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 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.

Kounis Syndrome: Subtypes and effects of mast cell mediators (Part 1 of 4)

Kounis Syndrome (KS) is an acute coronary syndrome that arises as a direct result of mast cell degranulation during an allergic or anaphylactic reaction.

KS usually presents as chest pain during an acute allergic or anaphylactic reaction. There are three recognized variants:

Type I: Patient has no predisposing coronary artery disease.

There are two possible outcomes:

  • Coronary artery spasm with no appreciable increase in cardiac enzymes or troponins
  • Coronary artery spasm that evolves to acute myocardiac infarction (heart attack) with accompanying increase in cardiac enzymes or troponins

Type II: Patient has history of coronary artery disease. There are two possible outcomes:

  • Coronary artery spasm with no appreciable increase in cardiac enzymes or troponins
  • Plaque erosion or rupture that evolves to acute myocardiac infarction (heart attack) with accompanying increase in cardiac enzymes or troponins

Type III: Patient has history of coronary artery disease and a drug eluting coronary stent. There are two possible outcomes:

  • Coronary artery spasm with no appreciable increase in cardiac enzymes or troponins
  • Thrombosis that evolves to acute myocardiac infarction (heart attack) with accompanying increase in cardiac enzymes or troponins

A number of mast cell mediators have effects that can cause coronary spasm or thrombosis.  Beyond their direct effects, they also perpetuate an inflammatory cycle that results in activation and infiltration by inflammatory cells

Mediator Effect
Histamine Coronary vasoconstriction, activation of platelets, increase expression of tissue factor
Chymase Activation of interstitial collagenase, gelatinase, stromelysin resulting in plaque rupture, generation of angiotensin II, a powerful vasoconstrictor
Cathepsin D Generation of angiotensin II, a powerful vasoconstrictor
Leukotrienes (LTC4, LTD4, LTE4) Powerful vasoconstrictor, levels increased during acute unstable angina
Tryptase Activation of interstitial collagenase, gelatinase, stromelysin resulting in plaque rupture
Thromboxane Platelet aggregation, vasoconstriction
PAF Vasoconstriction, aggregation of platelets
Platelets Vasoconstriction, thrombosis

 

References:

Kounis Syndrome (allergic angina and allergic myocardial infarction). Kounis NG, et al. In: Angina Pectoris: Etiology, Pathogenesis and Treatment 2008.

Lippi G, et al. Cardiac troponin I is increased in patients admitted to the emergency department with severe allergic reactions. A case-control study. International Journal of Cardiology 2015, 194: 68-69.

Kounis NG, et al. The heart and coronary arteries as primary target in severe allergic reactions: Cardiac troponins and the Kounis hypersensitivity-associated acute coronary syndrome. International Journal of Cardiology 2015, 198: 83-84.

Fassio F, et al. Kounis syndrome: a concise review with focus on management. European Journal of Internal Medicine 2016; 30:7-10.

Kounis Syndrome: Aspects on pathophysiology and management. European Journal of Internal Medicine 2016.

Symptoms, mediators and mechanisms: A general review (Part 2 of 2)

 

Gynecologic symptoms    
Symptom Mediators Mechanism
Irregular and painful menstruation Histamine (H1), bradykinin Smooth muscle constriction
Uterine contractions Histamine (H1), serotonin, bradykinin Smooth muscle constriction

Increased estrogen

 

 

Neurologic symptoms    
Symptom Mediators Mechanism
Appetite dysregulation Histamine (H1), histamine (H3), leptin Dysfunctional release of neurotransmitters, suppression of ghrelin
Disorder of movements Histamine (H2), histamine (H3) Dysfunctional release of neurotransmitters, increases excitability of cholinergic neurons
Memory loss Histamine (H1), histamine (H3) Dysfunctional release of neurotransmitters
Headache Histamine (H1), histamine (H3), serotonin (low) Dysfunctional release of neurotransmitters

 

Low serotonin

 

Decreased blood flow to brain

Depression Serotonin (low), TNF, histamine (H1) Low serotonin

Disordered release of dopamine

Irregular sleep/wake cycle Histamine (H1), histamine (H3), PGD2 Dysfunctional release of neurotransmitters
Brain fog Histamine (H3), inflammatory cytokines Dysfunctional release of neurotransmitters, neuroinflammation
Temperature dysregulation Histamine (H3) Dysfunctional release of neurotransmitters, dysfunctional release of catecholamines

 

 

Miscellaneous symptoms    
Symptom Mediators Mechanism
Bleeding diathesis (tendency to bleed easily) Tryptase, heparin Participation in anticoagulation pathways

Symptoms, mediators and mechanisms: A general review (Part 1 of 2)

Skin symptoms    
Symptom Mediators Mechanism
Flushing Histamine (H1), PGD2 Increased vasodilation and permeability of blood vessels

Blood is closer to the skin and redness is seen

Itching Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Possibly stimulation of itch receptors or interaction with local neurotransmitters
Urticaria Histamine (H1), PAF, heparin, bradykinin Increased vasodilation and permeability of blood vessels and lymphatic vessels

Fluid is trapped inappropriately between layers of skin

Angioedema Histamine (H1), heparin, bradykinin, PAF Increased vasodilation and permeability of blood vessels and lymphatic vessels

Fluid is trapped inappropriately between layers of tissue

 

Respiratory symptoms    
Symptom Mediators Mechanism
Nasal congestion Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production

Smooth muscle constriction

Sneezing Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production

Smooth muscle constriction

Airway constriction/ difficulty breathing Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Increased mucus production

Smooth muscle constriction

 

Cardiovascular symptoms    
Symptom Mediators Mechanism
Low blood pressure Histamine (H1), PAF,  PGD2, bradykinin Decreased force of heart contraction

Increased vasodilation and permeability of blood vessels

Impact on norepinephrine signaling

Change in heart rate

Presyncope/syncope (fainting) Histamine (H1), histamine (H3), PAF, bradykinin Increased vasodilation and permeability of blood vessels

Decrease in blood pressure

Dysfunctional release of neurotransmitters

High blood pressure Chymase,  9a,11b-PGF2, renin, thromboxane A, carboxypeptidase A Impact on renin-angiotensin pathway

Impact on norepinephrine signaling

Tightening and decreased permeability of blood vessels

Tachycardia Histamine (H2), PGD2 Increasing heart rate

Increasing force of heart contraction

Impact on norepinephrine signaling

Arrhythmias Chymase, PAF, renin Impact on renin-angiotensin pathway

Impact on norepinephrine signaling

 

Gastrointestinal symptoms    
Symptom Mediators Mechanism
Diarrhea Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction

Increased gastric acid secretion

Dysfunctional release of neurotransmitters

Gas Histamine (H1), histamine (H2), bradykinin Smooth muscle constriction

Increased gastric acid secretion

Abdominal pain Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction

Increased gastric acid secretion

Dysfunctional release of neurotransmitters

Nausea/vomiting Histamine (H3), serotonin Dysfunctional release of neurotransmitters
Constipation Histamine (H2), histamine (H3), serotonin (low) Dysfunctional release of neurotransmitters

 

IgE-independent anaphylaxis; or, I haven’t been this excited on a Tuesday night in a long time

Mast cell patients are intimately familiar with the phenomenon of testing positive for allergies to things you know aren’t problems and negative for things that almost killed you.  If you ask any health care provider what the allergy antibody is, they will say it is IgE.  And for the most part, that is true.  But mast cell patients suffer reactions that do not demonstrate an IgE pathway to their allergies and anaphylaxis, and it is reason most of us suffer for years before being diagnosed correctly.

The idea that anaphylaxis is a function directly executed by IgE is a deeply ingrained part of western medicine.  In this model, IgE specific for an allergen binds to the allergen, and binds to the IgE receptor on mast cells and basophils, resulting in massive degranulation.

