Version May 2024
INTRODUCTION — Mast cell disorders are conditions in which mast cells are either increased in number, hyper-reactive, or both. These conditions range in severity from relatively benign disorders that do not impact lifespan to malignant clonal diseases that progress rapidly. This topic will review the classification of mast cell disorders, provide a brief clinical description of each disorder, and then discuss an approach to the patient suspected of having a mast cell disorder.
Specific mast cell disorders are discussed in greater detail separately:
●(See "Systemic mastocytosis: Determining the subtype of disease".)
●(See "Advanced systemic mastocytosis: Management and prognosis".)
MAST CELL PHYSIOLOGY — Mast cell disorders present with signs and symptoms that are caused either by activation of mast cells or by mast cells infiltrating organs and interfering with normal function [1]. To understand the possible presentations, a brief review of the physiology of mast cells is helpful.
Mast cells reside within the connective tissue of all vascularized organs and in mucosal tissues. They are most numerous in the skin and in the mucosal tissues of the respiratory and intestinal tracts. Their numbers and densities are highest at interfaces between the internal and external environments where they act as sentinels and can respond rapidly to foreign organisms, antigens, and toxins. Evolutionarily, mast cells were probably most beneficial in rapid responses to venoms, parasites, and possibly bacterial infections [2].
When activated, mast cells release a variety of vasoactive mediators, such as histamine and arachidonic acid metabolites, from cytoplasmic granules and membrane lipids within minutes that form the immediate response and also generate and release cytokines and chemokines over hours that recruit other inflammatory cells into the involved tissues. These mediators are responsible for many of the signs and symptoms of allergic reactions and allergic diseases, including flushing, pruritus, urticaria, angioedema, bronchoconstriction, increased vascular permeability, and anaphylaxis. These same symptoms are seen in the various mast cell disorders (table 1). Thus, patients with mast cell disorders have signs and symptoms that overlap with those of allergic reactions and allergic diseases, making diagnosis challenging. The normal biology of mast cells and the functions of mast cell mediators are reviewed in more detail separately. (See "Mast cells: Development, identification, and physiologic roles" and "Mast cell-derived mediators" and "Mast cells: Surface receptors and signal transduction".)
Tryptase is the mast cell granule mediator that is most useful clinically, although its biologic functions are not fully understood. Although tryptase is released by both mast cells and basophils upon activation, mast cells contain approximately 500-fold more than basophils, and thus, serum tryptase is a relatively specific marker for mast cell burden and activity [3-5]. An acute rise in serum tryptase concentration indicates involvement of mast cells in clinical events, and a persistent elevation in serum tryptase indicates an increase in total body mast cell number. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis", section on 'Elevations of tryptase in nonanaphylactic patients'.)
CLASSIFICATION OF MAST CELL DISORDERS — Mast cell disorders can be broadly divided into three types: primary, secondary, and idiopathic (table 2) [6]. Mixed presentations can be seen in the same patient (eg, a patient with mastocytosis who also has IgE-mediated allergy). The relationship between them can also be depicted as a Venn diagram (figure 1). All of these disorders can present with signs and symptoms caused by widespread activation of mast cells (table 1). However, they differ in severity and involvement of various organ systems [1].
Mast cell activation syndrome — Mast cell activation syndrome (MCAS) was first proposed as a distinct idiopathic disorder in 2010 [7,8]. In 2022, an expert working group expanded the definition of MCAS to include primary and secondary mast cell disorders as well, making MCAS essentially an umbrella term that describes a clinical presentation rather than a specific diagnosis. Therefore, in patients meeting the criteria for MCAS, primary and secondary etiologies should be investigated. If these are not found, then idiopathic mast cell disorders should be considered (table 2).
The clinical presentation of MCAS involves episodes of symptoms due to mast cell-mediator release, which improve in response to therapies that target mast cells and their mediators (eg, antihistamines, cromolyn sodium, antileukotriene agents). There should be elevations of tryptase in the serum or elevations of mast cell mediators in the urine following episodes of symptoms, which return to normal between episodes. Interpretation of tryptase levels is discussed below. (See 'Measure serum tryptase' below.)
The diagnosis of MCAS requires that all of the following three criteria be met [9-12]:
●Episodic, objective signs and symptoms consistent with mast cell activation involving at least two of the following organ systems: skin, upper or lower respiratory systems, gastrointestinal, or cardiovascular (table 1). Note that subjective symptoms alone (fatigue, difficulty concentrating) in the absence of signs and symptoms in two other organ systems specified above does not warrant an evaluation for mast cell disorders.
