MGC wrote on 01/07/13 at 13:37:36:



Hi Gail!   I´ll talk with the Drs about the norepinephrine, thanks for the suggestion.   I have shown high cortisol a couple of times when I was in the beginning and not on constant antihistamines but once I got on them, then I had a means of cutting the crisis and it was not taking my cortisol up to higher levels even though I get hypertensive.  

Gail, I spoke with Dr. Afrin a little while back about an unusual finding in my sister.   She appears to be MCAS and she´s also beginning to get hipertensive during reacting, like me.  She´s trying to get doctors to investigate her.   But at least she is getting some attention, which she has not been able to get since she was not showing anything altered before.

I wrote to Dr. Afrin to ask him as to the elevated ferratin levels my sister is showing.   This is a finding which is seen on hemochromatosis patients will show, and since this is something which could be vaguely considered within the "flushing" disorders, it could be a long distant differential diagnosis which would need to be considered and thus ruled out.    Yet it is due to the valid suspicion by the Harvard doctors who are studying my family that my sister is suspected for MCAS and she has a history of severe anaphylaxis and other pseudo-allergic reactions which reinforce the suspicion.   She is showing the same autoimmune profile my son is showing - raised ANA, raised Rheumatoid Factor, but normal Rose Waaler and hypothyroidism and Hashimotos.   She's not been tested for tryptase but my son has and he has a 2.6ng whereas mine is 4.6ng and another son of mine has a 5.5ng.  From all likelihood my sister will have a tryptase which is below 13ng.  Yet she has osteoporosis and the MC mediator release is obviously affecting her bones.  

So, when my sister told me this, knowing that masto is in all likelihood the problem I asked Dr. Afrin if masto could raise the ferratin levels like this.   He said YES!  It could be a direct cause of the abnormal mediator release.

Gail, according to Dr. Afrin, you have a definite level of dysfunctional mediator release and that dysfunctional mediator release is going to create a chain reaction of other chemicals throughout the body which could be personalized to your genetic makeup.   I don't have the same ferratin levels my sister has and they're totally normal.  I don't have the RA markers nor does my other son.  This is the incredible quandry the doctors face with all of us, we are each such individual cases that it's hard to say what our bodies are going to do!   You could indeed have high NE levels and it still be masto as the cause of it.   And with a raised tryptase like yours there is NOTHING else you are going to have to take it that high, especially if you are not showing any signs or symptoms of a myelodyplastic disorder or are in end stage kidney failure of full of worms!!   Tryptase to that level on a baseline reading - two to be exact, is without a doubt diagnostic for systemic mastocytosis.  It's on the WHO criteria list as one of the 3 minor findings.   Your abnormal MCs are hidden somewhere, but here's the challenge, for some of us it's diffused for others its concentrated in a focal area.   My son has them in his intestines, but we can't find mine anywhere!   And yes, believe it or not you could have selective release of mediators and you may not be releasing histamine in quantities which are important enough to see all the time and they may only be released during a crisis event.   This is why the authorities will ask us to have our mediators - prostaglandins, histamines, typtase, heparin and more if it can be done, as baseline and another as crisis levels and there are times they will do this repeatedly because it is well know that these mediators are hard to catch and that the exams can be totally wrong or give off false negatives.

You see, Gail, your having normal levels doesn't mean you are not releasing histamines. You are.  It just may not be chronically, but occaisionally.   But, I'm willing to bet the test could be a false negative and until you've had about 3 or 4 readings with a consistent finding, then you can't just presume it's not there.     And yes, just as you said, you could indeed have a hyperadrenergic response going on and that the NE is indeed an indirect cause of the MC mediator release.   And I don't believe that tryptase comes from any other cell but the mast cell, so having that high reading is as I said diagnostic for SM.  



"Another person wrote to me about False Negative Test Results. I do understand about both False Negative and False Positive results, and hope others do as well. What convinced me my Histamine Test results were accurate, however, is my own reaction to Antihistamines. I was not able to take the Zertec and Zantac combo that many recommend, although I did take Claritin and Pepcid for some time before recently stopping both. I do, however, continue with Clonidine, Cromlyn Sodium, Hydroxyzine (for sleep only), and have recently started Aspirin at a higher than usual dose.

My point here, is that we may well have different symptoms, and we need to medicate our own symptoms. This difference is not unusual if you think about it. Systemic Mastocytosis will cause different symptoms than  TMEP for example."  


Okay, so let's address this issue about your antihistamine intolerance.   From what I have heard that Dr. Castells has told other patients, tolerating antihistamines is a major indicator that you do have MCAS and that the intolerance of them is suggestive that there is some other issue and not a MC disorder going on.