This is the classic model of anaphylaxis, with some creative license:

  1. You come into contact with something. Let’s say it’s Peanut, an anthropomorphic peanut.
  2. Immune cells called B cells think they once saw Peanut in a dark alley behind a bar. Peanut could have been waiting for a ride like any responsible peanut who has been drinking, but dark alley = shady = Peanut is trouble.
  3. The B cells make “Wanted!” posters with a picture of the peanut on it. Many, many posters.
  4. The B cells make lots of IgE to make sure every cell in the body sees the Wanted! posters. There will be nowhere for peanuts to hide. (I swear that as I was typing, I just heard the theme to the Good, the Bad and the Ugly.  I SWEAR.)
  5. Everyone knows that Peanut is a bad guy. They have seen the poster many times.  They do not need to see it again.  Do not show the poster again.  WE KNOW PEANUT IS BAD, IGE.  GO HOME, IGE, YOU’RE DRUNK.
  6. You guys know what happens next.  Peanut shows up.
  7. Someone remembers that IgE has been coming around the bar with the poster of Peanut. Peanut = bad guy.
  8. Everyone is hoping that if they tell IgE where Peanut is that IgE will leave them alone. No one really likes IgE but he is making such a big deal about Peanut and maybe Peanut is bad.  A little bad.  No one really knows but they know they do NOT want to deal with IgE if Peanut gets away.
  9. IgE and Peanut have a Western style gun duel at high noon. IgE captures Peanut by binding to him.
  10. While IgE is bound to Peanut, he also binds to a mast cell, which is like home base. IgE knows that Peanut is trouble and he is part of a Peanut gang and they are all bad, too.
  11. Mast cells deploy the tanks, duckboats, submarines, helicopters and fighter planes in the early allergy response to fight the Peanut gang. This causes massive inflammation with effects throughout the whole body.  Mediators released in the early response include histamine and tryptase.
  12. Mast cells start building more defenses and release them a little at a time later on in the late allergy response. Mediators released in the late response include prostaglandins and leukotrienes.

But we all know that it doesn’t always happen like this, because mast cell patients often have normal tryptase and IgE despite having a massive anaphylactic event, or even normal histamine or prostaglandins.

Last month, a comprehensive paper described alternative anaphylaxis pathways in mice that may be analogous to what is happening to mast cell patients having anaphylaxis that is not mediated by IgE.  That is to say, this pathway needs more research to know for sure if it is what is happening to us, but I have been watching the literature on this closely for a while and I100% think this is real.

There have now been multiple reports of the ability to induce anaphylaxis in mice while interfering with the IgE allergy pathway (either by not making IgE or the IgE receptor, or by treating the mice with anti-IgE, which blocks the IgE from binding to the receptor). Scientists found that by anaphylaxis could be mediated by IgG if the trigger was given intravenously. In particular, they were able to identify the murine IgG2b as the antibody subclass responsible.  In mice, IgG2b can cause anaphylaxis when IgE is not able to participate, at all.

The most important mediator in IgE anaphylaxis is histamine.  But the most important mediator in IgG anaphylaxis is platelet activating factor (PAF).  PAF levels have been linked with severity of anaphylaxis previously (I wrote a post about this around this time last year).  This could explain why many patients have normal tryptase, n-methylhistamine or histamine levels despite a very short amount of time elapsed from anaphylaxis. This is not a histamine show.  And maybe the reason so many mast cell patients cannot get complete relief despite taking huge doses of antihistamines is because histamine isn’t the PRIMARY issue.  (Author’s note: Please do not stop taking your antihistamines.  I love my antihistamines.  Just saying I think maybe there is something happening above histamine in these reactions.)

It’s also not just a mast cell show.  IgG can activate basophils, monocytes and macrophages, and neutrophils to release PAF.  Human neutrophils can mediate IgG dependent anaphylaxis when infused into mice.  So now we have a mechanism for anaphylaxis that is not IgE independent – it can also be mast cell independent.  Mind blowing. (Worth mentioning here that the phenomenon of mast cell independent anaphylaxis is not new or specific to IgG anaphylaxis – groups have found instances of mast cell independent anaphylaxis for almost thirty years.)

PAF levels are much higher in anaphylaxis patients than in control patients, and the enzyme that degrades PAF, called PAF acetylhydrolase, is much lower. It is important to note that binding at the IgE receptor can also produce PAF, but that also causes degranulation and release of histamine and tryptase, which seems to be absent in some patients.

