Mast cell disorders are increasingly recognized as a cause of chronic abdominal symptoms. Interestingly, the presenting signs and symptoms of mast cell activation are seen in all the types of mast cell disorders including disorders where abnormal clonal mast cells can be identified (eg, systemic mastocytosis) and disorders where the mast cells are believed to be nonclonal but with abnormal activation (eg, mast cell activation syndrome) (see Classification section for more details). Any of these patients may complain of abdominal pain, diarrhea, nausea and vomiting, reflux, and bloating. Patients with systemic mastocytosis may additionally be at risk for peptic ulcer disease, and in the more aggressive stage portal hypertension and intestinal malabsorption.

A thorough history and physical examination is necessary to illicit the signs and symptoms of mast cell activation (see Clinical Findings section). Objective evidence of mast cell activation can be obtained with various laboratory tests and further testing should be performed to further differentiate between the various disorders that present with mast cell activation. Once the diagnosis is suspected and other medical disorders have been ruled out, patients should undergo a trial of anti–mast cell mediator and mast cell stabilizer medications with a plan to carefully assess treatment response. Depending on the type of mast cell disorder, specific treatments and further testing may be warranted. The correct diagnosis of a mast cell disorder may lead to specific treatment with excellent symptom relief, improved quality of life, and prevention of unnecessary tests and procedures.

Once a mast cell disorder is suspected, it is important to try to classify the patient into the appropriate group of disorders. Although the underlying treatment of mast cell activation symptoms is not different (see Treatment section), there may be specific management strategies to consider for each subtype.

A. Clonal Mast Cell Disorders

1. Systemic mastocytosis

These patients present with the signs and symptoms of mast cell activation and may have characteristic skin lesions such as urticaria pigmentosa and a history of anaphylaxis. The hallmark is an accumulation of clonal forms of mast cells in clusters or sheets in the bone marrow and extracutaneous sites including the liver and intestine. The clonal population of mast cells may be identified by abnormal cell surface expression, morphology, or mutational analysis of the KIT gene. The serum tryptase is elevated on baseline testing >20 ng/mL or >11.4 ng/mL with coexisting anaphylaxis or high clinical suspicion of mastocytosis.

There are several subclassifications of systemic mastocytosis. The majority of adult patients have indolent mastocytosis with the features described earlier. A smaller minority will present with or progress to smoldering mastocytosis or aggressive mastocytosis. In the smoldering subclass, patients will display two or more “B” findings that are characteristic of an increased mast cell burden in the tissues but they maintain normal organ function. These may include a serum tryptase >200 ng/mL, a bone marrow biopsy that has >30% mast cells, and/or enlargement of the liver, spleen, and/or lymph nodes. In aggressive mastocytosis, patients may harbor at least one “C” finding that suggests that the mast cell burden is causing organ dysfunction. Patients with this subclass may therefore have cytopenias with an absolute neutrophil count <1000 cells/μL, hemoglobin <10 g/dL, and platelets <100,000 cells/μL, organ dysfunction including portal hypertension and associated complications, hypersplenism, intestinal malabsorption, and severe bone disease such as osteoporosis with pathologic fractures.

When classifying adult patients with systemic mastocytosis, an underlying clonal non–mast cell hematologic lineage disorder needs to be ruled out on a bone marrow biopsy. The presence of a myeloproliferative, myelodysplastic, or lymphoproliferative hematologic disorder in a patient with coexisting systemic mastocytosis typifies the fourth subclass. Finally, a fifth type is mast cell leukemia. This subclass is the least common but carries the highest mortality. It is characterized by abnormal mast cells identified in the peripheral circulation where mast cells are usually not detected. They may comprise >10% of the total circulating cells and appear as blasts, have a high nucleus to cytoplasm ratio, and/or contain mitotic figures. Mast cell leukemia is also suspected when >20% of a bone marrow aspirate has these abnormal features.

2. Monoclonal mast cell activation syndrome

Patients with this classification of clonal mast cell disorder also present with signs and symptoms of mast cell activation and may be at increased risk for anaphylactic episodes. Unlike systemic mastocytosis, the numbers of mast cells in the various tissues are thought to be in a normal range and abnormal clustering in the bone marrow or other tissues can not be identified on biopsies. However, these patients may express the abnormal surface markers CD2 and CD25 seen in systemic mastocytosis, or mutations in KIT on mutational analysis. Baseline tryptase levels in this clonal mast cell disorder are normal or mildly increased but generally <20 ng/mL.

3. Cutaneous mastocytosis

Patients with skin lesions, signs and symptoms of mast cell activation, and abnormal populations of mast cells confined to the skin have cutaneous mastocytosis. This will not be discussed in detail in this chapter.

B. Nonclonal Mast Cell Disorders

1. Mast cell activation syndrome

Although the clinical presentation and treatment of systemic mastocytosis has been well appreciated and studied, mast cell activation syndrome has only recently been characterized. In this mast cell disorder, patients present with signs and symptoms of mast cell activation but have normal numbers of mast cells in the bone marrow and tissues and no evidence of clonal forms that are seen in the clonal mast cell disorders. These patients may present with anaphylaxis but current expert consensus opinion is that patients who present with anaphylaxis without mastocytosis may be better characterized as having idiopathic anaphylaxis. The treatment and prognosis is described in the following text. Patients with mast cell activation syndrome may respond well to treatments and are not thought to have any complications related specifically to the abnormal mast cell activation. These patients are not known to progress to systemic mastocytosis.

2. Diseases that cause secondary mast cell activation

Signs and symptoms of mast cell activation may be seen in primary IgE-mediated allergic disorders and idiopathic anaphylaxis. Various autoimmune and chronic inflammatory conditions such as rheumatoid arthritis, lupus, and inflammatory bowel disease may also present with mast cell activation.

A. Systemic Mastocytosis

Signs and symptoms may be related to the mast cell mediators themselves or infiltration of the mast cells in the various tissues. On a molecular basis, mutations have been identified in the gene that encodes KIT which is a cell surface receptor for stem cell factor (SCF). SCF is a growth factor important for the development, proliferation, and survival of mast cells. The mutations that have been identified in KIT are thought to contribute to the marked expansion of clonal mast cells. KIT

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