important to our nervous system. Smaller amounts are released as a normal function of the body.
• A lot of histamine is released when mast cells are activated. The idea is that if your mast cells are more activated than they should be that your histamine level will be higher. However, the test recommended for us to consider the histamine level in mast cell patients is not for histamine. It is for n-methylhistamine. This is a molecule that is formed when the body breaks down histamine, which happens very quickly (within minutes of release). n-methylhistamine is more stable, which is why we look at it.
• The test for n-methylhistamine is most reliable when performed in a 24 hour urine sample. This is because the level in urine can fluctuate throughout the day.
• Mast cells make a lot of prostaglandin D2 (abbreviated PGD2). PGD2 is very important for cell communicating. It can carry a message from one cell to another, allowing cells to work together. Unlike histamine and tryptase, mast cells do not keep PGD2 stored in their pockets. They make it only when they need it and then release it.
• PGD2 is released in large amounts when mast cells are activated. However, because it is not stored in the pockets, it is not always elevated right away when you have a big activation event or anaphylaxis. Prostaglandin D2 is broken down quickly. While we do test directly for PGD2 for mast cell disease, we also test for 9a,11-PGF2, a molecule formed when PGD2 breaks down.
• The tests for PGD2 and 9a,11b-PGF2 are most reliable when performed in 24 hour urine samples. This is because the levels in urine can fluctuate throughout the day.
• Heparin is a blood thinning molecule that is stored in pockets inside mast cells. Mast cells are the only cells that release significant amounts of histamine. When the mast cell is activated and it releases histamine, the histamine comes out stuck to heparin. Heparin is broken down very quickly so it is hard to measure accurately.
• The test to assess heparin level actually looks for a molecule called anti-factor Xa that can interact with heparin. This test is performed in serum.
• Chromogranin A is released by mast cells. It is also released by a lot of other cells. The level of this molecule can be affected by many things, including common medications. It is sometimes tested for and considered a sign of mast cell disease if elevated when all other possible reasons can be excluded.
• Chromogranin A levels are most reliable in serum.

 

For more detailed reading, please visit these posts:

The Provider Primer Series: Management of mast cell mediator symptoms and release

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 4

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

8. Why are symptoms not the same for everyone?

  • Bodies are very complex. This sounds silly to say because of course bodies are complex, but the amount of work a body does on a second to second basis is staggering. All of your organs are working all the time. The way they are working depends on hormones, how recently you ate, if you are stressed out, what kind of environment you live in, if you have been or are pregnant, how old you are, if you are sexually active, where you are in your menstrual cycle, what medications you are on, and what things happened to you up to this point in your life. Not everyone’s body does the same things.
  • Mast cells are involved in regulating many processes at the same time that all of these things are happening. It is releasing chemicals to make these things happen and is receiving messages from other cells.
  • Mast cells are key cells in inflammation. Inflammation is when cells from the immune system tell the body that it is under attack. Some of those cells are white blood cels that were already present. Inflammation causes many white blood cells, including mast cells to go to the site of the inflammation. For example, if you break your arm, the cells near the broken bone will send messages that it needs help from immune cells. Those immune cells will then physically move to the place they were called to. Mast cells may move to the site of inflammation in this way.
  • When an area has been inflamed, sometimes white blood cells stick around even when the area is healed or healing. Mast cells can also do this. If an area is inflamed, you may end up with many mast cells in that spot where there had originally only been a few.
  • When an area has been inflamed, the immune cells nearby can be extra easy to activate for a while. They are “primed”. Primed cells are much more likely to start a new inflammatory episode, even for something tiny, because they are easier to activate. They remember that they previously had to call for help so their instinct is to do it again. In this way, old injuries may “act up” easily. This can keep nearby mast cells primed or even activated long term.
  • Mast cells have pockets called granules that store chemicals inside them. These chemicals are called mediators. They perform many of the mast cell’s normal functions.
  • Mast cells have different jobs in different places in the bodies. The mediators stored inside those pockets are not the same in all mast cells. They are full of the mediators that they need most to do specific jobs in that area. Mast cells can also make new mediators to do specific jobs. The mediators they make are also tailored to their specific jobs.
  • Some mediators are very specific and some are not. Think of this like sending an email. You can send an email to a particular person. This is specific. You can also send an email to an address used by many people, like an email account for several people who work in customer service. Any of them might see it and respond but you don’t know which one. This is nonspecific. Mast cell mediators might talk to just one type of cell or to several kinds of cells, either nearby or in other parts of the body. Which mediators are released can also depend on previous inflammation. Which mediators are released, where they are released, and how much is released also vary from person to person.

9. Why do symptoms change over time?

  • Symptoms can change over time for all of the reasons they are not the same from person to person.
  • It is also possible that symptoms can change due to progression of disease from one diagnostic category to another. For example, patients may suddenly notice their abdomen is swollen and hard. That could be because their liver is swollen and not working properly.
  • You CANNOT assume that the disease is progressing because symptoms change. Symptom change is NOT a marker for progression.
  • Mast cell disease is not inherently progressive. Many people never have a change in diagnosis.

For more detailed reading, please visit these posts:

The Provider Primer Series: Management of mast cell mediator symptoms and release

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The Provider Primer Series: Relevance of mast cells in common health scenarios (continued)

Reason for care Post op care
Role of mast cells Mast cells are inherently activated following surgery as they drive tissue remodeling, angiogenesis, and wound repair.[i]

Mast cells are involved in the transmission of pain stimuli.[iii]

Impact of condition on mast cells Mechanical trauma or pressure, such as dressing a wound or palpating the area, can directly induce degranulation and mast cell activation[ii].

Pain can trigger mast cell activation.[iii]

Psychological and physical stress can trigger an inflammatory response that involves mast cell activation.[iv]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation and cannot be taken by some mast cell patients.[iv]

Codeine and derivatives can trigger mast cell degranulation[v].

Vancomycin, gyrase inhibitors and cefuroxime should be avoided where possible due to risk of mast cell activation.[vi]

Amide caine anesthetics are preferred over ester caines.[vi]

ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management.[vi]

Fentanyl and fentanyl derivatives are the preferred narcotic for mast cell patients due to low risk of degranulation. Hydromorphone and oxycodone are suggested by some authors and see use in mast cell patients.[vi]

Benzodiazepines can provide anxiolytic and anticonvulsive support in mast cell patients are needed.[vi]

IV contrast poses significant to mast cell patients due to the high risk of systemic degranulation. If required, premedication is advised.[vi]

Adhesive allergy is not unusual and patients may require specific occlusive dressings, tapes, or wound glue.

Notes regarding mast cell treatment Antihistamines and mast cell stabilizers can be helpful in mitigating common post op symptoms such as opiate induced itching and nausea. COX inhibitors can help with pain management.[vii]
Special considerations for mast cell patients Mast cells are the largest reservoir of endogenous heparin. Patient should be monitored for coagulopathy.[viii]

Mast cells contribute significantly to post operative ileus.[ix]

Intestinal manipulation directly results in mast cell degranulation.[ix]

 

Reason for care Hypertension
Role of mast cells Mast cell mediators can impact blood pressure. Histamine acting on H2 receptor can promote hypertension.[xi]

Renin, chymase, and carboxypeptidase A all participate in hypertension by dysregulation of angiotensin II.[xi]

9a,11b-PGF2, the degradation product of prostaglandin D2, thromboxane A2, and leukotrienes increase blood pressure.[xi]

Impact of condition on mast cells Dysregulation of angiotensin II and renin levels can affect mast cell behavior.[x]
Notes regarding condition treatment ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management. Alternatives include calcium channel blockers, renin inhibitors, and ivabradine, among others.[vi]
Notes regarding mast cell treatment Several mast cell medications can impact levels of histamine, renin, and angiotensin II, all of which can affect blood pressure.
Special considerations for mast cell patients Mast cell patients taking β-adrenergic receptor antagonists (beta blockers) should carry a glucagon pen to increase efficacy of epinephrine in anaphylaxis.[xi]

As many as 31% of patients with mast cell disease demonstrate elevated arterial blood pressure secondary to mast cell activation. These elevations may be episodic or chronic.[xi]

Mast cell patients may also have hyperadrenergic postural orthostatic tachycardia syndrome (hyperPOTS), a condition that can cause hypertension.[xii]

 

Reason for care Heart disease
Role of mast cells Renin, chymase, and carboxypeptidase A all participate in hypertension by dysregulation of angiotensin II, contributing to evolution of arrhythmia.[xi]

Prostaglandin D2, VIP, PAF, IL-6 and nitric oxide are all vasodilating and can contribute to tachycardia.[xi]

Tryptase, histamine, PAF, IL-10, TNF, IL-4, IL-6, FGF, and TGFB can contribute to heart failure.[xi]

Mast cells participate in the formation, destabilization and rupture of atherosclerotic lesions.[xiii]

Histamine release is associated with acute coronary syndromes such as Kounis Syndrome, commonly known as “allergic MI” or “allergic angina”.[xiv]

Leukotriene C4, adrenomedullin, tryptase and chymase participate in the formation, destabilization and rupture of aneurysms.[xiii]

Impact of condition on mast cells Heart disease, especially heart failure, can disrupt release of catecholamines including norepinephrine.[xv] Norepinephrine dysregulation can impact mast cell behavior.

Dysregulation of angiotensin II and renin levels can affect mast cell behaviorx

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.xx

Acetaminophen is generally recommended for use in mast cell patients.[iv]

ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management. Alternatives include calcium channel blockers, renin inhibitors, and ivabradine, among others.[vi]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief of prostaglandin induced symptoms.[vi]

Several mast cell medications can impact levels of histamine, renin, and angiotensin II, all of which can affect blood pressure.

Epinephrine can provoke myocardial ischemia, prolong QT interval, and exacerbate coronary vasospasm and arrhythmia.[xiv]

Special considerations for mast cell patients Over 20% of systemic mastocytosis and mast cell activation syndrome patients experience palpitations and supraventricular tachycardia.[xi]

Prostaglandin D2 can cause tachycardia. PGD2 is associated with late phase allergic response and symptoms may be delayed for several hours after allergic event.[xi]

One study showed that 12/18 mast cell activation syndrome patients showed diastolic left ventricular dysfunction.[xi]

Mast cell patients may also have postural orthostatic tachycardia syndrome (POTS), a condition that can cause blood pressure and heart rate irregularities.[xii]

 

Reason for care Chest pain
Role of mast cells Mast cells participate in the formation, destabilization and rupture of atherosclerotic lesions.[xiii]

Histamine release is associated with acute coronary syndromes such as Kounis Syndrome, commonly known as “allergic MI” or “allergic angina”.[xiv]

Leukotriene C4, adrenomedullin, tryptase and chymase participate in the formation, destabilization and rupture of aneurysms.[xiii]

Mast cells participate in esophageal inflammation in several models, including from acid reflux.[xvi]

Mast cells contribute to GI dysmotility which can cause esophageal spasms.[xvii]

Mast cells are involved in the transmission of pain stimuli.[iii]

Impact of condition on mast cells Pain can trigger mast cell activation.[iii]

Psychological and physical stress can trigger an inflammatory response that involves mast cell activation.[iv]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.xx

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Fentanyl and fentanyl derivatives are the preferred narcotic for mast cell patients due to low risk of degranulation. Hydromorphone and oxycodone are suggested by some authors and see use in mast cell patients.[vi]

Benzodiazepines can provide anxiolytic and anticonvulsive support in mast cell patients are needed.[vi]

ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management. Alternatives include calcium channel blockers, renin inhibitors, and ivabradine, among others.[vi]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief of prostaglandin induced symptoms.[vi]
Special considerations for mast cell patients Mast cell patients may experience GI dysmotility which can cause esophageal spasms.[xviii]

Mast cell patients sometimes have eosinophilic esophagitis, causing esophageal spasms, food impaction, and pain.[xix]

Over 20% of systemic mastocytosis and mast cell activation syndrome patients experience palpitations and supraventricular tachycardia.[xi]

Prostaglandin D2 can cause tachycardia. PGD2 is associated with late phase allergic response and symptoms may be delayed for several hours after allergic event.[xi]

One study showed that 12/18 mast cell activation syndrome patients showed diastolic left ventricular dysfunction.[xi]

Mast cell patients can present with Kounis Syndrome. Management of Kounis Syndrome relies upon addressing both cardiovascular aspects of the episode as well as allergic aspects.[xiv]

Costochondritis can occur in mast cell patients and may present as chest pain.

Mast cell patients may also have postural orthostatic tachycardia syndrome (POTS), a condition that can cause blood pressure and heart rate irregularities.[xii]

IV contrast poses significant to mast cell patients due to the high risk of systemic degranulation. If required, premedication is advised.[vi]

References:

[i] Douaiher J, et al. (2014). Development of mast cells and importance of their tryptase and chymase serine proteases in inflammation and wound healing. Adv Immunol, 122, 211-252.