To induce IgG mediated anaphylaxis, you need more allergen than for IgE anaphylaxis.  A lot more. 100-1000x more.  So in mice that have both IgE and IgG for peanut (not really peanut), doesn’t it seem like the IgE would react first to the peanut, and you would have IgE anaphylaxis?  But that’s not what happens.  What happens is that the IgG scoops up the peanut faster than the IgE can.  The IgG can block IgE anaphylaxis.  (WHAT UP MAST CELL PATIENTS DOING WAY BETTER ON IVIG?!?!)

IgG anaphylaxis in mice has been exclusively isolated to triggers administered intravenously.  The reason this fact matters is because of the frequency with which people (who don’t always have mast cell disease) have anaphylaxis to intravenous antibody treats, like IVIG, monoclonal antibodies for treating various diseases, or transfusions (which contain IgG antibodies). Treatments of this kind provide a huge influx of allergen. This pathway favors IgG anaphylaxis over IgE anaphylaxis because of how the IgG will scoop the allergen up (see previous paragraph).

As a final aside, there is also the curious fact that a group of patients with CVID (common variable immunodeficiency, a primary immunodeficiency disease) have a mutation that makes one of the IgG receptors found on cells like mast cells WAY more active.  The CVID patients with this mutation also have antibodies to IgA and experience anaphylaxis after IVIG.

I know I have gone on and on but this is the most exciting thing to happen to tryptase and histamine normal anaphylaxis patients in the last decade, at least.  There is SO much work that needs to be done.  Mouse and human mast cells are different.  Mouse and human IgG antibodies are different.  They could not induce food allergy in mice with an IgG dependent mechanism.  We need to pursue research on the role of PAF specifically in anaphylaxis patients with normal tryptase and histamine.

But now, when you tell your doctor that anaphylaxis is not always IgE dependent, you can give them a reference to a solid paper that fairly describes the findings, the caveats and the strengths of the current research on IgE independent anaphylaxis.  And it’s not just speculation. PEOPLE OUTSIDE OF MAST CELL DISEASE RESEARCH GROUPS ACKNOWLEDGE THAT THIS IS REAL.  IGE INDEPENDENT ANAPHYLAXIS IS REAL.

Boom.

Someone hold my Epipens while I make my dog dance with me.

Reference:

Finkelman FD, Khodoun MV, Strait R. Human IgE-independent systemic anaphylaxis. J Allergy Clin Immunol 2016.

 

Cardiovascular manifestations of mast cell disease: Part 5 of 5

Low blood pressure causing lightheadedness or fainting is a classic manifestation of mast cell disease with as many as 22-55% of patients having experienced it at least one. For comparison, the control group demonstrated a frequency of 5%.  Some patients experience this symptom often while others only rarely experience it or never do.

A staggering amount of mast cell mediators can induce low blood pressure; indeed, this is the reason why low blood pressure is the hallmark sign of severe allergic reaction and anaphylaxis.  Histamine can induce hypotension through the H1 receptor.  Heparin makes histamine and tryptase less susceptible to degradation, allowing longer action.

Many mediators are vasodilating, widening the blood vessels. Vasoactive intestinal peptide (VIP) is a vasodilator.  PGD2 is also a very potent in this capacity. PGE2 is not released in large amounts by mast cells, but has the same effect. Platelet activating factor decreases blood pressure in multiple ways: by decreasing the force of heart muscle contraction, by slowing heart rate and by widening blood vessels. IL-6 and nitric oxide are also vasodilating.

Some mediators lower blood pressure by their participation in the bradykinin pathway.  Bradykinin is a potent stimulator of fluid loss from the blood to the tissues, causing low blood pressure and angioedema. Heparin can serve as an initiator for the production of bradykinin. Tryptase and chymase both participate in bradykinin formation.

Mast cell medications can be very effective in increasing blood pressure by decreasing fluid loss from the blood to the tissues.  As PGD2 can be a strong vasodilator, COX inhibitors like NSAIDs that interfere with prostaglandin production can help to increase blood pressure.  Aspirin, 81-325mg once or twice daily, is sometimes recommended for adults that are not sensitive to the medication.  Early data on the use of omalizumab (Xolair) in SM patients indicates that it may prevent episodes of sudden onset low blood pressure.