●Evidence of systemic mast cell-mediator release, corresponding temporally to the presence of symptoms. In case of frequent recurrent episodes, mediator release should be ideally documented on at least two occasions [10]. Serum total tryptase is the most specific for mast cell activation, and an increase from the patient’s baseline to a level of (1.2 x baseline) + 2 ng/mL is considered indicative of mast cell activation. (See 'Measure serum tryptase' below.)
Other mediators (ie, 2,3-dinor-11-beta-PGF2-alpha, N-methyl-histamine or LTE4 in a 24 hour or spot urine sample) can be used if serum tryptase assays are not available [10]. An increase of more than 100 percent (ie, to 200 percent or greater) above baseline has been proposed as a diagnostic threshold for these mediators, provided that the test result is above the normal range for the assay [9]. Stated differently, to be indicative of mast cell mediator release, the level of one or more of these mediators should at least double after an episode of symptoms, and the doubled value must exceed the upper limit of normal. However, specific cutoff limits for mediators other than tryptase are not well established, so if these are used to support the diagnosis, the clinical presentation should be highly suggestive of mast cell activation [13]. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis".)
●Response to medications that stabilize mast cells, reduce mast cell mediator production, block mediator release, or inhibit the actions of mediators. (See 'Initial management' below.)
Both overdiagnosis and underdiagnosis of MCAS can be problematic. MCAS can be overdiagnosed, for example, based on elevations in mediators that have not been validated or reproduced as clinically useful indicators of mast cell activation, such as chromogranin A or heparin [10,14,15].
Primary mast cell disorders — Primary disorders of mast cells are rare. They include mastocytosis (both cutaneous and systemic) and monoclonal mast cell activation syndrome. Primary mast cell disorders are characterized by clonal populations of mast cells that arise from an affected progenitor and display abnormal genetic and surface markers. The associated molecular defects affect mast cell proliferation or activation pathways.
Mastocytosis — The best characterized primary mast cell disorder is mastocytosis. Both systemic and cutaneous forms of the disease exist and both forms can be associated with systemic signs and symptoms due to release of mast cell mediators.
Systemic mastocytosis — Systemic mastocytosis (SM) primarily presents in adults, with an approximate prevalence of 1 per 10,000 in the population (all ages) [16,17]. Abnormal mast cells proliferate and infiltrate the skin, bone marrow, and other organs, leading to a variety of symptoms, physical findings, and abnormalities on routine laboratories (table 3). There are several types of SM, ranging from benign to malignant. Patients experience episodes of symptoms caused by mast cell-mediator release, which last a few minutes to several hours. Common signs and symptoms include flushing, itching, abdominal cramping, tachycardia, and hypotension. Some patients present with hypotensive reactions to Hymenoptera (eg, wasps, bees) stings, even in the absence of detectable venom-specific immunoglobulin E (IgE), or unexplained recurrent anaphylaxis. Episodes of symptoms may also be triggered by medications (narcotics, opioids, nonsteroidal anti-inflammatory drugs [NSAIDs], iodinated contrast agents), as well as by emotional stress, surgical procedures, and viral illnesses (table 4).
The majority (approximately 80 percent) of adult patients with SM demonstrate a characteristic skin finding called urticaria pigmentosa (UP), which is also called maculopapular cutaneous mastocytosis (MPCM) (picture 1A-B) [18]. A helpful diagnostic clue is Darier's sign, which is the development of urtication (localized swelling and erythema) directly over and around a lesion of UP/MPCM within a few minutes if it is scratched or rubbed. This is due to release of mediators from the mast cells in the lesion. UP/MPCM is unique to mastocytosis. It may be present in both the systemic and cutaneous forms of the disease. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)
An elevated baseline serum total tryptase in a patient who is in their normal state (ie, not during or within a few hours of symptoms) is strongly suggestive of SM. Tryptase elevations after systemic anaphylaxis can occur in patients without mast cell disorders as well. If tryptase is elevated after an episode of symptoms, it should be measured again at least a few days later to see if levels return to the normal range. Persistent tryptase elevations may indicate that the total body burden of mast cells is increased, which strongly supports the diagnosis of mastocytosis. Normal tryptase levels are between 1 and 11.4 ng/mL (some laboratories consider 15 ng/mL to be the upper limit of normal). Patients with SM typically demonstrate total serum tryptase at baseline >20 ng/mL. However, the more common explanation for a persistently elevated tryptase level is hereditary alpha-tryptasemia, a genetic trait that may occur in up to 6 percent of the general population. Patients can also have both SM and hereditary alpha-tryptasemia. (See "Hereditary alpha-tryptasemia".)
