• Dr. Tania Dempsey

Testing for Mast Cell Activation Syndrome: Measuring Tryptase

What is tryptase?

Tryptase is a protein manufactured by mast cells. In the human body, tryptase is made only by mast cells, and mast cells seem to make more tryptase than any other protein. Roughly a quarter of all the protein content in a mast cell is copies of the tryptase molecule.

Strange, then, that we don't yet know what tryptase's principal function in the human body is, but that really is the case. There is research demonstrating that tryptase has a key role in driving inflammation and allergic reactions and that it participates in the regulation of airway openness, blood vessel openness, intestinal muscle activity, and blood clotting. But its principal role? Why evolution brought us to the point where we have cells that devote so much of their energy to making this one molecule? We don't (yet!) know.

Measuring tryptase levels in MCAS—what does a tryptase blood test show?

Nevertheless, measuring the level of tryptase which "leaks" out from mast cells is useful. Most tryptase circulating freely in the blood doesn't truly "leak" from mast cells but rather is constantly released by mast cells -- again, for what purpose, we don't know. In addition to this "constitutively expressed" tryptase, there can also be more tryptase released by mast cells into the blood when mast cells become activated, such as during an allergic reaction or anaphylaxis. However, it's also clear now that there are many ways in which mast cells can activate and release plenty of other mediators without necessarily releasing any tryptase, creating a situation in which the tryptase level in the blood doesn't change despite clinical events reflecting mast cell activation.

What is a normal range of tryptase levels?

What the level of tryptase in a person's blood principally reflects is simply how many mast cells the person has. If the tryptase level is normal, then the person likely has a relatively normal number of mast cells. If the tryptase level is persistently elevated, then the person likely has a persistently increased number of mast cells. A persistent large increase (>20 ng/ml, roughly double the upper limit of normal) is more commonly associated with mastocytosis, a rare disease featuring chronic inappropriate mast cell activation and a chronic cancerous extent of mast cell growth/proliferation, though fortunately in most such patients, this "cancer" grows quite slowly and doesn't even wind up costing the patient any years of life. A persistent mild increase in tryptase is more commonly associated with mast cell activation syndrome (MCAS), a common (or "prevalent") disease which features chronic inappropriate mast cell activation (i.e., inappropriate production and release of the mast cells' large menagerie of potent mediators, which upon interaction with other cells throughout the body cause most of the symptoms of mast cell disease) with little to no excess in mast cell growth. However, this mild elevation of tryptase is found in only 15% of MCAS patients; the other 85% of MCAS patients have a normal tryptase level, again an indication that the principal problem in MCAS is *not* excessive growth of mast cells.

Several different tryptase assays are used by various clinical laboratories, and their lower limits and upper limits of normal vary slightly. For the most part, though, a tryptase level in the serum in excess of 11 ng/ml is considered elevated.

Thus, except in certain, relatively uncommon circumstances (such as kidney failure), an elevated tryptase is typically taken as a sign of the presence of a mast cell disease.

Can you have mastocytosis with normal tryptase levels?

While is it possible to have mastocytosis with normal tryptase levels, it is pretty uncommon. The more challenging situation is whether anything can be made of a normal tryptase level.

Some experts in mast cell disease have been asserting for the last several years that a rise in tryptase by 20% over a baseline asymptomatic level, plus an additional 2 ng/ml, identifies a state of mast cell activation (compared to the state of mast cells when the tryptase level has not risen by that much, and even when the "20% + 2" result is still within the normal range for tryptase levels in the blood) and that a rise of "20% + 2" should be the sole laboratory marker for diagnosing MCAS. However, so far this formula is only an assertion, and no data has yet been published demonstrating any validity to it.

Is an elevated tryptase level a reliable marker of mast cell activation syndrome?

In our combined clinical experience now across many thousands of MCAS patients, we (Dr. Dempsey and Dr. Afrin) have not seen a rise in tryptase to be a reliable marker of mast cell *activation*. Again, a persistently elevated tryptase may be a reliable marker of an increased *number* of mast cells in a person, and a clear, brief spike in the tryptase level over some lower, stable baseline level of tryptase probably represents a brief flare of mast cell activation, but such a spike it is not a *reliable* marker of mast cell activation. In fact, it appears that mast cells can become activated via so many different routes, releasing so many different mediators under different circumstances, that it is difficult to imagine how a spike (by any amount) in just one mast cell mediator could be a truly reliable marker of mast cell activation detectable in most activation events in most people. We have even seen many patients whose tryptase levels have gone *down* during events of flagrant mast cell activation, such as anaphylaxis. And we have seen that in patients whose symptoms are suggestive of mast cell activation, it almost always is the case that elevated levels of mast-cell-specific mediators other than tryptase can be found in the blood and/or urine.

MCAS: How to interpret elevated tryptase levels

Therefore, while the finding of a persistently elevated tryptase level is useful in signaling the likely presence of a mast cell disorder of some sort (i.e., MCAS or mastocytosis), it requires careful further interpretation to sort out which type of mast cell disorder is present. Conversely, the finding of a persistently normal tryptase level helps significantly (i.e., doesn't "seal the deal," but nevertheless helps significantly) toward ruling out mastocytosis, but it doesn't even begin to rule out the possibility that MCAS might be present, and in patients who have symptoms of mast cell activation but a normal tryptase level, other testing usually needs to be done to prove the presence of mast cell activation. The diagnostic utility of finding a *rise* in the tryptase level (whether by "20% + 2" or any other amount) remains unclear, all the more so if the "spiked" level still remains within the normal range. Experts advocating the "20% + 2" formula have published that it is supposed to be applied relative to a baseline level determined at an asymptomatic state, but in our experience, very few MCAS patients ever experience a truly asymptomatic state, making it even less clear what would constitute a "significant" rise in the tryptase level in somebody who in truth is never asymptomatic.

Hereditary Alpha-Tryptasemia (HAT)

As if the landscape regarding tryptase isn't already complicated enough, recently researchers at NIH and elsewhere identified that some people are genetically programmed, by virtue of having one or more extra copies of the tryptase gene, to make more tryptase than normal, and many of these patients have elevated tryptase levels in the blood. This condition often is found to run throughout certain families and has been christened "hereditary alpha-tryptasemia," or HAT. Usually, though, the elevations in the tryptase level in the blood in HAT patients are modest, more commonly in the range expected in MCAS than in mastocytosis. If the tryptase level in the blood in a HAT patient is high enough, suspicions of mastocytosis may be raised, but additional testing (typically a bone marrow biopsy) usually quickly rules out the presence of mastocytosis. HAT patients often have symptoms consistent with mast cell activation, but it remains unclear whether the elevated blood levels of tryptase in HAT patients have any role in bringing about the mast cell activation seen in those patients. So far no research has identified any difference between the typical course of a HAT patient and the typical course of an MCAS patient. Therefore, although testing for extra copies of the tryptase gene is now available in some clinical laboratories, we don't yet see any clinical utility to performing such testing. The situation with HAT is further complicated by the observation that some patients have extra copies of the tryptase gene but don't have increased levels of tryptase in their blood, making it even less clear what the significance is (if any) of finding such extra copies. We suspect that HAT eventually will be characterized as just one of a myriad variants of MCAS, but, clearly, much more research needs to be conducted to understand not only the significance of HAT, but also how to distinguish all the other variants of MCAS and how to leverage those distinctions toward being able to predict which treatments will likely best help which particular variants of MCAS. We are confident that these goals will be reached -- but we are also realistic that this quest could easily take many decades. Nothing worth having (or knowing) comes easy.

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