Diagnosis

Summary:

The most difficult part of the diagnosis is probably to develop an initial suspicion that it probably could be a mast cell activation disease (MCAD) and to consider this as a possible diagnosis in the procedure of diffe­rential diagnosis.

Choice of doctor

The necessary clarifications for the diagnosis of MCAD can be made or com­missio­ned by any family practice. Because of the overload of specia­lized doctors, it makes sense when the family doctors take the lead as far as possible. For specific questions or in difficult cases, the nearest center of excellence for mast cell disease can be contacted, or the patient will be transferred there.

Addresses of MCAD centers of excellence in Europe

Mast cells originate in the bone marrow and are counted among the blood cells (although they do not occur in the blood). Hemato­logists are specialized in blood and blood-forming organs (bone marrow). Not all allergists are familiar with MCAD. But allergists are usually competent specialists regarding the differential diagnosis (clarification of other incompa­tibili­ties, allergy screening) and can therefore also be visited for an initial assess­ment.

Diagnostic criteria for MCAD

Diagnostic definition of mast cell activation (MCA)

If all of these three criteria are met, it can be assumed that one is dealing with mast cell activation (MCA) [Valent et al. 2012, S. 215; Brockow 2013; Molderings et al. 2014]:

1. Typical symptoms are present, not otherwise explainable and in need of treatment.
2. Elevated concentrations of mediators or their degra­dation products are detectable
3. Response to treatment with mast cell specific drugs

Difficulties:

Criterion 1: The symptoms alone are non-specific and therefore not conclusive.

Criterion 2: The detection of mast cell mediators (or their degra­dation products) does not succeed very often, for the reasons explai­ned below. Therefore, the criterion 2 must in practice most often be dropped and is not a criterion for exclusion.

Criterion 3: The response to drugs may be hampered because of diarrhea (intra­venous admini­stration may then be attempted), because only the healthy, secon­darily activated mast cells can be influ­enced by therapy, but not those who are patho­logically altered. Another reason may be that unsuitable products with incompatible active substances or incompatible adjuvants were chosen, or in rare cases also due to an allergy to an ingredient.

Subsequently, by means of differential diagnosis, it must be clarified whether the mast cell activation is caused by a MCAD, or if it could be of secondary origin (e.g. allergies, inflammatory diseases).

It can be distinguished between primary, secondary, idiopathic and environ­mental mast cell activation:

1. Primary: forms of mastocytosis with known physical cause.
2. Secondary: other diseases with mast cell activation, for example, allergies
3. Idiopathic: unknown cause. Probably also counting for masto­cytosis, although the current WHO diagnostic criteria are not met.
4. Environmental: activation due to unfavorable external, non-physical causes. The mast cells of every healthy person can be activated as well, if stimulus intensity is strong enough.

Diagnostic criteria for MCAS and mastocytosis

Proposed diagnostic criteria for the mast cell activation syndrome (MCAS), and the official WHO criteria for the diagnosis of systemic mastocytosis (SM), based on Molderings et. al. [2011, Tab. 2]:

Diagnostic procedure

1. Anamnesis (case history interview )

The physician should always be aware of the following difficulties:

• The clinical picture is not uniform. It may present itself totally different in every case. It is as changeable as a chameleon.
• Patient's histories or experience reports are usually incomplete. The doctor sees only the tip of the iceberg.
• The triggers are difficult to identify. Incompa­tible food is often mistaken for tolerated.
• A mindset of combating just the symptoms dominates, instead to aim at a holistic under­standing of the system. There are merely given medicines for individual symptoms, rather than to understand the cause and to treat it as specifically as possible.
• Many diagnoses, but lack of thera­peutic success are typical. Often single mast cell mediator symptoms or secondary diseases (sequelae) are mistaken for the actual disease, without seeing the mast cell disease as the underlying cause (e.g. "irritable bowel syndrome", "non-allergic rhinitis", "urticaria", "chronic fatigue syndrome", "sleeping disorder", "psycho­somatics"). A flood of diagnoses and treat­ment failure in the past should therefore let the doctor think of an MCAD.
• Contrary to previous expert opinion MCAD are not rare, but affect a double-digit percen­tage of the popu­lation! Moreover, persons concer­ned are probably seeing a physician more often than the average popu­lation. The proba­bility might therefore be very high that a MCAD is the actual (but unrecog­nised) reason for a medical consul­tation.
• Mastocytosis is not a pure skin disease. Any organs or organ systems can be affected in different constel­lation, with or without skin involve­ment

