MCAS evaluation
Question:
1/25/2023
Neurology referred a 51-year-old RN with POTs to be evaluated for a possible mast cell disorder. She has a history of migraines, tachycardia, flushing of the head/neck/chest, rhinorrhea, and nasal congestion. No hives, no itching, no wheezing, no diarrhea. She was unable to undergo percutaneous allergy testing but had lab work which revealed IgE=24.0, IgE df mite=2.20, IgE dp mite=1.81, baseline tryptase=5.0. She was advised to undergo a post event tryptase (within 4 hours) which she did which was also 5.0. She was advised that her symptoms and labs were not consistent with MCAS. However, she reported that she did not feel that the post event tryptase was accurate. She also reported that she had read that tryptase levels are not accurate in diagnosing MCAS in POTs pts. I did find an article from JAHA from 08/16/21 that supported her concerns. This article reports that other lab tests were found to be more sensitive than tryptase levels including 24-hour urine histamine, 24-hour urine methylhistamine, prostaglandin levels, and plasma histamines. I advised her to undergo another on demand tryptase level and that it is the gold standard test. I did advise her she could undergo other testing. The local lab offers 24-hour urine histamines and 24-hour methyl histamine. She was advised that these tests are not considered the gold standard. She is also questioning the use of antihistamines when undergoing urine testing. I could not find any scientific data stating that she cannot take antihistamines when undergoing these urine tests. Any suggestions/comments regarding the validity of these tests? The study from AHA does have flaws.
Answer:
As you have stated, the most specific study for identifying mast cell activation is serum total tryptase. An increase from the patient’s basal tryptase to a level of (1.2 x baseline) + 2 ng/mL is considered indicative of mast cell activation. Four hours is a bit long; after its release, tryptase levels drop rather precipitously over three hours. Tryptase levels peal between 30 and 90 minutes. While some literature states with four hours, however drawing Tryptase level within 30 minutes to two hours of the event is preferred (1).
Spot urine studies have been shown to be reliable, so we have stopped ordering 24-hour testing. We order spot urine for Prostaglandin D2, Leukotriene E4 and N-methyl histamine. These studies are done at baseline and again during a symptomatic event. The best time frame for sample collection is within three hours after onset of symptoms.
A positive test is supportive, but not diagnostic. A negative test does not rule out MCAS. If these are used to support the diagnosis, the clinical presentation should be highly suggestive of mast cell activation.
These studies are available through ARUP, Mayo and likely other labs. Antihistamines do not have to be discontinued. however, there are medication recommendations for each. I have extracted this from ARUP guidance.
For PGD2: Aspirin, indomethacin, or anti-inflammatory medications should be discontinued, if possible, at least 48 hours prior to collection
For LTE4: Patients taking 5-lipoxygenase inhibitor Zileuton/Zyflo may have decreased concentrations of leukotriene E4 (LTE4). If possible, discontinue 48 hours prior to collection.
For N-methyl histamine: Patient must not be taking monoamine oxidase inhibitors (MAOIs) or aminoguanidine as these medications increase N-methylhistamine (NMH) levels. Specimen should be collected within a few hours of symptom onset.
Both overdiagnosis and underdiagnosis of MCAS can be problematic. The criteria for diagnosis of MCAS. (2)
1) Have signs and symptoms consistent with mast cell activation involving at least two organ systems.
2) Have evidence of systemic mast cell-mediator release.
3) Respond to medications that counter these mediators.
There are several case reports associating MCAS with POTS and other conditions, such as Ehlers Danlos. There is no evidence, to date, that implicates mast cell activation these conditions. There are a variety of symptoms associated with POTS, other than tachycardia, which may be confused with MCAS.
Hereditary a-tryptasemia, an autosomal dominant disorder, has a clinical phenotype that can include dysautonomia with POTS. (1) Even though your patient’s basal tryptase is normal, you may consider ordering TPSAB1. This can be done by buccal swab and sent to Gene-by-Gene. Gene-by-Gene will provide you a kit upon request.
1) Weiler CR, Austen KF, Akin C, et al. AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management. J Allergy Clin Immunol. 2019 Oct;144(4):883-896.
2) Weiler CR. Mast Cell Activation Syndrome: Tools for Diagnosis and Differential Diagnosis. J Allergy Clin Immunol Pract. 2020 Feb;8(2):498-506.
Jeffrey G. Demain, MD, FAAAAI