Q:

11/9/2013
What further workup is recommended in a 46 yo physician patient who has 18 month history of episodic flushing/burning with development of urticaria on face, anterior and posterior torso, and arms? Symptoms are not associated with headache, angioedema, hypotension, diarrhea, or respiratory compromise. Symptoms have occurred on at least 5 occasions (at least 2 preceded by ingestion of one Excedrin) and once with solar exposure and Excedrin. No particular foods. Her episodes have been successfully treated with Benadryl. Pt also had urticaria occur after hemorrhoidectomy surgery and it was thought to be from use of Unasyn. She has also had urticaria with ingestion of Cipro.

She is otherwise in excellent health and non atopic. Her history is significant for constipation and occasional migraine. Workup has included negative allergy testing, normal chem panel, normal thyroid, normal sed rate, normal CBC, neg ANA, neg RF, normal serum tryptase level 1.9. Pt also underwent ASA challenge (negative) and Acetominphen challenge (negative). The patient has also taken Excedrin several times since and previous without any reaction. Pt has no obvious skin lesions but has always had minor dermatographia. Is this simply to be considered Mast Cell Activation Syndrome? What further workup recommended....skin biopsy (but no obvious lesions), should tryptase level or 24 hour urine histamine be drawn after next episode? I have read that bone marrow biopsy is typically not indicated in a case such as this and is typically negative. How should I proceed with any further workup? Pt advised to take cetrizine 10mg daily currently.

A:

Thank you for your inquiry.

Before attempting to answer your question directly, I think it is important to make a few introductory comments.

I think it is important to clarify the terminology that we would employ to answer your question. You mentioned the term “mast cell activating syndrome.” In this regard I would like to call your attention to an excellent reference which discusses the terminology employed when referring to this type of disorder. The reference is: Lee and Akin. Mast cell activating syndromes. In: Annals of Allergy, Asthma, and Immunology 2013 (July); 111(1):5-8.

In this excellent review, mast cell activating diseases are divided into three distinct categories. These are:

  • Primary: classical systemic mastocytosis and monoclonal mast cell activating syndrome. Both of these entities are characterized by a clonal proliferation of mast cells.
  • Secondary: which includes allergic diseases, physical urticaria, chronic autoimmune urticaria, and other conditions in which there is mast cell degranulation related to an external trigger, but not associated with any marker of clonal disease.
  • Idiopathic: mast cell degranulating conditions like idiopathic anaphylaxis and idiopathic urticarial where there is no clonal marker and no detectable trigger.


I assume that when you refer to “mast cell activating syndrome,” since you mentioned a bone marrow, you are speaking of the first or primary category mentioned by Lee and Akin. In this group of conditions, patients have clonal markers such as CD25 present on their mast cells, but the biopsy findings may not be diagnostic of systemic mastocytosis. It is assumed that the clonality results in a lower threshold for degranulation.

What is important in this regard is the criteria necessary to make a diagnosis of a monoclonal mast cell activating syndrome, and therefore perhaps pursue this diagnosis further. The diagnostic criteria are:

  • Signs and symptoms of a mast cell activating disorder involving at least two organ systems (e.g., gastrointestinal, respiratory, skin, et cetera).
  • An increase in release of mast cell markers such as tryptase, histamine, et cetera.
  • Finally, a response to anti-mediator therapy.


At this point in time, based upon the classification described above your patient does not appear to have a primary or clonal mast cell activating disorder.

With the above comments in mind, I think we can proceed to try and help you directly with the questions you posed.

Is this simply to be considered Mast Cell Activation Syndrome?
At this time, we do not fulfill the criteria for primary mast cell activating syndrome which is what I think you were referring to, and there are peculiar points in the history (lack of pruritus, for example) which may point to other causes of flush - that is, causes that do not involve mast cells.

What further workup is recommended.... skin biopsy (but no obvious lesions), should tryptase level or 24 hour urine histamine be drawn after next episode?
A skin biopsy would be especially helpful if the lesions persisted greater than 24 hours, burned rather than itched, and left a bluish discoloration. These are all signs of potential urticarial vasculitis. There is less indication for doing a skin biopsy if these lesions were transient, lasting only an hour or so, and were pruritic. That would indicate that these were simply classical acute urticarial lesions and more than likely due to acute episodes of idiopathic urticaria. Nonetheless, I would certainly consider a skin biopsy if it could be obtained during one of her episodes. It would also be helpful to obtain a tryptase and a 24 hour urinary histamine during the episode. But I believe they more than likely will be normal.

How should I proceed with any further workup?
You mentioned a bone marrow. At this particular time, I would not proceed with a bone marrow. I would also like to reiterate that no matter what you do, it is not unlikely that you will not find a cause. However, there are other potential studies that you might consider related to disorders where the cause is not related to mast cell degranulation. This would include the conditions that produce flushing, but not characteristically urticarial lesions. In this regard, I would like to call your attention to another article which should be readily accessible to you. S The article itself is written about patients presenting with anaphylaxis, but the diagnostic tests mentioned in Table 4 would also apply to a patient who presents with flushing in the absence of multisystem involvement. The article is found in the Annals of Allergy, Asthma, and Immunology, 2013; Volume 111, pages 170-175. Some of the tests that you might consider would be a serum serotonin, urinary 5-hydroxyindolycitic acid, chromogranin A, and a number of vasointestinal polypeptides including, for example, substance P, vasointestinal polypeptide hormone, et cetera. Further testing could also be considered as mentioned in the discussion of this article and the table. However, once again, how far you carry this workup must be tempered by the fact that quite often patients presenting with symptoms such as you described defy any particular diagnosis or etiology.

Finally, you did not mention any drugs that she was taking chronically, but drugs themselves can be causes of similar symptoms, and there is a nice review of flushing per se which contains a list of suspect drugs at the Cleveland Clinic website.

Thank you again for your inquiry and we hope this response is helpful to you.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology