Initial diagnosis and treatment of mast cell activation disease: General notes for guidance

Mast cell disease is becoming more well known among both the public and medical providers, but there is still a lot of confusion regarding exactly what it is, how to diagnose and how to treat.

There are several tests that should be used when working up a patient for mast cell disease. Tryptase is the most well known of these tests, due to over 85% of patients with systemic mastocytosis (SM), a form of mast cell disease, having elevated tryptase. However, tryptase can be normal in mast cell patients, or may only be elevated during times of severe symptoms or anaphylaxis. While an elevated baseline tryptase can be used as confirmation for a mast cell disease (in the absence of frank hematologic disease), a normal tryptase test should not be used to discard the possibility of mast cell disease.

24-hour urine tests for mast cell mediators are most likely to capture evidence of mast cell activation when executed correctly. These tests measure n-methylhistamine, a metabolite of histamine, and prostaglandins D2 and F2a, which are all released by mast cells. Urine collected for this test should be kept refrigerated or on ice during collection and transport to the lab. I STRONGLY recommend communicating with the lab prior to beginning to this test to be sure that they understand the temperature requirements. The molecules being tested are not stable at room temperature and inappropriate storage can result in a negative test result in a positive patient. (For details on this topic and specific recommendations for testing, please refer to Afrin 2013).

Some providers also find utility in the measurement of other less specific mediators. Please refer to my previous post on this topic: http://www.mastattack.org/2014/10/mast-cell-mediators-recommended-testing-for-mcas-diagnosis/

Due to the well established time sensitive nature of these tests (Afrin 2013), a patient who presents a “mast cell clinical picture” and responds to typical mast cell medications may in fact have mast cell disease in the presence of negative tests.

Depending on the clinical picture, a provider may feel it necessary to order a bone marrow biopsy, skin biopsy or biopsy of another organ to determine if mast cell infiltrates are present. This is not always immediately done in the presence of positive tryptase, n-methylhistamine, D2 prostaglandin or F2a prostaglandin test and will not always affect treatment. It is common knowledge among mast cell fluent providers that a negative biopsy does not exclude mast cell disease, but it is instead used to rule in the presence of specific proliferative entities like systemic mastocytosis (Picard 2013, Molderings 2011). Furthermore, a single biopsy may fail to capture a positive specimen in a known-positive patient (Butterfield 2004).

For more specific details regarding differentiation among the diagnostic categories of mast cell disease, please refer to my previous post on this topic: http://www.mastattack.org/2014/07/diagnosis-of-mast-cell-diseases/

There are a number of well known, well tolerated medications that can be used to manage mast cell disease. First line medications include antihistamines, leukotriene inhibitors, and mast cell stabilizers (Cardet 2013, Picard 2013, Molderings 2011, Afrin 2013).

Histamine is released by activated mast cells in large quantities. Histamine acts on the body by interacting with four different types of receptors, called H1, H2, H3 and H4. Medications that block the H1 and H2 receptors are available in plentiful supply in many countries. Once diagnosed, mast cell patients generally begin daily treatment with both H1 and H2 antihistamines. Longer acting, non-sedating H1 blockers like cetirizine are typically used to provide a baseline H1 coverage. H2 coverage is achieved with medications like Zantac or Pepcid. Dosage can be increased as needed to provide effective symptom relief, and these medications are often taken in moderate to high doses by mast cell patients. It is not uncommon to take multiple drugs together to block one type of histamine receptor, but this should be managed by a provider.

Leukotrienes are also released by activated mast cells. Singulair is an example of a leukotriene inhibitor that is a common add-on for mast cell patients. This medication is not a replacement for antihistamines.

Mast cell stabilizers achieve effects by making mast cells less likely to release chemicals. Cromolyn is typically the first line mast cell stabilizer in the US. This medication can take several weeks to demonstrate its full effect, so patients and providers should be aware of this fact. Another mast cell stabilizer, ketotifen, is also available in the US through compounding pharmacies. Ketotifen is also an H1 antihistamine.

Medications should ideally be added one at a time to allow easy identification of a bad actor in the event of a med reaction. As a result, tweaking a patient’s medication regimen takes time and patience. If a patient reacts to a medication, care should be taken to determine if the medication is truly the issue or if it is an inactive ingredient in the preparation (lactose, etc).

Mast cell disease can result in a highly variable clinical picture and mast cell patients are often only diagnosed following years of investigation for other possible causes of their symptoms. For this reason, many mast cell patients have acquired a long list of diagnoses prior to a mast cell diagnosis. In some cases, these diagnoses may be accurate and co-existing. All existing prior diagnoses should be considered for their accuracy in light of a mast cell diagnosis.