[ii] Zhang D, et al. (2012). Mast-cell degranulation induced by physical stimuli involves the activation of transient receptor-potential channel TRPV2. Physiol Res, 61(1), 113-124.

[iii] Chatterjea D, Martinov T. (2015). Mast cells: versatile gatekeepers of pain. Mol Immunol, 63(1),38-44.

[iv] Dewachter P, et al. (2014). Perioperative management of patients with mastocytosis. Anesthesiology, 120, 753-759.

[v] Brockow K, Bonadonna P. (2012). Drug allergy in mast cell disease. Curr Opin Allergy Clin Immunol, 12, 354-360.

[vi] Molderings GJ, et al. (2016). Pharma,ological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Arch Pharmol, 389:671.

[vii] Molderings GJ, et al. (2011). Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol, 4(10).

[viii] Carvalhosa AB, et al. (2015). A French national survey on clotting disorders in mastocytosis. Medicine (Baltimore), 94(40).

[ix] Peters EG, et al. (2015). The contribution of mast cells to postoperative ileus in experimental and clinical studies. Neurogastroenterol Motil, 27(6), 743-749.

[x] Biscotte SM, et al. (2007). Angiotensin II mediated activation of cardiac mast cells. The FASEB Journal, 21(6).

[xi] Kolck UW, et al. (2016). Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research, x, 1-10.

[xii] Shibao C, et al. (2005). Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension, 45, 385-390.

[xiii] Kennedy S, et al. (2013). Mast cells and vascular diseases. Pharmacology & Therapeutics, 138, 53-65.

[xiv] Kounis NG. (2016). Kounis Syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med, 54(10), 1545-1559.

[xv] Florea VG, Cohn JN. (2014). The autonomic nervous system and heart failure. Circulation Research, 114, 1815-1826.

[xvi] Morganstern JA, et al. (2008). Direct evidence of mast cell participation in acute acid-induced inflammation in mice. J Pediatr Gastroenterol Nutr, 46(2), 134-138.

[xvii] De Winter BY, et al. (2012). Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Acta – Molecular Basis of Disease, 1822(1), 66-73.

[xviii] De Winter BY, et al. (2012). Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Acta – Molecular Basis of Disease, 1822(1), 66-73.

[xix] Nurko S, Rosen R. (2010). Esophageal dysmotility in patients with eosinophilic esophagitis. Gastrointest Endosc Clin N Am, 18(1), 73-ix.

The Provider Primer Series: Management of mast cell mediator symptoms and release

Mast cell disease is largely managed by treatment of symptoms induced by mast cell mediator release or by interfering with mediator release.

The following tables detail treatment recommendations described in literature by mast cell disease key opinion leaders. Please refer to source literature for future details on dosing, duration, and so on. These are not my personal recommendations and any and all treatment decisions must be made by a medical professional familiar with the patient.

Second and third generation H1 antihistamines are preferred to exclude neurologic symptoms accompanying use of first generation H1 antihistamines. However, first generation H1 antihistamines are sometimes used by mast cell patients and in the setting of anaphylaxis.

In advanced and aggressive forms of mast cell disease, use of cytoreductive agents, chemotherapy, and, very rarely, hematopoietic stem cell transplant may be considered.

Table 1: Primary treatment options (consensus) for mast cell mediator symptoms or release described in literature
Class Target Intended actions of target Symptoms associated with target Reference
H1 antihistamines (second or third generation preferred) H1 histamine receptor Promotes GI motility, vasodilatation and production of prostaglandins, leukotrienes and/or thromboxanes (via release of arachidonic acid) and nitric oxide  Hypotension, decreased chronotropy, flushing, angioedema, pruritis, diarrhea, headache, urticaria, pain, swelling and itching of eyes and nose, bronchoconstriction, cough, and airway impingement Valent 2007[i], Picard 2013[ii], Molderings 2016[iii], Hamilton 2011[iv]
H2 antihistamines H2 histamine receptor Release of gastric acid, vasodilation, smooth muscle relaxation, and modulates antibody production and release in various immune cells Increased chronotropy, increased cardiac contractility, hypertensioni, bronchodilation, increased presence of Th2 T cells, increasing IgE production Valent 2007, Picard 2013, Molderings 2016, Hamilton 2011
Mast cell stabilizer (cromolyn) Unknown targets to modulate electrolyte trafficking across the membrane to deter mast cell degranulation 

 

 

 

Unclear. Mast cell mediator release regulates many physiologic functions, including allergy response, immune defense against pathogens, angiogenesis, and tissue remodeling. In theory, all symptoms derived from mast cell mediator release. Research has demonstrated decreased release of mediators including histamine and eicosanoids. Valent 2007, Picard 2013, Molderings 2016, Hamilton 2011

 

Table 2: Primary treatment options (non-consensus) for mast cell mediator symptoms or release described in literature
Class Target Intended actions of target Symptoms associated with target Reference
Leukotriene receptor antagonists Leukotriene receptor Smooth muscle contraction, immune cell infiltration, production of mucus Bronchoconstriction, airway impingement, overproduction of mucus, pruritis, sinus congestion, runny nose Hamilton 2011, Valent 2007
N/A; Vitamin C decreases histamine levels by accelerated degradation and by interfering with production Unknown targets to deter mast cell degranulation  Mast cell mediator release regulates many physiologic functions, including allergy response, immune defense against pathogens, angiogenesis, and tissue remodeling. In theory, all symptoms derived from mast cell mediator release. Research has demonstrated decreased release of mediators including histamine and eicosanoids. Molderings 2016
H1 antihistamine; mast cell stabilizer Histamine H1 receptor and mast cell stabilizer (ketotifen) See above for function of targets for H1 antihistamines and mast cell stabilizer See above for symptoms targets for H1 antihistamines and mast cell stabilizer Molderings 2016

 

