Mast cell mediators: Recommended testing for MCAS diagnosis

Lab tests specific to mast cell activation for suspected MCAS patients should include serum tryptase, serum chromogranin A, plasma histamine, chilled plasma PGD2, stat chilled plasma heparin, chilled urine for PGD2, PGF2a and n-methylhistamine. 
Tryptase is the most famous mast cell mediator.  It is a complex molecule with many functions in the body.  It is easily damaged by heat and has a short half-life in the body (6-8 minutes in health subjects, 1.5-2.3 hours in patients with hypersensitivity reactions.  In separated serum, it can last approximately four days.  Serum tryptase value is usually normal in MCAS patients, but sometimes it is elevated.  Tryptase values that show an increase of 20% + 2 ng/ml above the baseline level are considered diagnostic for MCAS.
Chromogranin A is a heat-stable mast cell mediator.  High levels can suggest MCAS, but other sources must first be ruled out, such as heart failure, renal insufficiency, neuroendocrine tumors and proton pump inhibitor (PPI) use.  Starting or stopping PPI therapy will generally cause a change in value within five days.  Once other causes have been excluded, serum chromogranin A can be considered a reliable marker of mast cell activity. 
Heparin is a very sensitive and specific marker of mast cell activation.  However, due to its quick metabolism in the body, it is very difficult to measure reliably.  It has a very short half life and quickly deteriorates, even when refrigerated.  Values above 0.02 anti-Factor Xa units/ml are abnormal, but many commercial tests cannot test that low.  Elevated plasma heparin is sometimes found in MCAS patients. 
Histamine is also released by basophils, but the majority is released by mast cells.  It is heat stable and has a short half life in the body.  Serum histamine peaks at about 5 minutes after release and returns to baseline within 15-30 minutes in most patients.  In separated plasma, it is stable at room temperature for at least 48 hours.  It is broken down to n-methylhistamine, which is more stable and can be measured accurately longer.  N-methylhistamine is usually measured in a 24 hour urine test to account for the variability in release over the course of the day. 
Prostaglandin D2 is produced by several other cell types, but mast cell release is responsible for the dominant amount found in the body.  MCAS patients typically produce much higher levels of PGD2 than n-methylhistamine.  PGD2 is less stable than histamine, being metabolized completely in an estimated 30 minutes.  Its metabolite, PGF2a, is the preferred compound for detection due to its superior stability.    Accurate prostaglandin testing relies upon refrigeration of the sample from the start of collection through testing.  NSAIDs inhibit prostaglandin production and can lower PGD2 in blood and urine.  Renal insufficiency may produce an inaccurately low test value, but elevated prostaglandins are sometime seen in patients with renal disease.  Prostaglandins D2 and F2a can be tested in serum, but 24 hour urine samples are considered more accurate.

Leukotriene B4 and cysteinyl leukotrienes C4, D4 and E4 have been noted to be elevated in SM patients and during acute asthma attacks.  Though commercial testing for these compounds is not easily accessible, but they may be elevated in MCAS patients as well.  Other less specific mast cell mediators that are sometimes abnormal in MCAS patients include Factor VIII, plasma free norepinephrine, tumor necrosis factor alpha, and interleukin-6.

References:
Sur R, Cavender D, Malaviya R. Different approaches to study mast cell functions.  Int. Immunopharmacol. 2007 May;7(5):555-567.
Pregun I, Herszényi L, Juhász M, Miheller P, Hritz I, Patócs A, Rácz K, Tulassay Z. Effect of proton-pump inhibitor therapy on serum chromogranin A level. Digestion 2011; 84:22-28.
Seidel H, Molderings GJ, Oldenburg J, Meis K, Kolck UW, Homann J, Hertfelder HJ. Bleeding diathesis in patients with mast cell activation disease. Thromb. Haemost. 2011 Nov; 106(5):987-989.
Laroche D, Vergnaud MC, Sillard B, Soufarapis H, Bricard H. Biochemical markers of anaphylactoid reactions to drugs: comparison of plasma histamine and tryptase. Anesthesiol. 1991 Dec; 75(6):945-949.

Takeda J, Ueda E, Takahashi J, Fukushima K. Plasma N-methylhistamine concentration as an indicator of histamine release by intravenous d-tubocurarine in humans: preliminary study in five patients by radioimmunoassay kits. Anesth. Analg. 1995; 80:1015-1017.

Maclouf J, Corvazier E, Wang ZY. Development of a radioimmunoassay for prostaglandin D2 using an antiserum against 11-methoxime prostaglandin D2. Prostaglandins 1986 Jan; 31(1):123-132.
Freeman JG, Ryan JJ, Shelburne CP, Bailey DP, Bouton LA, Narasimhachari N, Domen J, Siméon N, Couderc F, Stewart JK. Catecholamines in murine bone marrowderived mast cells. J. Neuroimmunol. 2001 Oct;119(2):231-238.
Gordon JR, Galli SJ. Mast cells as a source of both preformed and immunologically inducible TNF-α/cachectin. Nature 1990 Jul 19; 346:274-276.

6 Responses

  1. donna October 29, 2015 / 12:51 pm

    great info.!!

  2. cityrose January 20, 2016 / 7:46 am

    Hi Lisa, My recent heparin XA level was 0.10. It was sent to Mayo. You mentioned that many assays/labs can’t test low enough to capture 0.02 levels. Can Mayo’s labs capture values low enough to get reliable results? I ask because either I DID capture a reliable HIGH value (I WAS having a major flush at the exact time the blood was drawn, AND the lab kept the vials on ice…even during collection, as it was done at Dr. Afrin’s lab), OR my value of 0.10 was simply the lowest value that Mayo’s assay could quantify. Which is the case, please?

    • Lisa Klimas January 22, 2016 / 6:46 pm

      I’m not sure what the Mayo’s scale for Xa assay is. I would ask Afrin’s office. I think most providers will need to look up how to interpret the test.

  3. cityrose January 20, 2016 / 9:51 am

    PS…Oh yes, one more thing….Since Mayo’s lab results only display normal values for THERAPEUTIC ranges of heparin–0.3 (on the low end) to 2.0 (on the high end)– I’m concerned about how the average PCP will interpret a value of 0.10. Wouldn’t a PCP who doesn’t believe in or know about MCAS, call a value of 0.10 LOW instead of high, given the normal ranges displayed on the lab printout, or do physicians familiar with what a REAL normal heparin value is supposed to be? It’s hard enough to get physicians on board with this diagnosis, let alone having Mayo’s lab values lend to the ambiguity by only displaying therapeutic values.

  4. Theresa Hemingway May 18, 2016 / 7:51 am

    I was diagnosed with MCAS based on my Progesterone D2 level, which was mildly elevated. However, I only just found out that the urine used for this test should have been kept cold, and it was not. What happens if the urine used to test Progesterone D2 is not kept chilled, but the result is still elevated? Would the result have been high if my urine had been kept cold?

  5. Theresa Hemingway May 18, 2016 / 7:56 am

    I feel silly because I wrote Progesterone instead of Prostaglandin. Chalk it up to the brain fog of MCAS!

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