Stem cell factor (SCF) is critical for mast cell growth, differentiation, and survival. The transmembrane receptor for SCF is KIT (encoded by the proto-oncogene kit). More than 90 percent of adult patients with SM have a gain-of-function point mutation (D816V) in exon 17 of kit. This mutation is the only well-characterized molecular defect associated with both increased mast cell numbers in tissues and clinical signs and symptoms of mast cell activation. KIT mutations are most readily identified in bone marrow mast cells, and a bone marrow biopsy is usually required to make the diagnosis.
SM is diagnosed according to major and minor criteria, including characteristic multifocal mast cell aggregates in the bone marrow (table 5).Evaluation and diagnosis of mastocytosis are discussed in detail elsewhere. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)
Cutaneous mastocytosis — Cutaneous mastocytosis (CM) typically presents in infants and young children and usually resolves spontaneously by adolescence. The estimated incidence is less than 1 per 20,000 in the population (all ages) [16]. In CM, mast cells accumulate in the skin but not in other organs, although patients may have systemic symptoms due to mast cell mediators diffusing from activated skin mast cells into the circulation. CM in infants and children typically presents with the distinctive skin findings of UP/MPCM (70 to 90 percent of cases). The appearance of UP/MPCM in children is often different from that in adults, with lesions that are more variable in size and shape (picture 1C). Other forms of CM in children are mastocytomas (picture 2) and diffuse cutaneous mastocytosis (DCM) (picture 3). Children with DCM do not have individually discernible lesions, but rather a diffuse thickening and slight darkening of the skin (picture 4A-B). Children with DCM are prone to blistering, severe pruritus, and severe systemic symptoms, such as systemic anaphylaxis, upper and lower gastrointestinal (GI) cramping, diarrhea, gastritis, ulcer disease, and GI bleeding.
Most children with UP/MPCM and mastocytoma have normal baseline serum tryptase, and any degree of elevation requires further follow-up and possible evaluation for systemic disease [19]. Children with DCM may have elevated baseline tryptase even without systemic disease, although persistently elevated or rising tryptase levels should prompt an evaluation for systemic disease. Evaluation and diagnosis of mastocytosis in children is reviewed separately. (See "Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis".)
Monoclonal mast cell activation syndrome — Monoclonal mast cell activation syndrome (MMAS) was first described in 2007 and recognized as a distinct primary mast cell disorder by an international consensus conference in the same year [20-22]. MMAS typically presents in adults with recurrent and episodic symptoms of mast cell activation, such as flushing, abdominal cramping, and hypotension, similar to patients with SM. However, these patients do not have UP/MPCM or the characteristic mast cell aggregates in their bone marrow (a major criterion for SM) and have baseline serum tryptase values that are normal or only mildly increased [20,21,23,24].
Patients with MMAS display one or two minor clonality criteria for SM, but do not fully meet requirements for that diagnosis [21,22]. A clonal population of mast cells in the bone marrow can be demonstrated by the presence of KIT point mutations (most commonly D816V) and aberrant mast cell surface expression of CD25 (alpha chain of the high affinity interleukin-2 [IL-2] receptor, not found on normal mast cells) and, less consistently, CD2 (lymphocyte function antigen-2 [LFA-2]) or CD30 expression [25]. However, the diagnosis of MMAS can be challenging because KIT mutations may be only detectable in a bone marrow sample enriched for mast cells (rather than in unfractionated bone marrow) or when sensitive diagnostic assays based on allele-specific PCR or digital droplet PCR are employed. Thus, referral to a specialty center is often required to make this diagnosis.
Secondary mast cell activation disorders — Secondary mast cell activation disorders include classic allergic disorders and other conditions in which mast cells are apparently normal in quantity and function but are responding to an identifiable external stimulus (figure 1 and table 2). Activating stimuli include allergens, autoantibodies, physical factors, infections, drugs, or products of complement activation (table 6). Secondary causes of mast cell activation disorders are far more prevalent than primary or idiopathic mast cell disorders. In most cases, clinicians would not think of the above disorders as secondary mast cell activation disorders. However, secondary mast cell activation disorders must be considered and excluded before a primary or idiopathic mast cell disorder can be diagnosed.
Secondary mast cell activation disorders include:
●Allergic diseases – IgE-mediated allergies to foods, drugs, and a variety of other allergens to which the person is exposed systemically.
●Physical forms of urticaria – Physical factors that can activate mast cells in susceptible individuals include pressure or vibration on the skin, sudden shifts in temperature, exercise, and exposure to water or ultraviolet (UV) light. (See "Physical (inducible) forms of urticaria".)