Additionally, there are a number of conditions which are frequently comorbid with mast cell disease, including Ehlers Danlos syndrome, postural orthostatic tachycardia syndrome (POTS), a variety of autoimmune diseases and several digestive conditions.  Patients should be evaluated according to their clinical picture and laboratory findings.

 

References:

Afrin, Lawrence B. Presentation, Diagnosis and Management of Mast Cell Activation Syndrome. 2013. Mast Cells.

Juan-Carlos Cardet, Maria C. Castells, and Matthew J. Hamilton. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.

Matthieu Picard, Pedro Giavina-Bianchi, Veronica Mezzano, Mariana Castells. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics, Volume 35, Issue 5, May 2013, Pages 548–562.

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology 2011, 4:10.

4 Responses

  1. Maria April 8, 2015 / 8:22 pm

    Frist I wanted to say thank you for all that you do! You have helped many of us find our way. I was wondering what you thoughts are with regards to testing for CKIT mutations in peripheral blood. I have read in many places that it has not been considered the gold standard, because it is not sensitive enough. But, Dr. Akin and other leading mast cell researchers released a new paper talking about a ‘highly sensitive CKIT essay’ earlier this year. I was given this test in December vs. being subjected to a BMB (at the Brigham). Is the highly sensitive CKIT essay going to dramatically decrease the number of BMB in the mast cell population? Or is it still best to ask for a BMB?

    • Lisa Klimas April 8, 2015 / 11:12 pm

      This is a great question. I love questions like this! (I work in diagnostics, so this is right up my alley.) Currently, peripheral blood testing for the D816V mutation is done by PCR. PCR basically works by making a copy of a gene. The D816V mutation in most mast cell patients is only found in mast cells rather than mast cells and other cell types. Mast cells don’t circulate very long in the blood, so getting a negative test result might just mean there weren’t any mast cells around at the time in the bloodstream. It also might mean not enough mast cells were circulating, as that particular test is not very sensitive so the limit of detection is higher than I would like. There is also another possibility – that some of the mast cells have the mutation and some don’t. It is uncommon but you do occasionally have a situation where a patient may test CKIT-in bone marrow but CKIT+ in blood. Some people chalk this up to sampling error, but other blood diseases demonstrate precedent for having two genetically distinct populations of the same cell type, so I’m not convinced. So the conventional thinking is that if you’re CKIT+ in blood with the PCR test, you are truly CKIT+, but if you come up CKIT-, you might still be CKIT+. Kind of a pain in the ass. The current test when done in bone marrow is much better. This test is done by ARUP labs and it is solid.

      The newer CKIT assay was developed as part of a panel used for rapid diagnosis of blood cancers. The D816V mutation is found in some other disorders, and was originally included for this purpose (I believe, I don’t have a reference for this – this might be something I heard in a conversation. In any case, it makes the most sense to me that it would be included for this reason.) I have not yet seen sensitivity and specificity numbers on this as it was internally validated, but the word on the street is that it is pretty slick. A lot of the people I have talked to about it are not easily impressed, and they are impressed. So I feel good about the chances that this will eventually reduce the need for bone marrow biopsies, but I don’t think it should replace BMB completely as there is other useful information that can be gleaned from biopsy (morphology, receptor expression, things that we are learning can impact prognosis and disease progression).

      One thing to keep in mind is that it takes time and money for diagnostics like this to be fully validated on a multicenter scale (as well as clinical trials, FDA submissions, etc). So it may be some time before this is being offered regularly to patients being worked up for mast cell disease. However, once it is implemented, I think it will be a great help, especially as this assay also looks for some other prognostically important mutations. And of course, it will make life much easier for SM-AHNMD patients, which is a fair amount of SM patients (figures vary, but 15-30% of SM patients develop an associated hematologic disorder). In the meantime, a BMB is still going to be the most accurate, but I wouldn’t do a biopsy just to find out CKIT mutation status.

  2. Mia February 5, 2016 / 12:43 pm

    I know some patients with hereditary angioedema and mast cell disease. Do you have any knowledge if these two usually occur together or is it just a coincidence? They all have been gene tested for HAE so there is no misdiagnose of that.

  3. Cris April 28, 2016 / 12:27 pm

    Can those markers on the 24hr urine test can be tested by blood serum also. We suspect my son has MCAS, tryptase is normal and we are having a hard time testing the urine because he still on diapers. Doctor is puzzled in how to test him

Comments are closed.