Table 3: Secondary options for mast cell mediator symptoms or release described in literature
Symptom Treatment Reference
Abdominal cramping H2 antihistamines, cromolyn, proton pump inhibitors, leukotriene antagonists, ketotifen Picard 2013
Abdominal cramping H1 antihistamines, H2 histamines, oral cromolyn, leukotriene receptor antagonists, short course glucocorticoids Valent 2007
Abdominal pain H1 antihistamines, H2 histamines, oral cromolyn, leukotriene receptor antagonists, short course glucocorticoids Valent 2007
Angioedema H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, aspirin, ketotifen Picard 2013
Angioedema Medications used for hereditary angioedema, including antifibrinolytic such as tranexamic acid, bradykinin receptor antagonist Molderings 2016
Blistering Local H1 antihistamines, H1 antihistamines, H2 antihistamines, systemic glucocorticoids, topical cromolyn, dressing Valent 2007
Bone pain Analgesics, NSAIDS, opiates and radiation if severe Valent 2007
Bone pain Bisphosphonates, vitamin D, calcium, anti-RANKL therapy Molderings 2016
Colitis Corticosteroids active in GI tract or systemic Molderings 2016
Conjunctival injection H1 antihistamines, topical H1 antihistamines, topical corticosteroids, topical cromolyn Picard 2013
Conjunctivitis Preservative free eye drops with H1 antihistamine, cromolyn, ketotifen or glucocorticoid Molderings 2016
Dermatographism H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, aspirin, ketotifen Picard 2013
Diarrhea H1 antihistamines, H2 histamines, oral cromolyn, leukotriene receptor antagonists, short course glucocorticoids Valent 2007
Diarrhea H2 antihistamines, cromolyn, proton pump inhibitors, leukotriene antagonists, ketotifen Picard 2013
Diarrhea Bile acid sequestrants, nystatin, leukotriene receptor antagonists, 5-HT3 receptor inhibitors, aspirin Molderings 2016
Flushing H1 antihistamines, leukotriene receptor antagonists, H2 antihistamines, glucocorticoids, topical cromolyn Valent 2007
Flushing H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, aspirin, ketotifen Picard 2013
Gastric symptoms Proton pump inhibitors Molderings 2016
Headaches H1 antihistamines, H2 histamines, oral cromolyn Valent 2007
Headaches, poor concentration and memory, brain fog H1 antihistamines, H2 antihistamines, cromolyn, ketotifen Picard 2013
Interstitial cystitis Pentosan, amphetamines Molderings 2016
Joint pain COX-2 inhibitors Molderings 2016
Mastocytoma (if symptomatic, growing) Local immunosuppressants, PUVA, removal Valent 2007
Miscellaneous/ overall elevated symptom profile Disease modifying anti-rheumatoid drugs, antineoplastic drugs, kinase inhibitors with appropriate target, anti-IgE, continuous antihistamine infusion Molderings 2016
Nasal pruritis H1 antihistamines, topical H1 antihistamines, topical corticosteroids, topical cromolyn Picard 2013
Nasal stuffiness H1 antihistamines, topical H1 antihistamines, topical corticosteroids, topical cromolyn Picard 2013
Nausea H2 antihistamines, cromolyn, proton pump inhibitors, leukotriene antagonists, ketotifen Picard 2013
Nausea H1 antihistamines, H2 histamines, oral cromolyn, leukotriene receptor antagonists, short course glucocorticoids Valent 2007
Nausea Dimenhydrinate, benzodiazepines, 5-HT3 inhibitors, NK1 antagonists Molderings 2016
Neuropathic pain, paresthesia Alpha lipoic acid Molderings 2016
Non-cardiac chest pain H2 antihistamines, proton pump inhibitors Molderings 2016
Osteopenia, osteoporosis Bisphosphonates, vitamin D, calcium, anti-RANKL therapy Molderings 2016
Peptic ulceration/bleeding H2 antihistamines, proton pump inhibitors, blood products as needed Valent 2007
Pre-syncope/syncope H1 antihistamines, H2 antihistamines, corticosteroids, anti-IgE Picard 2013
Pruritis H1 antihistamines, H2 antihistamines, topical cromolyn, PUVA treatment, leukotriene receptor antagonists, glucocorticoids Valent 2007
Pruritis H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, aspirin, ketotifen Picard 2013
Pruritis Topical cromolyn, topical palmitoylethanolamine containing preparations Molderings 2016
Recurrent hypotension H1 antihistamines, H2 antihistamines, systemic glucocorticoids, aspirin Valent 2007
Respiratory symptoms Leukotriene receptor antagonists, 5-lipoxygenase inhibitors, short-acting β-sympathomimetic Molderings 2016
Severe osteopenia or osteoporosis Oral bisphosphonates, IV bisphosphonates, interferon alpha Valent 2007
Tachycardia H1 antihistamines, H2 antihistamines, systemic glucocorticoids, aspirin Valent 2007
Tachycardia H1 antihistamines, H2 antihistamines, corticosteroids, anti-IgE Picard 2013
Tachycardia AT1 receptor antagonists, agents that target funny current Molderings 2016
Throat swelling H1 antihistamines, H2 antihistamines, leukotriene antagonists, corticosteroids, anti-IgE Picard 2013
Urticaria H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, aspirin, ketotifen Picard 2013
Vomiting H1 antihistamines, H2 histamines, oral cromolyn, leukotriene receptor antagonists, short course glucocorticoids Valent 2007
Vomiting H2 antihistamines, cromolyn, proton pump inhibitors, leukotriene antagonists, ketotifen Picard 2013
Wheezing H1 antihistamines, H2 antihistamines, leukotriene antagonists, corticosteroids, anti-IgE Picard 2013

 

[i] Valent P, et al. (2007). Standards and standardization in mastocytosis: Consensus statements on diagnostics, treatment recommendations and response criteria. European Journal of Clinical Investigation, 37(6):435-453.

[ii] Picard M, et al. (2013). Expanding spectrum of mast cell activation disorders: Monoclonal and idiopathic mast cell activation syndromes. Clinical Therapeutics, 35(5):548-562.

[iii] Molderings GJ, et al. (2016). Pharmacological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Arch Pharmol, 389:671.

[iv] Hamilton MJ, et al. (2011). Mast cel activation syndrome: a newly recognized disorder with systemic clinical manifestations. Journal of Allergy and Clinical Immunology, 128(1):147-152.e2

The Provider Primer Series: Mast cell activation syndrome (MCAS)

Mast cell activation syndrome (MCAS), also called mast cell activation disorder (MCAD), is an immunologic condition in which mast cells are aberrantly activated, resulting in inappropriate mediator release.