Now, that being said, I honestly don't think that you are correct in your correlating a lack of a raised histamine level and the reason for your intolerance to antihistamines, Gail.   The reason why is this, although some of us do not have raised levels of histamines, the use of antihistamines is still needed in most masto patients, but it doesn't always have to be the H1 and H2 combination and sometimes it can be only the one or the other.  It often depends upon where you are having the most issues.  But even then, they are considered the base of our treatment and that has been held up in all of the MCAS diagnostic papers which have been coming out since 2010.  But this is because of several reasons.   First it could be that you are releasing histamines only during a crisis and again, the reason why histamines and the other mediators need to be measured at baseline and at a crisis and several times over to confirm the readings.   Histamine tests are notoriously easy to mess up, thus the theories of false negatives.   But again, you can be releasing only tryptase and not histamine and the reason why is because the mast cell has been discovered to do selective release of its mediators!!!   It can release it when it chooses or has been signaled to release it and when it choses or has been signaled to release it.  All of this depends upon genetics and cell signalling and this is so very brand new that the doctors don't understand it all.  I know of one patient whose only raised mediator was prostaglandins and I've read one article by Dr. Butterfield where the patient had raised prostaglandins and normal histamines and those patients were put on aspirin treatment to counteract the prostaglandins and on H2 blockers and not H1 and thats because they had gastric issues.   This is valid.  

There may be another reason why you are intolerant to the combo and this would be also my issue.   I'm not intolerant to the h1 - h2 combo, but according to my dermatologist, IN SOME PATIENTS this combination creates a beta blocker affect which in turn causes the heart to beat incorrectly - arrythmias.   She has taken me off of my antihistamines several times taking only H1 for a while and then switching to H2 for a while.   I can tolerate being off the H2 but not the H1 blockers.  I need them too much cause otherwise I begin itching and sneezing and having tons of fun, but without the H2 I notice very little difference.   This could be your issue too.   You see, having the beta blocker effect created by the antihistamines isn't good.  This is because our body NEEDS the histamine to function properly.  The heart is FULL of MCs and this is where Kouris Syndrome comes into play and why some patients will even end having a heart attack while they are in anaphylaxis!!  This is all due to the overload of the histamines during anaphylaxis.   But with the betablocker affect I believe it will create either arrhythmias or bradicardia.   But whatever it is, in being on ONLY one of the blockers, this will no longer create those issues.  

So, there are many reasons why you may be having these issues, Gail and it's not because your histamine levels are low.    So, when you look at your meds, the fact that you are taking both a MC stabilizer and hydroxizine this may be enough for you.   I'm taking only Loratadine at the moment!   I am amazed at this fact for it shows that I've gained a lot of improvement from 2 and 3 years ago!!  I'm in need of singulair, but I'm managing without it and the omeprazol is keeping my tummy happy.  
So, Gail, you are right, there are those who may not need the high doses of antihistamines, as you are saying, but to correlate these with NE and other mediators is not really a good thing to do for those mediators are an indirect result of MC activation and that could be just part of the cascade of chain reacting which the dysfunctional MC release is creating.   And to be intolerant of the antihistamine combined therapy doesn't necessarily mean that your histamine levels are low or that you are intolerant to the meds themselves, but that there can be other issues that the combined treatment is creating which you can mistake for intolerance.

This is why we always, always encourage patients here to work WITH their doctors.  There is so much that we just don't understand about medicine due to our lack of proper schooling and then experience to balance it all off.   You've done a great job studying Gail and I'm proud of you, but be careful, Dear, because we patients can fall into that trap of feeling too secure in our gained knowledge.   I've been teaching English to some doctors lately and since I need to work their ability to speak with other doctors in English I have to speak with them about medical information.  It's been really great to be able to take advantage of our classes in order to gain more understanding, and the more I am learning the more stupid and even foolish I feel in realizing how much MORE I need to learn!!!  When I was speaking with one of my students about lipothymia and what it was she told me that this was a group of symptoms which mimic anaphyalxis and is seen with pulmonary embolism patients!!!    This is what was suspected of me following my histerectomy and this is what got me put into the ICU for 2 days when all along it was anaphylaxis!  I've never come across this word in my journeys and when she began listing off the symptoms for pulmonary embolism I was shocked and then she said there are perhaps 60 different causes for PE alone when related to surgery and another 50 or so when it is a clinical cause!!!   She's got med school, clinical and residency under her belt with 25 years of practicing medicine on top of it!!  I feel like a fool next to her when I see just how complex and incredible it all is!!!   And when I begin to realize the complexity of it all, the more I realize that I MUST have doctors helping me to keep it all balanced and especially when it comes to taking my meds!   The more I learn, the more I see how little I know!!

