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Lisa Klimas

I'm a 35 year old microbiologist and molecular biologist with systemic mastocytosis, Ehlers Danlos Syndrome, Postural Orthostatic Tachycardia Syndrome, Adrenal Insufficiency, and an assortment of other chronic health issues. My life is pretty much a blast.

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 4 of 5

Heart failure is uncommon in mast cell patients, but is noteworthy as a condition that involves mast cell activation.  One study of adults with SM found 12 patients out of 548 had congestive heart failure.  A small study with 18 MCAS patients found that persistent mast cell activation did not affect such parameters as systolic left ventricular function, systolic and diastolic left ventricular diameter, or shortening fraction.  These markers are often tied to heart failure. In that same study, 12/18 MCAS patients did exhibit a diastolic left ventricular dysfunction.  This defect is a sensitive indicator of changes to the myocardium, muscle around the heart and can be found using Doppler imaging. Five of those MCAS patients also showed hypertrophy in the left ventricle, a thickening of tissue that can be linked to heart damage.

Importantly, these findings were not linked to chronic heart failure in this population.  Mast cell patients should be aware that while these anatomical changes of the left ventricle may be present, there is not currently any indication that their increase the frequency of symptomatic heart failure in this population.  Mast cells are heavily involved in tissue remodeling and it is possible that local mast cell activation can lead to laying of additional tissue or scarring.  Tryptase, chymase and matrix metalloproteinases, all released by mast cells, participate in tissue remodeling and fibrosis.

Tryptase has been associated with both heart failure and atherosclerosis, involved in coronary disease and syndromes.  A number of other mediators can also contribute to heart failure, including histamine, platelet activating factor, IL-4, IL-6, IL-10, TNF, fibroblast growth factor (FGF) and transforming growth factor beta (TGFB).

Treatment of heart failure in mast cell patients is not terribly different from that of the general population.  Diuretics are often used first, including furosemide. Angiotensin receptor antagonists like losartan are good choices for mast cell patients since ACE inhibitors and beta blockers should be avoided wherever possible.  Calcium channel blockers like verapamil can be used. Spironolactone or similar medications may provide additional benefit. Ivabradine, a newer medication that works by affecting the funny current (Author’s note: Not a joke!  My favorite pathway name), is also a consideration.  Digoxin is appropriate for atrial fibrillation (afib) where other attempts to correct rhythm have failed.

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.

 

The difference between CD117+ and CKIT+

Hey, everyone –

I received a request to clarify the difference between being CD117+ and CKIT+.

CD117 is a receptor on the outside of mast cells. It is normal and all mast cells are CD117+. This is how we identify them as mast cells. If you have a bone marrow biopsy done and it says no CD117 is found, this is not because there are no mast cells there. It is because the test for CD117 isn’t sensitive enough to find those few mast cells. This is called the limit of detection (LoD).

When there is more of something present, it is easier to find it. Say I am in a field and there are five tennis balls scattered. If I walk around for a long time, maybe I will find three tennis balls. But if there is only one tennis ball to be found, I may not find it. I have less of a chance of finding it because there aren’t as many so it’s harder.

Being CD117+ is NORMAL for mast cells. It just means that it’s a mast cell. But mast cells that are constantly activated have more CD117+ on their outside membranes. Think of it like the tennis balls – if there are five CD117 receptors on a mast cell, it’s easier for the test to find one. If there is only one, the test might miss it.

CD117 is also called the CKIT receptor. It is a receptor that gives mast cells the signal to stay alive and encourage more mast cells to mature. If you get a biopsy report back and it is CD117+, then it will say CD117. The reason the report doesn’t call it positive for CKIT is historical and has to do with the fact that it was identified first as CD117 and later called CKIT because of similarities with other proteins of similar names.

When mast cell patients say CKIT+, it is a misnomer. It means that they are positive for the D816V mutation in CKIT, which is a marker for systemic mastocytosis. So being CD117+ and CKIT+ are not the same. CD117+ just means mast cell. CKIT+ (D816V) means neoplastic mast cell.

The D816V mutation changes the shape of the CD117 (CKIT) receptor and tells the mast cell to stay alive and encourage other mast cells to mature even when it shouldn’t.

Being CD117+ does not affect medication profile for mast cell disease at all. It just means it’s a mast cell. Some drugs are approved only for CKIT- patients (negative for D816V).

CD117/CKIT is a tyrosine kinase, which is a kind of protein. There are hundreds of known tyrosine kinases, CD117/CKIT is just one. Tyrosine kinase inhibitors can affect cells by blocking the signal to stay alive. Tyrosine kinases do not take up tyrosine from the environment, it has literally nothing to do with tyrosine metabolism at all.