2. Differential diagnosis

The differential diagnosis (clarification of other diseases that may also be respon­sible for the observed symptoms) is a compli­cated detective game that we can not represent compre­hensively here by a simple scheme. The procedure is very dependent on the individual case.

If the symptoms are triggered by several physical causes, treatment of only one of these diseases will not be successful. Don't forget to consider the possibility of a sero­negative gastro­intestinal allergy, which is undetectable by means of prick or blood test.

3. Laboratory Diagnostics

The diagnosis of MCAD will at least in the foreseeable future primarily be based on laboratory tests to detect elevated levels of mast cell-specific mediators or their breakdown products (metabolites) in blood and urine. However, these as well as the other methods described here have their weaknesses.

Mediator detection

Evidence of the many liberated mast cell mediators or their degradation products fail very often or even most. That is because they bind to receptors or are degraded before they get into the bloodstream, or for many other reasons. This leads to two conclusions:

1. Only a positive result can be conclusive. A negative result can not exclude the existence of a MCAD.
2. The detected concentrations do not allow conclusions about the severity of the disease or on the intensity of the symptoms [Broesby-Olsen S et al. 2013].

To confirm the diagnosis and for the subclassifi­cation of a MCAD the determi­nation of tryptase and heparin in blood and methyl­histamine in the urine is recom­mended. In the future, other biomarkers should be included as soon as these will be available in the commercial routine diagnostics. [Molderings 2014]

Gastroscopy, colonoscopy, tissue samples

Since almost always the digestive tract is concerned as well, a gastroscopy and colonoscopy is recommended for a more accurate evaluation. These studies are also used for removal of tissue samples (biopsies) in order to find noticeable arrange­ments and shapes (morphology) of the mast cells and increased mast cell density. Only positive biopsy findings are conclusive. Negative results should not be seen as an exclusion criterion.

Mutation analysis

Since MCAD are caused by genetic mutations in mast cells, it is natural to seek for different gene variants by means of genetic tests or mutation analysis. Our knowledge, however, is still very incomplete do determine how relevant each possible combination of several acquired gene defects affecting several genes is. As in the tissue sample only a few single cells show the acquired mutation, such mutation analysis is methodologically more complex than a common genetic test, where a mutation can be found in every cell of the entire body. Currently, only the specific PCR for the mutation KIT D816V is routinely available.

Bone marrow biopsy

The examination of a tissue sample from the pelvis bone marrow can be used as an additional diagnostic criterion. It can draw the attention to any existing additional haematological disease (disease of blood cells) or it can show an excessive migration of mutated mast cells. It is applied at most if the other diagnostic criteria indicated a suspected systemic mastocytosis (basal tryptase level >20 ng/ml; morphologically abnormal mast cells in the biopsies from the gastrointestinal tract). False negative results are common, because with the biopsy often none of the spread nest with mutant mast cells is hit. Only a positive finding can be conclusive.

Tentative implementation of the therapy

The diagnostic methods listed above provide a positive test result only in a small proportion of cases. Most persons concerned with MCAD would fall through the cracks without getting a diagnosis (false negative result). Not only the tested positive but especially also the tested negative, should therefore undergo a further diagnostic step: The tentative (experi­mental) performing of a mast-cell-specific therapy (avoid triggers, medication) for a limited period of time. For details see page Therapy and subpages. For doctors, it may perhaps be unfamiliar and unusual to start therapy before an iron-clad diagnosis exists. However, in the absence of better alternatives this is the most sensible and effective one can do in this case.

If the patient is not responding to the medication and this could be the case because of diarrhea, medication may be administered intra­venously where possible.