Presentation

  • MCAS can be responsible for chronic symptoms in multiple organs that cannot be attributed to another cause[vi].
  • Patients frequently receive diagnosis for a number of idiopathic conditions prior to correct diagnosis with MCAS[vi].
  • Mast cell activation syndrome is overwhelmingly a secondary condition. MCAS can be secondary to a number of conditions, including autoimmune diseases, connective tissue diseases, and atopic conditions[i].
  • The term “primary MCAS” refers to mediator release symptoms associated with mastocytosis[xvii] . However, the term “mastocytosis” generally conveys the understanding that both proliferation and mediator release symptoms are possible.
  • In idiopathic MCAS, no cause for symptoms can be identified[xvii] .
  • The presence of multiple mast cell patients in one family is not uncommon. A heritable gene has not yet been identified. Epigenetic mechanisms are suspected for transmission of mast cell disease to another generation[iv].
  • Approximately 75% of mast cell patients have at least one first degree relative with mast cell disease and not always the same subtype[ii]. For example, a mother may have MCAS, while one of her children has SM and the other has CM.

Diagnostic criteria

  • MCAS is a recently described diagnosis. In the absence of large studies, several groups have developed their own, sometimes conflicting, diagnostic criteria.
  • Differential diagnoses with potential to cause similar symptoms should be considered and excluded[iii].
  • The criteria most frequently used include those by a 2010 paper by Akin, Valent and Metcalfe[iii]; a 2011 paper by Molderings, Afrin and colleagues[iv]; and a 2013 paper by Castells and colleagues[v].
  • The criteria described in the 2011 paper by Molderings, Afrin and colleagues have been updated to include response to medication[vi].
  • Of note, a 2012 consensus proposal[x] was authored by a number of mast cell experts including Valent, Escribano, Castells, Akin and Metcalfe. It sees little practical use and is not generally accepted in the community.
  • The major sets of criteria listed above all include the following features:
    • Recurrent or chronic symptoms of mast cell activation
    • Objective evidence of excessive mast cell mediator release
    • Positive response to medications that inhibit action of mast cell mediators
  • Valent warns that in some cases, patients may not fulfill all criteria but still warrant treatment: “In many cases, only two or even one of these three criteria can be documented. In the case of typical symptoms, the provisional diagnosis of ‘possibly MCA/MCAS’ can be established, and in acute cases, immediate treatment should be introduced.”[vii]

Evidence of mediator release

  • Mast cells produce a multitude of mediators including tryptase, histamine, prostaglandin D2, leukotrienes C4, D4 and E4, heparin and chromogranin A[viii].
  • Serum tryptase and 24 hour urine testing for n-methylhistamine, prostaglandin D2, prostaglandin 9a,11b-F2 are frequently included in testing guidelines in literature (Castells 2013)[ix], (Akin 2010)[x], (Valent 2012)[xi].
  • It can be helpful to test for other mast cell mediators including 24 hour urine testing for leukotriene E4[xii]; plasma heparin[xiii]; and serum chromogranin A[xiv].
  • In most instances, elevation of a mediator must be present on two occasions[ix]. This helps to exclude situations of appropriate mast cell activation, such as infection or wound healing.
  • For patients with baseline tryptase level >15 ng/mL, elevation of tryptase above this baseline is only required on one occasion[viii].

Symptoms associated with mast cell activation

  • Mediator release causes a wide array of symptoms, including hypertension[xv], hypotension, hypertension, wheezing, itching, flushing, tachycardia, nausea, vomiting, diarrhea, constipation, headache, angioedema, fatigue, and neurologic symptoms[iv].
  • In a small MCAS cohort (18 patients), 17% had a history of anaphylaxis[xvii] . A larger data set is desirable.
  • Patients with history of anaphylaxis should be prescribed epinephrine autoinjectors[v]. If patient must be on a beta blocker, they should be prescribed a glucagon injector for use in the event of anaphylaxis[v].

Response to medications that inhibit action of mast cell mediators

  • Treatment of MCAS is complex and may require a number of medications. Second generation H1 antihistamines; H2 antihistamines; and mast cell stabilizers are mainstays of treatment[xvi].
  • Additional options include aspirin; anti-IgE; leukotriene blocker; and corticosteroids[xiii] .
  • First generation H1 antihistamines may be used for breakthrough symptoms[xiii] .
  • “An important point is that many different mediators may be involved in MCA-related symptoms so that the final conclusion the patient is not responding to antimediator therapy should only be drawn after having applied several different antimediator-type drugs[xiii] .
  • Inactive ingredients are often to blame for reaction to mast cell mediator focused medications. Many mast cell patients see benefit from having medications compounded[xvii].

Natural history

  • In one MCAS cohort of 18 patients, 33% had a complete (no unmanaged symptoms) response and 33% had a major (only one serious symptom) response after one year of mast cell treatment[xviii].
  • In another MCAS cohort of 135 patients, 51% demonstrated significant improvement, 11% had no obvious change in symptom severity and 38% experienced worsening symptoms[v]. (Author’s note: While described in an Afrin 2016[v] paper, the data from this cohort has not yet been published. Molderings is the principle investigator.

 

References

[i] Frieri M, et al. (2013). Mast cell activation syndrome: a review. Current Allergy and Asthma Reports, 13(1), 27-32.

[ii] Molderings GJ, et al. (2013). Familial occurrence of systemic mast cell activation disease. PLoS One, 8, e76241-24098785

[iii] Akin C, et al. (2010). Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol, 126(6), 1099-1104.e4

[iv] Molderings GJ, et al. (2011). Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology, 4(10), 10.1186/1756-8722-4-10

[v] Castells M, et al. (2013). Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clin Ther, 35(5), 548-562.

[vi] Afrin LB, et al. (2016). Often seen, rarely recognized: mast cell activation disease – a guide to diagnosis and therapeutic options. Annals of Medicine, 48(3).

[vii] Valent P. (2013). Mast cell activation syndromes: definition and classification. European Journal of Allergy and Clinical Immunology, 68(4), 417-424.

[viii] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[ix] Picard M, et al. (2013). Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clinical Therapeutics, 35(5), 548-562.

[x] Akin C, et al. (2010). Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol, 126(6), 1099-1104.e4

[xi] Valent P, et al. (2012). Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol, 157(3), 215-225.

[xii] Lueke AJ, et al. (2016). Analytical and clinical validation of an LC-MS/MS method for urine leukotriene E4: a marker of systemic mastocytosis. Clin Biochem, 49(13-14), 979-982.

[xiii] Vysniauskaite M, et al. (2015). Determination of plasma heparin level improves identification of systemic mast cell activation disease. PLoS One, 10(4), e0124912

[xiv] Zenker N, Afrin LB. (2015). Utilities of various mast cell mediators in diagnosing mast cell activation syndrome. Blood, 126(5174).

[xv] Shibao C, et al. (2005). Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension, 45(3), 385-390.