References:

Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016; x:1-10.

Gonzalez-de-Olano D, et al. Mast cell-related disorders presenting with Kounis Syndrome. International Journal of Cardiology 2012: 161(1): 56-58.

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 2013; 138: 53-65.

 

Cardiovascular manifestations of mast cell disease: Part 3 of 5

Recurrent or perpetual elevation in blood pressure has been observed in multiple studies and may affect up to 31% of patients with mast cell activation disease (systemic mastocytosis, mast cell activation syndrome/disorder, monoclonal mast cell activation syndrome). Despite this high prevalence, many providers continue to believe that this symptom cannot be inherently from mast cell activation.

A number of mast cell mediators are vasoconstrictors, narrowing the blood vessels and elevating blood pressure. Histamine can both increase and lower blood pressure depending on which receptor it acts upon (H1: hypotension; H2: hypertension).

Several mediators participate in the angiotensin-renin pathway. Angiotensin II, the level of which is largely determined by mast cell mediators like renin, strongly elevates blood pressure. Chymase, involved in the angiotensin-renin pathway, can also either increase or lower blood pressure depending on concentration relative to other mediators present. Carboxypeptidase A can also affect angiotensin II level as well. Renin regulates the level of a molecule that becomes angiotensin II and can increase blood pressure this way.

Phospholipases, which help produce the molecule needed to make prostaglandins, leukotrienes and thromboxanes can contribute to either high or low blood pressure depending upon which molecule is made. Prostaglandin D2 (PGD2) is a vasodilator, lowering blood pressure; but its metabolite, 9a,11b-PGF2, increases blood pressure. (Author’s note: I personally believe this to be the reason for the rapid blood pressure fluctuations in mast cell patients, but do not have evidence to directly support this.) Thromboxane A2, a molecule related to prostaglandins and leukotrienes, increases blood pressure, as do leukotrienes.

Management of high blood pressure is complicated in mast cell patients by the interaction of common antihypertensives with mast cell activation. Beta blockers are contraindicated in mast cell patients because they interfere with epinephrine, both naturally produced and medicinally.  Use of beta blockers is a risk factor for fatal anaphylaxis.  Any patient on beta blockers that carries an epipen should also carry a glucagon pen, which can be administered prior to the epipen to increase efficacy.

ACE inhibitors interfere with angiotensin converting enzyme, which increases blood pressure through the angiotensin II pathway.  ACE inhibitors affect bradykinin levels, a mast cell mediator that is also mast cell activating.  For this reason, ACE inhibitors can increase mast cell reactivity and symptoms like angioedema.

Author’s note:  I extended this series to four posts to discuss heart failure in mast cell patients.  Following this series, I will be posting a series dedicated exclusively to Kounis Syndrome, including diagnosis and treatment.  Sit tight!

References:

Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016; x:1-10.

Gonzalez-de-Olano D, et al. Mast cell-related disorders presenting with Kounis Syndrome. International Journal of Cardiology 2012: 161(1): 56-58.

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 2013; 138: 53-65.

 

Cardiovascular manifestations of mast cell disease (Part 2 of 5)

Abnormalities of heart rate and rhythm can occur due to action of several mast cell mediators. Histamine binds at histamine receptors numbered in the order of identification: H1, H2, H3 and H4. Histamine binding at H1 receptors on cardiomyocytes (heart muscle cells) slows the heart rate, while histamine binding at H2 receptors increasing heart rate and the force of heart contraction.

As I mentioned in the previous post, histamine binding at the H3 receptor decreases the release of norepinephrine. Another mast cell product, renin, modulates angiotensin II, which can increase norepinephrine release.  Increased levels of norepinephrine triggers increases in heart rate and force of contraction.  This means that whether or not mast cell activation causes tachycardia depends largely on how much renin and histamine are released. Much less histamine is necessary to trigger the H3 inhibition of norepinephrine release relative to the amount needed to affect heart rate through H1 and H2 receptors.