If there any questions, ask in the comments.

Coexistence

The list of offensive things people say to patients with chronic illness is seemingly endless. Even after all this time, it still amazes me what people feel entitled to say about my health. It also still amazes me how much it can hurt.

My diseases permeate and affect every single part of my body and my life. That’s not because I’m “obsessed” or “caught up in it” or “looking for an excuse.” It’s because my body makes too many defective mast cells, defective collagen, antibodies to my thyroid, nuclei of my cells and joints, not enough cortisol, and a cardiovascular system that is pathologically incapable of maintaining stable blood pressure and heart rate. I work hard to live around the hindrance of multiple rare diseases, and I do, to a certain extent. But that’s not the same as “moving on” or “getting past it.” It’s like eventually learning to live with a roommate that leaves their hair in the drain, is always late with rent and sometimes poisons your food.

I am actively engaged in a power struggle with my body pretty much constantly. I take medication about every thirty minutes while I’m awake and continuously overnight. I plan every part of my day, including when I have to go to the bathroom. I identify triggers I may encounter and try to minimize exposure.

One of the most important ways I reduce exposure to triggers is by communicating them to the people around me. In situations where people know me and/or I am reliant upon them to care for me, I try to educate as much as possible. Otherwise, I just give my elevator speech: “I have a rare blood disorder that causes me to have severe allergic reactions to things I’m actually not allergic to. I have hundreds of these false allergies.” Sometimes I do it to avoid confusion, sometimes because I don’t feel like talking about my health and sometimes because I know that what I say won’t change their behavior.

I rarely eat in restaurants and when I do, it is because I have talked to the chef (usually ahead of time) and identified a safe meal for me. Even when I have done this, there can be misunderstandings that require my food to be sent back and made again. Even outside of restaurants, I prefer not to eat food that wasn’t prepared by me or someone I trust. There is too much risk.

People often don’t understand how easy it is to unintentionally contaminate my food. They sometimes think the amount of an ingredient is too small to elicit a reaction and therefore not worth the trouble to make it without. And then there is the biggest risk of all: the people who want to “test” me and see if I’m “really allergic.” They think it’s too much of a strain to just accept that if I say I need something prepared a certain way that it is necessary.

Or worse, they believe we can be sickened in the way we say, but feel absolved of social responsibility.  That society should not have to change to protect the few and neither should they.

When I am trying to explain the sort of things people like me experience regularly, I ask them to first think about pregnancy. Pregnant women observe a number of restrictions to keep themselves and their babies safe, such as avoidance of certain foods and medications, regular medical care, and avoidance of particular physical activities.

You know what I almost never hear people say to pregnant women?

“Why do you keep talking about being pregnant? Can’t you focus on something else?”

“It’s not healthy to talk about being pregnant all the time.”

“It’s probably not that dangerous, you should just try it.”

“I have never heard of that, I know lots of pregnant women and they say doing [triggering thing] is fine.”

“You’re not pregnant, you don’t even look pregnant.”

“You should give up your seat to that person, you don’t look like you need it to me.”

“Have you ever tried just not being pregnant?”

“Pregnancy is a mindset.”

“If I [make it without triggering ingredient], I’m going to have to cook your meal separately. Is it really worth it?”

“It’s only a little alcohol.”

“Why do you go to the doctor all the time?”

“Why would you go to the hospital for a tiny thing like that?”

“Well, it’s obviously your fault that you’re having pregnancy complications because you did [unrelated thing].”

“Your pregnancy is too much of a pain in the ass of us.”

“You can’t expect us to change things just to make it safe for you.”

“You would probably feel a lot better if you would just lose some weight.”

“You don’t need to listen what your doctor says, they are shills for Big Pharma. My cousin took [current popular panacea] and they did way better on it.”

So why is it okay to say things like this to people like me who are sick? If you replace “pregnant/pregnancy” with “chronically ill/chronic illness,” every single one of these things has been said to me many times over.

I’m a pretty brassy woman. It is not easy to embarrass me or make me uncomfortable. Except in this way. Requiring the assistance of people I don’t know well and don’t trust is inherently disarming and leaves me vulnerable. When I have to tell someone that I can’t eat that/go there/commit time to something worthwhile, I have to steel myself. I need to be safe but I also need to feel like I’m not a burden and an outsider.

I don’t ask most people to help keep me safe from every trigger I have, I just ask them to keep me safe from the worst ones. Once you start listing things, people either assume you are being dramatic or lying; or they realize you aren’t, but just don’t care. They might care that you’re sick but not enough to alter their routine in small ways.

