MCAD diagnostic mediators

[Muon]

Votes can be changed. u= urine, ru= random urine, 24u = 24 hour urine

If you haven't been tested for any of the above parameters then only select the last option.

Selecting one option, like tryptase normal, implies that you only have been tested for tryptase and nothing else (it reflects in the total voter's count).

The diagnostic parameters run from top down to Factor VIII. The supportive cytokines which are used in conjuction with the diagnostic parameters for support and can't be used for diagnosis alone (they could be from other sources). Factor VIII is experimental at this point in time.

There are more MC mediators that can be used as support. If there is one elevated then use the 'conspicious laboratory' option. For example: VEGF. See list of MC mediators (not complete): https://poiscenter.com/forums/index.php?topic=3236.0

There is also a difference in sensitivity between plasma, u and 24u measurements: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341697/table/T6/

Many histamine metabolites are in the poll because multiple enzymes are responsible for degradation. If one enzyme is inactive you will get an accumulation in one of the other metabolites.

"Histamine, or ?-aminoethylimidazole, is produced from the amino acid precursor histidine by histidine decarboxylase. Its action is terminated by metabolic breakdown, which involves conversion to N-methylhistamine by histamine-N-methyltransferase and to N-methyl imidazole acetic acid by MAO or to imidazole acetic acid by diamine oxidase. "Ref

Figure

[Clues]

Muon, just a heads-up about a related issue: My dermatologist called me up with the results from a skin biopsy taken from one of many skin lesions that made my endocrinologist suspect Mastocytosis. The test was negative for both Mastocytosis and MCAS according to the dermatologist. I was surprised that they could determine the absence of any MCAD with certainty from a skin biopsy alone. I'm heading back to his colleague (the endocrinologist) in September for a follow-up, will ask what they looked for in the biopsy specifically.

[Muon]

That's the first time I heard about MCAS being ruled out by skin biopsy.

[Muon]

Here is a refresher about the current diagnostic criteria for MCAS:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4903110/table/Tab3/

Major criterion consists of mostly chronic non-specific multisystem symptoms of generally inflammatory ± allergic theme often provoked by triggers.

Clinical representations are extremely diverse: Table 1, potential manifestations of mast cell disease

[Clues]

Here is a refresher about the current diagnostic criteria for MCAS

Thanks a lot Muon. I don't know what he looked for in the biopsy, but yeah based on these documents it seems very unlikely you'd be able to conclusively rule out MCAS based on a single biopsy.

Salient quote:

Many factors routinely confound
accurate testing (40). Negative initial testing does not
refute a presentation suggestive of MCAD, and repeat
testing (ideally when particularly symptomatic) often
proves diagnostic.

I've forwarded both links to the dermatologist.

[Muon]

Discussion about the diagnosis of MCAS. Diagnosis of mast cell activation syndrome: a global “consensus-2”

"The proposals differ, too, in the laboratory criteria they consider. The consensus-1 proposal asserts (though seemingly without evidence) that a rise in serum total tryptase by “20%+2” ng/mL is a preferred marker of MCA, though if a patient cannot be shown to have “20%+2,” then elevations in a few other relatively MC-specific mediators can be considered diagnostic. These other mediators include prostaglandin D2 (PGD2) or its immediate 11-beta-PGF2alpha metabolite, and urinary histamine metabolites [generally taken to be just N-methylhistamine (N-MH) as N-methylimidazolacetic acid (MIMA) is no longer readily testable at clinical laboratories, at least in the United States].

The “consensus-2” proposal states that levels of a slightly wider range of mediators relatively specific to the MC [tryptase, chromogranin A (CgA), heparin, PGD2, histamine, N-MH, 11-beta-PGF2alpha, and leukotriene E4 (LTE4)], which rise above their normal ranges can be taken as diagnostic laboratory evidence of MCAS in the proper clinical context of otherwise unexplained chronic multisystem issues of generally inflammatory±allergic±dystrophic themes. Like tryptase, heparin is highly (though not perfectly) specific to the MC [58], and some published research now suggests an elevated plasma heparin level likely is the single most sensitive marker of MCA, with approximately 80% of patients clinically demonstrating symptoms consistent with MCA showing increased levels of plasma heparin when measured using a sufficiently sensitive assay [58].

In clinical practice, the biological and logistical challenges of measuring heparin need to be addressed to ensure accurate results. CgA is a known product of the MC [59], [60], and if the few other diseases known to produce elevated chromogranin A (heart or kidney or liver failure, proton pump inhibitor use, neuroendocrine cancer, chronic atrophic gastritis) can be reasonably confidently excluded in a patient with symptoms consistent with chronic aberrant MC mediator release, it seems reasonable to consider that an elevated serum CgA level likely is stemming directly from the aberrantly activated MCs.

PGD2 is produced by several types of cells [61], [62], [63], [64], [65], [66], [67], [68], [69], but the MC produces roughly a thousandfold more PGD2 than any of the other types of cells [70], [71], so when an elevated PGD2 level – in serum and/or urine – is seen in a patient with symptoms consistent with MCA, it seems most likely that the elevated PGD2 level is dominantly sourced from dysfunctional MCs. 11-beta-PGF2alpha is the principal immediate metabolic product of both PGD2 and PGE2 [72], [73], [74]. Although the MC is known to bear receptors for PGE2 [75], [76], [77], it appears to produce only low levels of PGE2 [78] and does not appear to increase PGE2 production in inflammatory conditions [79], so it is possible that elevated levels of 11-beta-PGF2alpha may be rooted in activation of cells other than MCs, which are producing elevated levels of PGE2 (e.g. endothelial cells [79]).