[xvi] Cardet JC, et al. (2013). Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep, 13(1), 10-18.

[xvii] Afrin LB. “Presentation, diagnosis and management of mast cell activation syndrome.” In: Mast Cells. Edited by David B. Murray, Nova cience Publishers, Inc., 2013, 155-232.

[xviii] Hamilton MJ, et al. (2011). Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations. Journal of Allergy and Clinical Immunology, 128(1), 147-152.e2

The Provider Primer Series: Mediator testing

Evidence of mediator release

  • Mast cells produce a multitude of mediators including tryptase, histamine, prostaglandin D2, leukotrienes C4, D4 and E4, heparin and chromogranin A[i].
  • Objective evidence of mast cell mediator release is required for diagnosis of MCAS (Castells 2013)[ii], (Akin 2010)[iii], (Valent 2012)[iv].
  • Serum tryptase and 24 hour urine testing for n-methylhistamine, prostaglandin D2, prostaglandin 9a,11b-F2 are frequently included in MCAS testing recommendations (Castells 2013)[ii], (Akin 2010)[iii], (Valent 2012)[iv].
  • It can be helpful to test for other mast cell mediators including 24 hour urine testing for leukotriene E4[v]; plasma heparin[ix]; serum chromogranin A[ix]; and leukotriene E4[ix].

Tryptase

  • Tryptase is extremely specific for mast cell activation in the absence of hematologic malignancy or advanced kidney disease. Of note, rheumatoid factor can cause false elevation of tryptase[ix].
  • Serum tryptase levels peak 15-120 minutes after release with an estimated half-life of two hours[vi].
  • Per key opinion leaders, tryptase levels should be drawn 15 minutes to 4 hours after onset of anaphylaxis or activation event (Castells 2013[ii]), (Akin 2010[iii]), (Valent 2012)[iv]). Phadia, the manufacturer of the ImmunoCap® test to quantify tryptase, recommends that blood be drawn 15 minutes to 3 hours after event onset[vii].
  • Serum tryptase >11.4 ng/mL is elevated[i]. In addition to measuring tryptase level during the event, another sample should be drawn 24-48 hours after the event, and a third sample drawn two weeks later. This allows comparison of event tryptase level to baseline[vi].
  • An increase in serum tryptase level during an event by 20% + 2 ng/mL above patient baseline is often accepted as evidence of mast cell activation[v],[i].
  • Absent elevation of tryptase level from baseline during an event does not exclude mast cell activation[viii].
  • Sensitivity for serum tryptase assay in MCAS patients was assessed as 10% in a 2014 paper[ix].
  • A recent retrospective study of almost 200 patients found serum was elevated in 8.8% of MCAS patients[x].
  • Baseline tryptase >20.0 ng/mL is a minor criterion for diagnosis of systemic mastocytosis. 77-85% of SM patients have baseline tryptase >20.0 ng/mL[ix].

Histamine and degradation product n-methylhistamine

  • N-methylhistamine is the breakdown product of histamine.
  • Histamine is degraded quickly. Samples should be drawn within 15 minutes of episode onset[vii].
  • Serum histamine levels peak 5 minutes after release and return to baseline in 15-30 minutes[vii].
  • Sample (urine or serum) must be kept chilled[xi].
  • In addition to mast cells, histamine is also released by basophils. Consumption of foods or liquids that contain histamine can also inflate the level when tested[ix].
  • A recent retrospective study of almost 200 patients found that n-methylhistamine was elevated in 7.4% of MCAS patients in random spot urine and 5.4% in 24-hour urine[xi].
  • Sensitivity of 24-hour n-methylhistamine for MCAS was assessed as 22% in 24-hour urine[ix].
  • Plasma histamine was elevated in 29.3% of MCAS patients[xi].
  • 50-81% of systemic mastocytosis patients demonstrate elevated n-methylhistamine in 24-hour urine[ix].

Prostaglandin D2 and degradation product prostaglandin 9a,11b-F2

  • 9a,11b-prostaglandin F2 is the breakdown product of prostaglandin D2.
  • Prostaglandin D2 is only produced in large quantities by mast cells. Basophils, eosinophils and other cells produce minute amounts[ix].
  • A recent retrospective study of almost 200 patients found that PGD2 was elevated in 9.8% of MCAS patients in random spot urines and 38.3% in 24-hour urine[xi].
  • PGD2 was elevated in 13.2% of MCAS patients in plasma[xi].
  • 9a,11b-PGF2 was elevated in 36.8% in 24-hour urine[xi].
  • 62-100% of systemic mastocytosis patients demonstrate elevated prostaglandin D2 or 9a,11b-PGF2 in urine[ix].
  • Prostaglandins are thermolabile and begin to break down in a minutes. This can contribute to false negative results[xi].
  • Medications that inhibit COX-1 and COX-2, such as NSAIDs, decrease prostaglandin production[xi].

Leukotriene E4

  • Leukotriene E4 is produced by mast cells and several other cell types[ix] including eosinophils, basophils and macrophages.
  • A recent retrospective study of almost 200 patients found that LTE4 was elevated in 4.4 % of MCAS patients in random spot urines and 8.3% in 24-hour urine[xi].
  • 44-50% of systemic mastocytosis patients demonstrate elevated leukotriene E4 in urine[ix].
  • Medications that inhibit 5-LO, such as lipoxygenase inhibitors, decrease leukotriene production[xii].

Chromogranin A

  • Chromogranin A is produced by mast cells and several other cell types including chromaffin cells and beta cells.
  • Proton pump inhibitors can cause increased values during testing[xi].
  • A 2014 paper reported chromogranin A was elevated in 12% of MCAS patients and 63% of systemic mastocytosis patients tested[ix].

Heparin

  • Heparin is a very specific mediator for mast cell activation[ix].
  • Heparin is extremely heat sensitive. The sample must be kept on ice or refrigerated at all times[ix].
  • Venous occlusion of upper arm for ten minutes has been successful in provoking mast cell activation leading to heparin release[ix].
  • A 2014 paper reported plasma heparin was elevated in 59% of MCAS patients and 47% of systemic mastocytosis patients tested[ix].
  • A recent retrospective study of almost 200 patients found that plasma heparin was elevated in 28.9% tested[ix].

 

References

[i] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[ii] Picard M, et al. (2013). Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clinical Therapeutics, 35(5), 548-562.

[iii] Akin C, et al. (2010). Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol, 126(6), 1099-1104.e4

[iv] Valent P, et al. (2012). Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol, 157(3), 215-225.

