Clinical Information

Leukotrienes (LT) are eicosanoids generated from arachidonic acid via the 5-lipoxygenase pathway. Leukotriene E4 (LTE4) is the stable end product of this pathway and, therefore, regarded as a biomarker of total cysteinyl leukotriene production.(1-3) Assessment of LTE4 in urine allows for noninvasive specimen collection and avoids artifactual formation of LT during phlebotomy. Generation of LTE4 occurs nonspecifically from active mast cells (MC), basophils, eosinophils, and macrophages and is modulated through a variety of mechanisms.(1) Elevated concentrations of LTE4 are associated with mast cell disorders, including mastocytosis and mast cell activation syndrome (MCAS).

Mastocytosis is a rare disease characterized by the clonal expansion of mast cells which infiltrate the skin (cutaneous mastocytosis, CM) or extracutaneous organs (systemic mastocytosis, SM). The most common form, CM, typically presents in young children and resolves spontaneously by adolescence. In SM, MC infiltration of at least one extracutaneous organ system is the distinguishing feature separating it from CM. Clinically, SM can be divided into 2 main categories, non-advanced and advanced SM. Non-advanced SM includes indolent SM, bone marrow mastocytosis and smoldering SM, while advanced SM includes aggressive SM, SM associated with a hematologic neoplasm,  and MC leukemia.

In most cases, clonal mast cell disorders such as SM are associated with activating KIT mutations such as D816V, or aberrant surface expression of CD2, CD25 or CD30 on MC. Patients with SM should fulfill the diagnostic criteria endorsed by the international consensus working group(5) and World Health Organization for this disorder. Diagnosis requires the presence of the major criterion plus one minor criterion, or 3 minor criteria.(1,4,5,6)

The consensus diagnostic criteria for SM include:

Major criterion:

Multifocal dense infiltrates detected in bone marrow or extracutaneous organ biopsy

Minor criteria:

1. Identification of atypical morphological features in greater than or equal to 25% of MC from biopsy

2. Detection of the activating point alteration at codon 816 in the KIT gene

3. CD2, CD25, and/or CD30 expression in MC

4. Elevated baseline serum tryptase (>20 ng/mL)

Mast cell activation syndromes are a group of clinical disorders characterized by recurrent episodes of systemic mast cell activation and excessive release of MC derived mediators, affecting multiple organ systems.(7). MCAS can be classified as primary (clonal), secondary (non-clonal), combined, or idiopathic.  Based on consensus criteria, the diagnosis of MCAS can be established when typical clinical symptoms arising from recurrent (episodic) acute systemic MC activation (typically in the form of recurrent anaphylaxis in at least 2 organ systems) have been documented; MC-derived mediators increase substantially in serum (tryptase) or urine (LTE4, N-methylhistamine or 2,3-dinor-11beta -prostaglandin F2alpha) over the individual's baseline; and the symptoms respond to drugs blocking MC activation, MC mediators, mediator production, or mediator effects.(7)

Serum tryptase is the most widely used biomarker for mast cell activation; however, diagnostic evaluation requires blood collection for both baseline and acute specimens obtained during or shortly after a symptomatic episode. Because mast cell activation events are often unpredictable and may not occur in a medical setting, urine mediator metabolites such as LTE4 provide a convenient, noninvasive alternative for assessing mast cell activation.(1,3,7)

Beyond its utility in mast cell disorders, growing clinical evidence supports the use of LTE4 in patients with aspirin-exacerbated respiratory disease and other forms of asthma.(8-10) For example, elevated LTE4 concentrations have been shown to correlate with traditional markers and represent a noninvasive approach to asthma phenotyping in patients with type 2 asthma mediated in part by MC and eosinophils.(10) In this study, increased urine LTE4 levels were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in adult and adolescent patients with asthma. Based on these and other findings, there is interest in the use of therapeutics that target the production of inflammatory eicosanoids, such as LTE4, in the management of these diseases.(11-13)