So, this is why here on this site we ALWAYS ask members to speak with their doctors in regarding their cases and any choices they are making towards their meds.  There are so many things we just don't understand, no matter how much we study, that go be without that support is dangerous.  

So, yes, this thread you began is excellent, but we need to temper it in saying that patients need to work with their doctors, as partners, asking their doctors to be partners in their health care.  Yes, patients need to study and to learn for it helps them take better care of themselves as well as renews their sense of control over their lives, but when it comes to living with masto, we must not go it all alone - doctor support is a must.


I hope I've helped, at least a bit.

Lisa

Probably should have looked at my genetic info more before I started this thread, but better late than never, as the saying goes. Leaving this info particularly for those with H POTS.

Defects in SLC6A2 are a cause of orthostatic intolerance (OI)[1]This link leads to a site outside Genetics Home Reference.. OI is a syndrome characterized by lightheadedness, fatigue, altered mentation and syncope. It is associated with postural tachycardia. Plasma norepinephrine concentration is abnormally high.

http://ghr.nlm.nih.gov/gene/SLC6A2

Gail

This reply is from Lisa (Forum Advisor/Moderator), who is unable to post right now. This post will be relayed in 2 separate posts:

PART 1

Yes, Gail, I see what you are saying, and what you are saying makes sense, but I don't think you're quite understanding what I'm trying to say to you.   You are saying that the histamines, in your case, are not an issue since they are not at elevated levels.   Yet what you are saying is not the root cause of the problem here - the root cause you and I both have is a MC disorder, a dysfunctional, genetically damaged mast cell. Histamine is not what is driving the alterations of the high NE but the dysfunction of the mast cell itself is the problem.
 
You see, the MC is chock full of mediators, various mediators and they in turn create chemical chain reactions in millions of ways throughout the body including methylation or demethylation, which is one of things you are focusing on.  

What it seems to me that you are not understanding is that when you have a defective, dysfunctional mast cell, which is unable to function properly, it means that it's dysfunctioning in a great many ways.   Cells speak with one another.  It has been proven that the MCs are capable of selective mediator release.   If a dysfunctional MC is not receiving the right signals or instructions or if it's misreading them or if it itself choses to release whatever whenever it wants to release at the wrong time or the wrong amounts or not enough when it should be more or the wrong mediator for the wrong situation, or its calling into play other cells and forcing them to function when they really aren't needed then any one of these factors or responses is going to create a huge cascade of chemical reactions further down the line! Were not talking about just the direct result of the MC mediators, but also the great many INDIRECT reactions which are chain reacted by the direct mediator release.

If you will notice, the authors of this second article openly state, " may constitute a mechanism of POTS".  This means two things, they are not certain, and that they are looking directly at POTs, not at MCA itself.   Until you have a masto doctor looking at POTS you are not going to get a really clear view of the mechanisms here.  Masto patients have a known dysfunction of their MCs, but the patients they may be looking at could or could not have this going on and if they purposefully checked for masto and made sure those patients were outside of the study group then you still will not have a good idea of what is happening within a masto patient.   In speaking with Dr. Afrin he has helped me see the incredibly HUGE consequences which a dysfunctional mast cell will create with their innumerable chemical chain reactions.   So, your NE alteration may not be a direct result of MCA but could easily be an indirect result, one of the chain of reactions which your dysfunctional MCs are creating - the methylation problems could be a result of this but then it could be a comorbid, parallel issue adding to your "fun"!   But in working with doctors who haven't any REAL understanding of the mast cell itself you are going to get doctors saying all kinds of things which can totally miss the mark.   I'm not saying that they are not good doctors and fully correct in their understanding as according to the research in that area, but the study of the MC itself is research which has only really begun to be considered within the past 10 years or less.  Until recently the only REAL research into mast cells was that of mastocytosis and only those doctors were the ones who really understood mast cells, their functions and their mediators.   Now that researchers are looking at the MCs in regards to other pathologies, you have a larger group of researchers, but in truth only those researchers are understanding the MC and their mediators and how they behave and function.  

Dr. Castells will tell you, very few doctors understand mast cells.  They aren't taught this in med school because it's still only in research. It takes TIME and INTEREST for this kind of information to reach the university levels.  

(See next post for Part 2)

So, again the issue isn't the histamine relase causing the altered NE, it's the defective MC causing irregular MC mediator release which indirectly generate irregular NE release.