●Chronic inflammatory and neoplastic disorders – Secondary increases in mast cell numbers causing symptoms (urticaria, angioedema, and or pruritus) and infiltrating affected tissues can be seen in occasional patients with chronic inflammatory/autoimmune disorders (eg, rheumatoid arthritis, lupus, psoriasis, atopic dermatitis, pulmonary fibrosis) or neoplastic conditions.
Neoplasms sometimes associated with increased mast cells on tissue biopsies include solid tumors (eg, breast cancer), Hodgkin lymphoma, and skin and connective tissue tumors. In addition, aplastic anemia is variably associated with increased expression of SCF, leading to a proliferation of mast cells in the bone marrow. Elevated tryptase levels are seen in some myeloproliferative variants of hypereosinophilic syndromes. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Diagnosis of HES subtypes'.)
In secondary mast cell disorders, mast cells in tissue biopsies generally have a mature appearance (round in shape and fully granulated in bone marrow) and lack surface marker abnormalities found in primary mast cell disorders.
Idiopathic mast cell disorders — Idiopathic mast cell disorders are conditions in which mast cell activation occurs, but there is no consistent trigger that accounts for all of the symptoms, and a clonal population of mast cells cannot be demonstrated. This group includes chronic spontaneous urticaria, idiopathic anaphylaxis, idiopathic angioedema, and idiopathic mast cell activation syndrome (IMCAS) (table 2). Mast cell activation may be mostly localized to one organ system (eg, the skin in chronic spontaneous urticaria) or it may be systemic (idiopathic anaphylaxis and IMCAS).
It is possible that disorders that are classified as idiopathic may ultimately be shown to be primary mast cell disorders in the future if new genetic defects are identified. Alternatively, these disorders may prove to be secondary mast cell disorders for which a mast cell-activating stimulus exists but has not been identified. For example, delayed anaphylaxis to meat ingestion caused by the carbohydrate allergen galactose-alpha-1,3-galactose was probably classified as idiopathic anaphylaxis in many patients until IgE directed against this allergen was identified. Likewise many patients with MMAS were diagnosed with idiopathic anaphylaxis until it was recognized that they had features of a monoclonal mast cell population [21]. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history" and "Idiopathic anaphylaxis" and "Allergy to meats", section on 'IgE-mediated reactions'.)
Idiopathic mast cell activation syndrome — Patients with idiopathic MCAS (IMCAS) are a subset of all patients who meet the criteria for MCAS (figure 1). However, in IMCAS, episodes of symptoms are not always caused by triggers that the patient has been shown to be allergic to, so the designation of idiopathic is assigned. For example, a patient with episodic flushing and abdominal symptoms, with elevated serum tryptase after symptoms and no identifiable allergic trigger would be appropriately classified as IMCAS. Skin findings of UP/MPCM are not seen in IMCAS.
Idiopathic anaphylaxis — Idiopathic anaphylaxis is a diagnosis of exclusion, which also represents a subset of patients meeting criteria for MCAS (figure 1). Idiopathic anaphylaxis is assigned to patients whose symptoms fulfill the clinical definition of anaphylaxis (table 7), such as a patient with unexplained episodes of hypotension and flushing. Skin findings of UP/MPCM are not seen in idiopathic anaphylaxis. The definitions of these two disorders will likely evolve over time. (See "Idiopathic anaphylaxis".)
SIGNS AND SYMPTOMS — The organ systems most often involved in mast cell disorders are the skin, gastrointestinal (GI) tract and upper and lower respiratory tracts, and the cardiovascular system (table 1). The signs and symptoms arise from the ways mast cell mediators affect these organ systems.
Skin and soft tissues — Patients with mast cell disorders often experience flushing, caused by vasodilatory effects of histamine and other mediators. Flushing may be induced by exercise, alcohol, temperature changes, and emotional events. In the author's experience, patients with mast cell disorders develop flushing in association with signs and symptoms in other organ systems, whereas flushing in isolation (eg, chest or the upper neck) is an uncommon presentation and may be due to other causes, such as autonomic dysfunction. The differential diagnosis of flushing is extensive and includes hormonal, neurologic, dermatologic, iatrogenic, and cardiovascular etiologies [26]. The flushing observed in mast cell disorders is episodic, of longer duration, lasting minutes to a few hours, and usually is not accompanied by sweating, whereas perimenopausal hot flashes usually last two to four minutes and are often accompanied by sweating. (See "Approach to flushing in adults".)
Patients may also present with pruritus, dermographism, urticaria, and/or angioedema, although these symptoms are more characteristic of secondary (such as IgE-mediated allergic causes) or idiopathic mast cell activation disorders, whereas flushing is prominent in primary mast cell disorders (such as mastocytosis). (See 'Classification of mast cell disorders' above.)