[v] Lueke AJ, et al. (2016). Analytical and clinical validation of an LC-MS/MS method for urine leukotriene E4: a marker of systemic mastocytosis. Clin Biochem, 49(13-14), 979-982.

[vi] Payne V, Kam PCA. (2004). Mast cell tryptase: a review of its physiology and clinical significance. Anaesthesia, 59(7), 695-703.

[vii] Phadia AB. ImmunoCAP® Tryptase in anaphylaxis. Retrieved from: http://www.phadia.com/Global/Market%20Companies/Sweden/Best%C3%A4ll%20information/Filer%20(pdf)/ImmunoCAP_Tryptase_anafylaxi.pdf

[viii] Sprung J, et al. (2015). Presence or absence of elevated acute total serum tryptase by itself is not a definitive marker for an allergic reaction. Anesthesiology, 122(3), 713-717.

[ix] Vysniauskaite M, et al. (2015). Determination of plasma heparin level improves identification of systemic mast cell activation disease. PLoS One, 10(4), e0124912

[x] Zenker N, Afrin LB. (2015). Utilities of various mast cell mediators in diagnosing mast cell activation syndrome. Blood, 126(5174).

[xi] Afrin LB. “Presentation, diagnosis and management of mast cell activation syndrome.”  Mast Cells, edited by David B. Murray, Nova Science Publishers, Inc., 2013, 155-231.

[xii] Hui KP, et al. (1991). Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. Thorax, 46, 184-189.

The Provider Primers Series: Introduction to Mast Cells

Mast cells : Introduction

  • Mast cells are bone marrow derived. They migrate to tissues before maturity and remain tissue bound.[i]
  • Mast cell development in tissues is regulated by a number of molecules, most significantly stem cell factor (SCF) which binds at the CKIT (CD117) receptor. A number of other molecules, including IL-3, IL-4 and IL-10, also participate in this process.[ii]
  • Mast cells are long lived, with some living for years in tissue.[ii]
  • Mast cells are versatile actors. Their functions and granule contents are tailored to the needs of the local microenvironment.[iii]
  • Mast cells perform a number of critical roles, including immune defense against microbes and larger parasites; clotting; wound repair; tissue remodeling; angiogenesis; regulation of reproductive cycle; digestion and GI motility; pain response; participation in stress response via interaction with HPA axis; inflammatory response; and regulation of sleep and some aspects of cognition.[iv]
  • Mast cells produce a multitude of mediators which are stored in granules or produced de novo. Stored mediators of consequence include histamine; tryptase; heparin; bradykinin; serotonin; and substance P. De novo mediators include prostaglandin D2; leukotrienes C4, D4, and E4; platelet activating factor; tumor necrosis factor; interferons; and a number of interleukins, including IL-1a, IL-1b and IL-6, among many others. [iii]

Mast cell involvement in disease

  • Mast cells are involved in the pathology of many conditions, including asthma[iv]; autoimmune diseases[iv]; GI dysmotility, including post-operative ileus[v]; cardiovascular events[iv], such as myocardial infarction, rupture of atherosclerotic plaques or aneurysms, and coronary syndromes, including Kounis syndrome[vi]; cardiovascular disease; malignant and neoplastic [iv]; chronic kidney disease[iv]; cutaneous conditions[iv], including many forms of urticaria; depression and anxiety; and chronic pain[vii].
  • Mast cells are effectors in all mast cell diseases.
  • Most famously, mast cells are involved in allergy and anaphylaxis.[viii]

Mechanisms of mast cell activation

  • Mast cells are primarily activated via IgE crosslinking at the FcεRI receptor. This is the mechanism for the classic allergy model in which specific IgE binds the target allergen and crosslinks at the FcεRI receptor on the surface of mast cells and basophils. In this traditional model, crosslinking causes immediate degranulation of stored mediators and late phase release of mediators produced de novo upon activation[viii].
  • There are several other mechanisms for direct mast cell activation that are independent of IgE.
  • A number of inflammatory molecules can directly activate mast cells by binding surface receptors including corticotropin releasing hormone; substance P; histamine; cysteinyl leukotrienes; adenosine; stem cell factor; IL-3; IL-4; IL-9; and IL-33, among others[ix].
  • Substances associated with immune defense and infection can directly activate mast cells. Products derived from pathogens can activate via toll like receptors (TLR2 and TLR4), Dectin-1 or CD48. Host production of β-defensins and complement C3a and C5a can also provoke mast cell activation[ix].
  • IgG can bind at FcγR receptors on mast cell surfaces. Immunoglobulin free light chains have triggered degranulation in murine models but this has not yet been demonstrated in humans[ix].

Definition of anaphylaxis

  • The definition of anaphylaxis continues to be disputed. The 2006 NIAID/FAAN criteria detailed below have been validated and are widely used.[x]
  • Anaphylaxis is likely when any one of the following three criteria is met:
  • Criterion 1: Acute onset of illness with skin and mucosal issue involvement (hives, itching, flushing, swelling of lips/tongue/uvula) with at least one of the following: compromised airway (difficulty breathing, wheezing, low blood oxygenation); or reduced blood pressure or symptoms thereof (fainting, incontinence.)
  • Criterion 2: Two or more of the following occurring after exposure to a likely allergen: skin or mucosal tissue involvement (hives, itching, flushing, swollen lips/tongue/uvula), compromised airway (difficulty breathing, wheezing, low blood oxygenation); reduced blood pressure or symptoms thereof (fainting, incontinence); or persistent GI symptoms (cramping, abdominal pain, vomiting).
  • Criterion 3: Reduced blood pressure after exposure to known allergen.  For adults, this is <90 mm Hg systolic, or at least 30% decrease from baseline.  For children under 1 year of age, this is <70 mm Hg systolic; ages 11-17, <90 mm Hg systolic.  For children 1-10 years of age, this is <(70 mm Hg + (2x age)).  So for a child who is 8 years old, this would be <(70 + (2 x 8)) = <86 mm Hg.

References:

[i] Dahlin JS, Hallgren J. (2015). Mast cell progenitors: origin, development and migration to tissues. Molecular Immunology 63, 9-17.

[ii] Amin K. (2012). The role of mast cells in allergic inflammation. Respiratory Medicine, 106, 9-14.

[iii] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[iv] Rao KN, Brown MA. (2008). Mast cells: multifaceted immune cells with diverse roles in health and disease. Ann NY Acad Sci, 1143, 83-104.

[v] De Winter, BY. (2012). Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Acta, 1822, 66-73.