Lisa, let's try to clear up this misconception first. I tried before, but it didn't work it seems. I do not think  that Histamine is/should cause the NE. And conversely, if no histamine, then no NE? I am not sure what I said to cause you to believe this. If you will point me to whatever it was, I will try to correct it.

As to MCs causing high NE, that is the sticking point. As I have said before, I am waiting for something to be published on this. There has been nothing as far as I know.

If you will notice, the authors of this second article openly state, " may constitute a mechanism of POTS".  This means two things, they are not certain, and that they are looking directly at POTs, not at MCA itself.  

True enough, and if you will notice, when Vandy published the paper that really brought these issues to the notice of some, they said:

With regard to the pathophysiology underlying the association between POTS and MCA, we propose a positive feedback loop by which MCA, with the subsequent release of vasoactive mediators, may contribute to vasodilation, reflex sympathetic activation, central volume contraction, norepinephrine release, and orthostatic intolerance (Figure 4). Conversely, our results indicate that exercise can lead to MCA, presumably through sympathetic activation.

So, researchers research. They propose. They speculate based upon their findings. They present findings, which serve a springboard for other research until they find the cause. At least that is the way I understand this.

And speaking of Findings, I don't think we can ignore the findings of this most recent paper. They say:
The expression of norepinephrine transporter was lower in POTS patients compared with healthy volunteers. In the absence of altered SLC6A2 gene sequence or promoter methylation, this reduced expression was directly correlated with chromatin modification

I didn't see any exception in the paper which means all the POTS patients had the reduced expression of the gene.  And since this gene has already been looked at before and found to be associated with POTS, I will bet this paper will have some weight in the research community.

So again, unless you are reading research of researchers who are studying the MCs involvement in pathologies or unless you are reading research based upon masto patients, you are not going to get a clear picture of what the mediators are doing there.

But Lisa, I could say the same about H POTS! Most Drs, if they have even heard about POTS, think of the most common type. If one starts taking about POTS, that is what they believe the person is speaking of generally. However, H POTS is the least common, most rare POTS with some unique issues.

And to again speak about this last article, you need to see that there can be more than one genetic defect on a patient, that the genetic defect on the MCs can couple together with the genetic defect in other areas of the body.

Yes, been reading some here:

http://severus.dbmi.pitt.edu/wiki-pi/index.php/pair/view/6804/6530

Gail

I'm glad you have had a smile, Deborah. If anyone has any popcorn, I could eat some myself.  

Gail

I have now identified a snp in my genetic data which indicates I probably have Ehlers Danlos. The risk allele located on this snp is 'A'. I have A,A. These are generally of Autosomal Dominance inheritance.

So, I now have evidence of (in order of discovery) H POTS, Mast Cell Disease, and EDS. My problem is that I simply cannot understand how Mast Cells could determine whether I would inherit one or two As, or any at all for that matter, for example. I am open to possible explanations, however.

Gail

A recent paper reported findings of inherited, elevated Tryptase, POTS, and Connective Tissue Disorders in some families....

Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities

"Gastrointestinal manifestations, whether chronic or episodic, were another prominent feature seen in 28 of 33 subjects with increased tryptase levels; these included eosinophilic gastrointestinal disease, gastroesophageal reflux disease, tenesmus, fecal urgency, irritable bowel syndrome, and diarrhea. Atopic symptoms were present in 31 of 33 tryptasemic subjects, with environmental allergies and asthma being reported among 28 of 33 affected subjects. Connective tissue abnormalities were present in 23 of 33 subjects with increased tryptase levels from 8 of 9 families, and chronic musculoskeletal pain was present among 11 of 33 tryptasemic subjects from 6 of 9 families. Autonomic dysfunction, manifesting as postural orthostatic tachycardia syndrome, was reported in 10 of 33 affected subjects, and a neuropsychiatric diagnosis was present in 17 of 33 affected subjects (Fig 1). Each of these 5 clusters of clinical characteristics (cutaneous, connective tissue, gastrointestinal, atopic, and neuropsychiatric) were independently and significantly associated with increased tryptase levels (Fig 2, A). For additional clinical characterization of the families, see the Results section in this article's Online Repository at www.jacionline.org."

http://www.jacionline.org/article/S0091-6749%2813%2901924-6/fulltext

Conditions that can mimic Mast Cell Disease, from a paper authored by Drs Theoharides, Valent, and Akin.  

http://www.nejm.org/action/showImage?doi=10.1056/NEJMra1409760&iid=t01

NEJM Blog..

http://blogs.nejm.org/now/index.php/mastocytosis-and-related-disorders/2015/07/1...

Gail