Gastrointestinal — Mast cell activation can cause GI complaints, such as intermittent pain, heartburn, nausea, vomiting, diarrhea, and abdominal cramping [27,28]. Heartburn and nausea may be partially caused by gastric acid hypersecretion from parietal cells, which can be stimulated by histamine in patients with increased mast cell burden. Histamine and lipid-derived mast cell mediators (such as leukotrienes) contribute to abdominal pain and diarrhea. Multiple food and environmental intolerances with negative testing for IgE-mediated allergy does not warrant further evaluation of MCAS as the primary origin of symptoms, although these patients may have other immune or non-immune basis for their reaction to multiple foods and chemicals.
Respiratory and naso-ocular — Mast cell activation can result in upper and lower airway symptoms, including rhinorrhea, nasal congestion, conjunctival injection and ocular itching, and bronchoconstriction, resulting in shortness of breath and wheezing. Angioedema of the mucosal linings in the upper airways (eg, laryngeal edema) and wheezing are relatively uncommon in primary mast cell disorders and are more characteristic of secondary (eg, allergic) or idiopathic disorders.
Cardiovascular — Systemic mast cell degranulation can lead to episodic hypotension with resultant lightheadedness and syncope. A compensatory tachycardia is typically associated with the hypotensive event, although other rhythm abnormalities and life-threatening myocardial perfusion abnormalities can be superimposed, especially in patients with coexisting structural or ischemic heart disease. Mast cell disease is thus included in the differential diagnosis of patients with unexplained recurrent syncopal episodes, especially those associated with other symptoms, such as flushing and GI complaints [29]. However, there are many causes of sinus tachycardia [30]. Postural orthostatic tachycardia syndrome can be diagnosed with MCAS in some patients based on clinical grounds, although a pathologic basis for the role of mast cells in this disorder is lacking. (See "Postural tachycardia syndrome".)
Neuropsychiatric — Headache, fatigue, lethargy, lack of concentration, and mild cognitive problems are frequent complaints in patients with primary and secondary mast cell activation (ie, with mastocytosis, as well as those with allergic disorders) [1,31-35]. In infants, apneic spells and irritability are seen with extensive cutaneous mastocytosis. These symptoms may be due to the effects of mast cell mediators, medications, or (in adults) psychosomatic effects of having a chronic illness.
Note that subjective neuropsychiatric symptoms, in isolation, do not warrant an evaluation for a mast cell disorder. Rather, subjective symptoms should be accompanied by objective signs and symptoms affecting other organ systems before mast cell disorders are considered.
Systemic — Sudden, rapid mast cell activation affecting multiple organ systems causes anaphylaxis, and patients with mast cell disorders may present with unexplained anaphylaxis.
DIAGNOSTIC APPROACH — Primary or idiopathic mast cell disorders are usually considered when patients have symptoms consistent with mast cell activation, such as flushing, urticaria, diarrhea, abdominal cramping, wheezing, syncope, or near-syncope. Characteristic skin lesions are unique to the cutaneous and systemic forms of mastocytosis and are therefore very helpful when present. In most cases, the clinician has already considered a wide array of more common allergic disorders (secondary mast cell disorders), but none accounts for the entire presentation.
●In infants and children, most mastocytosis is limited to the skin (cutaneous mastocytosis [CM]). The typical presentation of CM involves characteristic skin lesions of urticaria pigmentosa/maculopapular cutaneous mastocytosis (UP/MPCM) combined with symptoms of mast cell activation (picture 4A-B). The evaluation is discussed in more detail separately. (See "Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis".)
●In adults presenting with recurrent anaphylaxis or recurrent episodes of apparent mast cell activation without an IgE-mediated or other secondary etiology, the mast cell disorders that should be considered are systemic mastocytosis (SM) and CM, monoclonal mast cell activation syndrome (MMAS), idiopathic mast cell activation syndrome (IMCAS), and idiopathic anaphylaxis. All are rare. The evaluation is discussed in more detail separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis" and "Idiopathic anaphylaxis".)
●In addition to diagnoses discussed in this topic, ICD10-CM includes additional diagnostic coding for two entities: D89.40 mast cell activation, unspecified, and D89.49 other mast cell activation disorder. Diagnostic guidelines for these entities are not established and it is not recommended to assign these codes as primary diagnoses [9].
Clinical history — Each episode of symptoms that the patient can describe should be reviewed in detail to determine if the signs and symptoms are consistent with mast cell activation. Review of objective findings such as vital signs, physical exam, emergency department records, and lab results can be helpful if patient does not remember specific details. In addition, the clinician should attempt to discern triggering factors. Triggers should be considered as possible causes of a secondary mast cell disorder. (See 'Search for allergic disease or other causes of secondary mast cell activation' below.)