Yet, when an elevated level of 11-beta-PGF2alpha is seen in the context of symptoms more consistent with MCA than other processes, it seems reasonable to consider that the elevated 11-beta-PGF2alpha level is sourced primarily from dysfunctional MCs. More recently, it has been suggested that 17-beta-PGD2alpha is the best of the PGD2 metabolites to measure in seeking evidence of MCA, but this test is not yet routinely available at any commercial clinical laboratories [80]. Histamine is produced by the MC and a range of other cells [81], and it is acknowledged that histamine, like tryptase and CgA, can be elevated in a range of diseases and pathologic states.

Yet, again, when histamine is found elevated (in whole blood, serum, plasma, or urine) in the context of symptoms more consistent with chronic aberrant MC mediator release than any other known pathologic process, it seems reasonable to consider that the elevated histamine level is sourced primarily from dysfunctional MCs. Via histidine N-methyltransferase, N-MH is the principal immediate metabolic breakdown product of histamine filtered by the kidney into the urine [82], [83], but given the range of possible cellular (and even dietary) sources of histamine, it would seem no more feasible to pinpoint the source of an elevated N-MH on MCA than on any other process producing an elevated level of histamine.

Thus, we again note the importance of context in interpreting relevant findings in an MCAS patient and assembling an overall clinical picture more supportive of this diagnosis and less supportive of any other. With the possible exceptions of heparin and tryptase, it simply is not possible at present to identify the precise range of cellular sources for each of the mediators presently proposed for testing in one MCAS diagnostic proposal or another. Therefore, it would seem to be unnecessarily restrictive to exclude consideration of, say, histamine testing or CgA testing simply because one can never be perfectly sure that such mediators are dominantly MC sourced.

Identification of other mast cell mediators which might have utility in diagnosing MCAS is an area of active investigation (e.g. [84], [85]), but questions remain regarding whether such mediators (e.g. interleukin-1beta [84] and interleukin-6, interleukin-31, tumor necrosis factor, or vascular endothelial growth factor [85]) are “sufficiently” specific to the MC to warrant their having significance vis-à-vis a diagnosis as important as MCAS. It is possible that some MC mediators, while being of insufficient specificity for diagnostic purposes, may nevertheless eventually demonstrate utility for therapeutic efficacy monitoring purposes in at least some MCAS patients, i.e. in at least some variants of MCAS."

[Clues]

Wow this is awesome Muon. A consensus in the medical community should make it easier for myself and others to insist on a proper diagnosis.

[Clues]

Muon, I had a response from my dermatologist. He claims that the absence of mast cells in the skin biopsy almost rules out MCAS, but not completely. Looking at the suggested diagnostic criteria from one of the papers you posted, they do mention excessive mast cells, but not in the skin. (I'm assuming "extracutaneous organ" means any organ except the skin?)

Multifocal or disseminated dense infiltrates of MCs in marrow and/or extracutaneous organ(s) (e.g., gastrointestinal or genitourinary tract)

[Muon]

Looking at the suggested diagnostic criteria from one of the papers you posted, they do mention excessive mast cells, but not in the skin. (I'm assuming "extracutaneous organ" means any organ except the skin?)

It sounds like your dermatologist is clueless. Correct, that's because increased MC numbers aren't found in the skin of MCAS patients. They are not commonly found to be increased in bone marrow but relatively more often in the gastrointestinal or genitourinary tract, although I'm not sure in what part of those systems.

Here is an example: https://youtu.be/lrKqlv6VK_w?t=144

Serum tryptase: normal
N-Methylhistamine: normal
Bone marrow and skin rash biospsies: normal
Urinary PGD2: elevated
GI-tract, CD117 staining: increased numbers

Since many POISers claim to have IBS: https://poiscenter.com/forums/index.php?topic=3188.0
And IBS is commonly diagnosed in MCAS, one should take a look in the GI-tract. Although I'm not surprised when there is something wrong with mast cells in the genitourinary tract.

Minor criteria:
1) Numbers. Staining for CD117 is the prefered method.
2) Shape
3) Looking for extra surface molecules (CD2 and CD25) on the already stained CD117 mast cells.

[Clues]

It sounds like your dermatologist is clueless. Correct, that's because increased MC numbers aren't found in the skin of MCAS patients.

Yeah I suspected as much.   Thankfully the endocrinologist is the one who's supposed to follow up my case, and he's not as quick to rule out MCAS, although I'm not confident he knows enough to diagnose properly.

They are not commonly found to be increased in bone marrow but relatively more often in the gastrointestinal or genitourinary tract, although I'm not sure in what part of those systems.

That is really useful information. Have you got a link to any peer-reviewed stats on this? That would be really useful for when I go see my endocrinologist again. I've basically got 10 minutes to talk to him and then potentially have to wait for months for another appointment. So if he's going down a pointless diagnostic path, I've got a tiny window of time to shift his attention to something else.

[Muon]

Have you got a link to any peer-reviewed stats on this?

Can't remember where I have read or heard that. This is pointless if testing is insufficient.

[Clues]

Can't remember where I have read or heard that. This is pointless if testing is insufficient.

No problem. Just handy data in the sense that if I go back to my endocrinologist and he's wanting to take me down a pointless diagnostic path, I've got as much concrete evidence as possible to suggest something else. But the papers you've linked earlier should be sufficient for that anyway.