[vi] Kounis NG. (2016). Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med, 54(10), 1545-1559.

[vii] Chatterjea D, Martinov T. (2015). Mast cells: versatile gatekeepers of pain. Mol Immunol, 63(1), 38-44.

[viii] Galli SJ, Tsai M. (2013). IgE and mast cells in allergic disease. Nat Med, 18(5), 693-704.

[ix] Yu Y, et al. (2016). Non-IgE mediated mast cell activation. European Journal of Pharmacology 778, 33-43.

[x] Sampson HA, et al. (2006). Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol, 117(2), 391-397.

Patient questions: Why isn’t tryptase used to track SM progression in patients with SM-AHNMD?

Tryptase can be a useful tool for measuring progression of systemic mastocytosis. However, it is not used in patients with systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD). Patients with SM-AHNMD have systemic mastocytosis and also have another blood disorder that causes excessive proliferation of cells that aren’t mast cells. It is essentially having individual diseases that affect the bone marrow.

The reason tryptase is not tracked in patients with SM-AHNMD is because other proliferative diseases of bone marrow can increase production of mast cells. (Actually, proliferative diseases in most organs can cause increased production of mast cells). This is called mast cell hyperplasia, overproduction of mast cells. It is NOT the same as SM. A patient with no mast cell disease of any kind who has a blood disorder like chronic myelogenous leukemia or essential thrombocythemia could experience an increase in mast cells. It is not uncommon for people with conditions like this to experience allergic symptoms due to mast cell activation.

This can occur for a few reasons. The blood disorder might increase the amount of cells that could become mast cells. The blood disorder could cause increased release and production of molecules that encourage mast cell development. Mast cells are also part of the immune response and heavily involved in tumor biology. Proliferation of another cell type can be interpreted by the body as tumor formation so more mast cells can be made to address the “tumor”, whether or not it actually is a tumor..

A patient with SM-AHNMD may have a baseline tryptase before developing the second blood disorder of 30 ng/mL. (Just making up a number here). After diagnosis with the second blood disorder, a tryptase test could reveal an increase to 35 ng/mL. However, if this were the case, we wouldn’t know if the additional tryptase is coming from mast cells made by SM ramping up or as a side effect of the other blood disorder. Because we can’t tell, it isn’t used as an indicator of increased mast cell production as a direct cause of SM.

For patients with SM-AHNMD, other markers are used to track disease progression of SM. That includes checking for things like inappropriate blood cell counts and organ swelling and dysfunction (B and C findings).

Patient questions: Everything you wanted to know about tryptase

I get a lot of questions about tryptase.

Tryptase is one of the most well characterized mast cell mediators and the first to be unique to mast cells. Serum tryptase is the most well known test for systemic mastocytosis and anaphylaxis. But mast cell patients sometimes test negative, complicating their lives and care.

There are a lot of reasons why mast cell patients test negative for tryptase. One reason is that a lot of the understanding of anaphylaxis hinged upon the ability of mediators to get quickly to the bloodstream to quickly spread to various organ systems. While this does happen, not all mediators move at the same speed. Tryptase is released from granules as large complexes with other mediators, like heparin. It takes time for it to dissociate enough to be active.

Tryptase also does a lot of things and breaks down lots of things. If there are things for it to break down in the immediate environment, it will still break them down whether or not you are having anaphylaxis. Eventually, the tryptase that wasn’t used up breaking things down gets to the bloodstream. This is why the ideal time to test for tryptase in blood is about 90-120 minutes after an allergic event/severe reaction/anaphylaxis. Following severe reaction/anaphylaxis, it can take about two weeks for tryptase to return to baseline.

The reason that most patients with systemic mastocytosis have high tryptase levels is because they have more mast cells and many mast cells secrete tryptase at rest. This means that even if they aren’t activated, they will still release tryptase regularly. The reason why baseline tryptase level is such an important marker for SM is because it distinguishes mastocytosis from anaphylaxis.

However, we have learned a lot about tryptase in the last several years, and it doesn’t seem like all mast cells secrete tryptase all the time. Mast cells are heavily influenced by their environment and the cells around them. Some mast cells make more tryptase than others and some release tryptase regularly and some don’t.

About 80-90% of SM patients have a baseline tryptase over 20 ng/ml. This means they tested over 20 ng/ml on two separate occasions when they had not recently had a severe event. But not all SM patients have elevated tryptase, but that doesn’t mean they don’t have more mast cells than usual. It is possible that their mast cells are concentrated in places in the body where tryptase will be used up before it gets to the bloodstream or that it will take too long to get there for the test to catch it. There is some evidence that tryptase testing is less reliable in overweight and obese women, and I’m sure that’s true. Some mast cells live in adipose tissue and that tissue is harder for large molecules to move through, like tryptase.

Our understanding of MCAS is that there is aberrant mast cell behavior without an abnormal number of mast cells. These patients generally have repeat negative biopsies and so the assumption is that they definitely don’t have SM. But tryptase is a crummy test and I think as a community we can’t really know if they have too many mast cells until we have more robust tests. I’m not saying MCAS patients have too many mast cells, but I’m saying I don’t really trust tryptase for detection of reaction/anaphylaxis in MCAS patients or, to be frank, in anyone.

So why do we still use tryptase if it’s a crummy test? It’s not a crummy test for everything. In particular, it is a very good indicator of disease progression (ISM to SSM to ASM) in patients who have a lot of mast cells. A steadily increasing tryptase level means that there is increased proliferation and can indicate moving to a state where organ damage is more likely. So it is helpful for those people. It’s not helpful for everyone else.

Tryptase testing is not affected in a meaningful way by any medications that I can think of. Mast cell stabilizers can decrease degranulation, but tryptase can also be released in other ways, and there has not been any demonstration that mast cell stabilizers are effective enough to affect this test. Antihistamines/other meds/steroids don’t affect tryptase level.

There was a consensus paper that came out several years ago in which it was posited that an increase in tryptase level of 2 ng/ml + 2% from baseline was indicative of mast cell activation and could be used in the diagnosis of MCAS. This is not widely agreed to in the US and the data supporting this has never been published so I personally understand the reluctance of providers to acknowledge this as a marker of mast cell activation.

The other big reason why mast cell patients may test normal for tryptase is that their reactions/anaphylaxis are not mediated by a pathway that triggers tryptase release like IgE does.  IgG activation and other pathways do not always demonstrate tryptase release.

I think I got everything. If you have more questions about tryptase, let me know.