Clinical pearls — There are several observations that can be helpful when considering the likelihood that a patient has a mast cell disorder [6]:
●Recurrent or chronic urticaria, angioedema, and/or upper airway swelling are not characteristic of mastocytosis and patients with these symptoms in the absence of other findings do not need to be evaluated for mastocytosis.
●Anaphylaxis with hypotension in response to a bee or wasp sting is a classic manifestation of mastocytosis and may be the presenting scenario. A serum tryptase (when the patient is in the baseline state) should be measured for any patient with severe systemic reactions to Hymenoptera stings.
●The presence of hypotension during anaphylaxis increases the odds that a patient has a clonal (primary) mast cell disorder. Clinicians should have a low threshold for referring such patients for bone marrow biopsy if an IgE-mediated cause does not explain all episodes, even if tryptase levels are normal.
Determine if skin findings of mastocytosis are present — A complete skin examination should be performed to determine if UP/MPCM skin lesions or the other forms of CM that develop in infants and children (diffuse cutaneous mastocytosis [DCM] or mastocytoma) are present.
UP/MPCM is unique to CM and SM, although not all patients with SM have skin findings. In most cases, cutaneous forms of mastocytosis are recognizable by simple inspection of the skin, and skin biopsy is not essential, particularly if the clinician is familiar with the appearance of CM. However, a 3 mm punch biopsy of lesional skin should be performed when the diagnosis of CM is in doubt. Skin biopsy confirms the presence of mast cells in the lesion, but does not provide information about systemic involvement. Specific histologic features and staining techniques are discussed elsewhere. (See "Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis" and "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)
Search for allergic disease or other causes of secondary mast cell activation — Any defined allergic disorders that could explain all or part of the patient's presentation should be considered. These include chronic urticaria/angioedema, allergies to foods or drugs, physical factors (exercise-induced anaphylaxis, cold urticaria, cholinergic urticaria, and delayed-pressure urticaria), allergic asthma, or other defined disorders. (See 'Referral' below.)
For patients presenting with anaphylaxis, efforts should be made to identify a trigger. An approach to this evaluation is outlined separately. (See "Anaphylaxis: Confirming the diagnosis and determining the cause(s)", section on 'Testing for allergen cause(s)'.)
The differential diagnosis of anaphylaxis is reviewed separately. (See "Differential diagnosis of anaphylaxis in adults and children".)
Measure serum tryptase — Serum tryptase is the most specific marker of mast cell activation available. An assay for serum total tryptase is available as "ImmunoCAP tryptase" and can be obtained through many commercial laboratories [36]. A "baseline" level (ie, a level when the patient is in their usual state of health) should be obtained. Values >11.4 ng/mL are considered elevated in most diagnostic laboratories. A tryptase level should also be obtained within four hours after symptoms, when possible, to provide evidence that mast cells are responsible for the patient's symptoms. Increases greater than 1.2 x baseline value + 2 ng/mL are considered indicative of mast cell activation [8]. For example, if a patient's baseline total tryptase were 5 ng/mL, a value of 8 ng/mL or greater drawn within four hours of symptoms would represent a significant increase and implicate mast cells as the cause of the patient's symptoms. Medications to treat allergic symptoms, such as epinephrine, antihistamines, anti-leukotriene agents, or cromolyn, do not affect serum tryptase.
●Tryptase >20 ng/mL is seen in many cases of SM when the patient is in a baseline state, which is one of the leading ways in which SM is distinguished from other mast cell disorders. If baseline tryptase is elevated on two occasions, an evaluation for SM should be pursued. If the blood was collected during symptoms, then another sample should be obtained in a few days when the patient is in a baseline state. Return to a normal level indicates episodes of mast cell activation without an increase in total body mast cells, which suggests mast cell activation, but not mastocytosis.
Milder baseline elevations or normal baseline tryptase levels may be seen in MMAS and IMCAS. If the serum tryptase is <20 ng/mL (ie, mildly elevated or normal) when the patient is at baseline, then a serum tryptase should be drawn during or soon after a future episode of symptoms. It is helpful to provide the patient with a letter to give to providers in urgent care facilities or emergency departments (form 1). Serum tryptase should be obtained between 15 minutes and 4 hours after the onset of symptoms. A relative increase in serum total tryptase is indicative of mast cell activation. A detailed discussion about the interpretation of serum tryptase levels is provided separately. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis", section on 'Tryptase'.)