Prostaglandin D2, a mast cell mediator, can also cause tachycardia.  Of note, prostaglandin D2 is not stored in mast cell granules.  It is made following mast cell activation and is considered part of the “late phase allergy response”, which can occur several hours after exposure to a trigger.

Tachycardia is a common symptom for mast cell patients.  The recommendation in a recent review article is to treat when the heart rate is perpetually over 100-120 bpm, or when it is extremely distressing to the patient. There are a number of options for treatment. As it can be caused directly by mast cell behavior, mast cell medications such as antihistamines (H1 and H2) should be adjusted for maximum effect. Renin inhibitors, such as aliskiren (Tekturna in the US), can be used to treat supraventricular tachycardia (SVT) in mast cell patients, as can angiotensin receptor blockers like losartan, valsartan and others. Patients on renin inhibitors or angiotensin receptor blockers can also decrease blood pressure.

Calcium channel blockers, like verapamil, are also an option.  The medication ivabradine treats tachycardia in patients who have a regular heart rhythm and does not affect blood pressure.  Ivabradine is not used to treat atrial fibrillation. β-blockers are contraindicated in mast cell patients because it interferes with the action of epinephrine, making patients more likely to have reactions and epinephrine less likely to treat effectively.

References:

Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016; x:1-10.

Gonzalez-de-Olano D, et al. Mast cell-related disorders presenting with Kounis Syndrome. International Journal of Cardiology 2012: 161(1): 56-58.

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 2013; 138: 53-65.

Cardiovascular manifestations of mast cell disease (Part 1 of 5)

Mast cells are present in the cardiovascular system under normal conditions both in the heart and near vasculature, often in spaces close to nerve endings.  They perform a variety of necessary functions including participating in the pathway to generate the hormone angiotensin II, which encourages an increase in blood pressure.  Mast cells in the heart and vasculature are usually positive for both chymase and tryptase in granules. Mast cells in the cardiovascular system have also been tied to a number of conditions, including atherosclerosis, arrhythmias and aneurysm.

Mast cell patients may experience a number of cardiovascular symptoms or events. 29% of SM patients and at least 20% of MCAS patients report palpitations and supraventricular tachycardia.  31% of patients with mast cell activation disease (MCAS, MMAS, SM) experience episodic or chronic elevation in arterial blood pressure due to mast cell activation. Ventricular fibrillation, cardiac arrest and Kounis Syndrome can occur in mast cell patients due to mast cell activation.  Few cases of heart failure in SM patients have been reported.

Kounis Syndrome is an acute coronary syndrome provoked by mast cell mediator release. In one series, ten mast cell patients (5 MCAS, 3 MMAS, 2 ISM) suffered acute coronary syndromes.  These patients reported “oppressive” chest pain of the type commonly seen in ischemic cardiac events.  The triggers for these events were diverse: venom immunotherapy, mepivacaine, exercise, penicillin, general anesthesia, wasp sting, metamizole and moxifloxacin.  In seven patients, the echocardiogram was normal.  In the remaining, left ventricular hypertrophy, anteroseptal hypokinesia, medioapical hypokinesia, inferoseptal akinesis, lateral apical akinesia and left ventricular ejection fraction of 40% were found on echo. Only six patients had elevation of troponin, a test commonly used to diagnose heart attack and acute coronary syndromes.

Mast cell mediators exhibit a wide range of effects on the cardiovascular and nervous systems. Mast cell mediators can affect release of norepinephrine by sympathetic nervous system, contributing to arrhythmias.  In some instances, release of norepinephrine has been linked to sudden cardiac death, although not linked specifically to mast cell patients. Histamine actually decreases norepinephrine release by binding to H3 receptors on nerve endings.

As mentioned above, mast cells participate in modulating the level of angiotensin II. Mast cells release renin, which leads to the formation of angiotensin II. Angiotensin II then binds to AT1 receptors on sympathetic nerve endings, raising blood pressure. Angiotensin II can also cause arrhythmias without involving the nervous system.

References:

Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016; x:1-10.

Gonzalez-de-Olano D, et al. Mast cell-related disorders presenting with Kounis Syndrome. International Journal of Cardiology 2012: 161(1): 56-58.

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeurics 2013; 138: 53-65.