We are not inventing our triggers to make your life more difficult. We are not pretending to be sick to get “special treatment” and are not just being “picky.” We are not sick because we don’t want to get better. We are struggling to make it through every day without triggering a reaction that could hospitalize or kill us.

Last night, my mastsister Addie was exposed to something that many people refuse to believe can actually trigger anaphylaxis.  She was not even in the same room as the trigger.  She need two doses of epinephrine, multiple doses of IV Benadryl, IV SoluMedrol and fluids.  She was sick for hours and is recovering today.

Addie asks people to help keep her safe

Please take our triggers seriously.  Please take our disease seriously.  People die from anaphylaxis every year.  In some cases, it could have been avoided if their allergies were taken seriously.

We are not telling you that the world needs to accommodate us in every way. We are asking you to help us live in it.

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.

Neuropsychiatric features of mast cell disease: Part 2 of 2

Mast cell activation can induce neuropsychiatric symptoms. Degranulation has been linked previously to headache. It is possible that peptidergic and cholinergic neurons receive mast cell mediators and that this plays a role in headache pathology.  TNF is speculated to participate in depression.  Histamine may cause memory deficits, although there is conflicting information on this topic. Some patients have improvement in neuropsychiatric symptoms with antihistamines.

Mastocytosis patients who have GI and neuropsychiatric symptoms often have low serum serotonin.  Tryptophan is a precursor to serotonin. Plasma tryptophan is also often low in mastocytosis patients, while plasma IDO1 (indoleamine-2,3-dioxygenase 1) activity is higher. IDO1 breaks down tryptophan through an alternate pathway that does not form serotonin. In this pathway, IDO1 breaks down tryptophan, forming kynurenic acid and quinolinic acid.  The accumulation of these substances could explain the fatigue and cognitive impairment in mastocytosis patients.  Low tryptophan and low serotonin in this population were associated with perceived stress and depression.

Treatment of neuropsychiatric symptoms in mast cell patients can include a variety of medications.   SSRI medications can reduce fatigue and depression in some inflammation models.  Some mast cell patients take these medications, usually with low starting doses in case mast cell degranulation in these people has conversely led to higher serotonin levels.  Bupropion, SNRIs and tricyclic medications are also commonly used for depressive symptoms in many chronic illness populations.

Some tricyclic antidepressants have antihistamine properties, with doxepin being a common choice.  Another tricyclic, amitriptyline, can inhibit release of mast cell mediators. Mianserin and mirtazapine can be prescribed for insomnia but also have antihistamine properties. Aprepitant could potentially be used in treatment of depression and cognitive impairment in mastocytosis and MCAS patients. Prochloperazine also decreases mast cell mediator release. Amantadine has improved depression and fatigue symptoms in multiple sclerosis patients. Inhibition of TNF with infliximab has improved depression in patients with high levels of inflammation.

Kynurenic acid, formed in the alternate tryptophan breakdown pathway described above, can block acetylcholine receptors, causing neurologic symptoms.  A7 agonists like nicotine could potentially overcome this effect.  Quinolinic acid binds at the NMDA receptor, cause neurologic symptoms.  Ketamine, an NMDA antagonist, can produce significant improvements in depressive symptoms in treatment resistant depression. As quinolinic acid is typically present in higher levels than kynurenic acid in mastocytosis patients, ketamine might offer a treatment for these patients with depression and high perceived stress.

Masitinib, a tyrosine kinase inhibitor, was shown to decrease depression, anxiety and cognitive difficulties in a significant amount of mastocytosis patients. Mindful meditation may also help patients to lessen activation caused by psychological stress and therefore decreasing biological stress.

References:

Georgin-Lavialle S, et al. Mastocytosis in adulthood and neuropsychiatric disorders. Translational Resarch 2016; x:1-9.

Georgin-Lavialle S, et al. Leukocyte telomere length in mastocytosis: correlations with depression and perceived stress. Brain Behav Immun 2014; 35: 51-57.

Moura DS, et al. Neuropsychological features of adult mastocytosis. Immunol Allergy Clin North Am 2014; 34(2): 407-422.

Moura DS, et al. Depression in patients with mastocytosis: prevalence, features and effects of masitinib therapy. PLoS One 2011, 6: e.26375.

Moura DS, et al. Evidence for cognitive impairment in mastocytosis: prevalence, features and correlations to depression. PLoS One 2012, 7: e.39468.

Smith JH, et al. Neurologic symptoms and diagnosis in adults with mast cell disease. Clin Neurol Neurosurg 2011, 113: 570-574.