Other conditions in which baseline tryptase can be persistently elevated include hereditary alpha-tryptasemia (HaT), other myeloid hematologic disorders (eg, chronic eosinophilic leukemia, myelodysplastic syndromes, acute leukemias), chronic renal insufficiency, and bone marrow suppression states. These disorders can generally be diagnosed based on peripheral blood and bone marrow findings and renal function tests. Familial tryptase elevations inherited in an autosomal dominant pattern due to duplications or higher copy numbers of alpha-tryptase gene (TPSAB1) have been described; however, it is not clear whether tryptase elevation in these families is associated with mast cell activation [37]. It should be noted that a finding of HaT in a patient with elevated tryptase does not rule out mastocytosis as HaT can be seen together with mastocytosis in some patients. Absence of HaT, on the other hand, in a patient with elevated level should generally prompt a workup for mastocytosis or other causes of elevated tryptase. The differential diagnosis of an elevated tryptase level is discussed elsewhere. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis" and "Laboratory tests to support the clinical diagnosis of anaphylaxis", section on 'Elevations of tryptase in nonanaphylactic patients'.)
●Tryptase is transiently elevated in some cases of anaphylaxis when measured within four hours of the episode and is more likely if the patient experienced hypotension. The diagnosis of anaphylaxis is clinical (table 7). Elevations in tryptase following symptoms support the diagnosis, although a normal tryptase does not exclude the possibility of anaphylaxis because some episodes of anaphylaxis (such as those triggered by food allergens) may not result in elevated tryptase. (See "Anaphylaxis: Acute diagnosis", section on 'Laboratory tests'.)
●If the patient does not fulfill the clinical criteria for anaphylaxis and elevations in tryptase are not detected at baseline or during symptoms, other disorders should be strongly considered. (See "Differential diagnosis of anaphylaxis in adults and children".)
REFERRAL — If a primary (eg, mastocytosis) or secondary mast cell disorder potentially explains the presentation (eg, food allergy, a physical urticaria), referral to an allergy specialist for further evaluation of specific disorders is appropriate.
If the patient is found to have symptoms or laboratory findings suggestive of a primary mast cell disorder or idiopathic mast cell activation syndrome, referral to a mast cell disease research center is suggested [38-40]. Experts in mast cell disorders are usually either allergy/immunology or hematology specialists. Distinguishing between systemic mastocytosis, monoclonal mast cell activation syndrome, idiopathic mast cell activation syndrome and idiopathic anaphylaxis can be challenging.
In contrast to the scenarios above, referral for evaluation of a mast cell disorder is not indicated in the patients with the following:
●Multiple environmental and chemical sensitivities
●Multiple food intolerances not explained by IgE-mediated food allergy
●Primarily neuropsychiatric or musculoskeletal symptoms
●Chronic nonspecific symptoms, such as fatigue
A controversial issue is the association of mast cell activation symptoms with Ehlers Danlos syndrome-hypermobility type and postural orthostatic hypotension and dysautonomia [41]. These patients may have symptoms such as flushing, abdominal pain, diarrhea, dizziness, and tachycardia that overlap between dysautonomia and mast cell activation. However, a definitive study to prove mast cell activation in these patients has not been published.
INITIAL MANAGEMENT — The patient may be treated with one or more therapies to counteract the various mediators released from mast cells, even if a definitive diagnosis has not yet been made [28]. Therapies are chosen based on the patient's symptoms:
●Anaphylaxis, hypotension, near-syncope – Any patient with anaphylaxis or symptoms affecting the airway or cardiovascular system should be given epinephrine autoinjectors and instructed in how and when to use them. (See "Prescribing epinephrine for anaphylaxis self-treatment".)
●Pruritus or urticaria – Nonsedating H1 antihistamines are appropriate for patients with pruritus or urticaria. Commonly used H1 antihistamines (adult dosing) include oral cetirizine (10 mg daily), fexofenadine (180 mg daily), loratadine (10 mg daily), desloratadine (5 mg daily) or levocetirizine (5 mg daily) [42]. Each of these agents may be used in children at age/weight-appropriate doses. In some patients, a combination of two or more H1 antihistamines or doubling the dose of a nonsedating agent may provide better symptom control than the use of a single agent. Diphenhydramine (25 to 50 mg four times daily for adults) or hydroxyzine (25 mg every six hours in adults or at age/weight-appropriate doses in children) may be added on an as-needed basis to manage breakthrough symptoms, although these first-generation antihistamines are not recommended as daily scheduled therapy due to sedation and anticholinergic side effects.
Antileukotriene agents may be added in patients with bronchospasm, flushing, itching, and abdominal cramping unresponsive to H1 and H2 antihistamines [43]. Specific agents (adult dosing) include montelukast (10 mg daily), zafirlukast (20 mg daily), and less commonly zileuton (1200 mg twice daily, extended release). Patients should be warned about possible psychiatric adverse events.
●Gastrointestinal symptoms – H2 antihistamines can be helpful for patients with hyperacidity and other gastrointestinal (GI) symptoms. Specific agents include famotidine (10 to 20 mg every 12 hours) and cimetidine (400 mg twice daily) [42]. Famotidine may be used in children at age/weight-appropriate doses.
Cromolyn sodium stabilizes mast cell and eosinophil membranes in vitro and its oral formulation (Gastrocrom, Nalcrom in the United Kingdom) is helpful in some patients with GI symptoms [44]. Dosing of the oral formulation (100 to 200 mg per dose) is up to four times daily, although treatment should be initiated at the lower end of the dose range and gradually increased, as it is minimally absorbed through the intestine and can cause osmotic diarrhea if introduced at high doses in some patients.
Response to antimediator therapies — Improvement of symptoms with drugs that target mast cell mediators provides further supporting evidence of mast cell involvement in disease process. Response to therapy is a component of the diagnosis of mast cell activation syndrome. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Disorders with similar clinical manifestations'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mast cell disorders".)
SUMMARY
●Categorization of mast cell disorders – Disorders of mast cells can be divided into three categories: primary, secondary, and idiopathic (table 2). All of these disorders can present with signs and symptoms of mast cell activation but differ in severity and involvement of various organ systems (table 1). The relationship among disorders that involve mast cell activation can be expressed as a Venn diagram (figure 1). (See 'Classification of mast cell disorders' above.)
•Primary disorders of mast cells include mastocytosis (both cutaneous and systemic) and monoclonal mast cell activation syndrome. All are rare. Primary mast cell disorders are characterized by clonal populations of mast cells that arise from an affected progenitor and display abnormal genetic and surface markers. The associated molecular defects affect mast cell proliferation or activation pathways. (See 'Primary mast cell disorders' above.)
•Secondary mast cell activation disorders are relatively common conditions in which mast cells are normal in quantity and function and are responding to an activating stimulus. Such stimuli include allergens, autoantibodies, physical factors, infections, drugs, or products of complement activation. Examples of secondary mast cell activation disorders include allergies to foods, drugs, and medications, physical urticaria, and, rarely, mast cell activation disorders associated with autoimmune disorders or malignancies. (See 'Secondary mast cell activation disorders' above.)
•Idiopathic mast cell disorders are conditions in which mast cell activation occurs, but there is no consistent trigger that accounts for all of the symptoms, and a clonal population of mast cells cannot be demonstrated. This group includes idiopathic anaphylaxis, chronic spontaneous urticaria, and idiopathic angioedema, as well as idiopathic mast cell activation syndrome. Mixed presentations can occur in individual patients. (See 'Idiopathic mast cell disorders' above.)
●Characteristic signs and symptoms – The organ systems most often involved in mast cell disorders are the skin, gastrointestinal tract, respiratory (upper and lower) tracts, and the cardiovascular system (table 1). Common signs and symptoms of mast cell activation include flushing, urticaria, diarrhea, naso-ocular congestion, wheezing, or syncope or near-syncope due to hypoperfusion of the brain. (See 'Signs and symptoms' above.)
●Approach to diagnosis – The diagnostic evaluation for mast cell disorders involves a detailed review of symptoms and possible triggers, a physical examination for skin lesions that are characteristic of mastocytosis (picture 1A, 1C), exclusion of secondary causes of mast cell activation, and measurement of serum tryptase (form 1). Any plausible secondary mast cell disorder should be excluded. (See 'Diagnostic approach' above.)
●Serum tryptase – Serum tryptase is the most specific marker of mast cell activation available. Tryptase is persistently elevated (usually >20 ng/mL) in systemic mastocytosis, and milder elevations are variably seen in other mast cell disorders and in some cases of diffuse cutaneous mastocytosis in infants and children. In patients with a normal tryptase at baseline, the demonstration of transient elevations of tryptase immediately after symptoms is important in proving that mast cell activation is the cause of the patient's symptoms. (See 'Measure serum tryptase' above.)
●Referral – If a secondary mast cell disorder potentially explains the presentation, referral to an allergy specialist for evaluation of specific disorders is appropriate. If the patient is found to have symptoms or laboratory findings suggestive of a primary mast cell disorder or idiopathic mast cell activation syndrome, referral to a mast cell disease research center is suggested. (See 'Referral' above.)
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