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Leukotrienes (LTs) 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 (cys-LT) production. Assessment of LTE4 in urine allows for noninvasive specimen collection and avoids artifactual formation of LTs during phlebotomy. Generation of LTE4 occurs nonspecifically from active mast cells, basophils, eosinophils, and macrophages, and modulated through a variety of mechanisms. Elevated concentrations of LTE4 are associated with inflammatory and accelerated mast cell activation conditions, specifically in patients with systemic mast cell disease.(1)
Systemic mastocytosis (SM), or systemic mast cell disease, is a myeloproliferative neoplasm which has infiltrated extracutaneous organs. Release of mast cell inflammatory mediators leads to disease symptoms including those associated with allergic and anaphylactic reactions, while increased mast cell number leads to organ dysfunction. Consensus diagnostic criteria for SM include 1 major criterion: imaging of the multifocal infiltrates; and 4 minor criteria: 1) identifying morphological features of >25% of mast cells from bone marrow biopsy, 2) detection of the point mutation at codon 816 in the KIT gene, 3) CD2 and/or CD25 expression in mast cells, and 4) persistently elevated serum tryptase. Diagnosis requires either 1 major plus 1 minor criterion or 3 minor criteria.(2)
Measurement of urinary mast cell activation biomarkers can aid in the initial evaluation of suspected cases of systemic mast cell disease, potentially avoiding the need for imaging and bone marrow examination. Patients with SM frequently have elevated urine concentrations of LTE4(1), N-methylhistamine(3,4), and/or 2,3-dinor 11 beta-prostaglandin F2 alpha.(4)
Urinary LTE4 has also demonstrated significant utility in patients with asthma and respiratory diseases. In a study of adults with mild to moderate asthma on 5-lipoxygenase inhibitors, urine LTE4 concentrations decreased approximately 40% compared to asthma control subjects, suggesting modest decreases in LTE4 production correlates with clinical improvements in asthma severity.
An aid to evaluate patients suspected of having systemic mastocytosis
Elevated urinary leukotriene E4 (LTE4) concentrations >104 pg/mg creatinine are consistent with the diagnosis of systemic mast cell disease when combined with clinical signs and symptoms. Pharmacological treatment with 5-lipoxygenase inhibitors or leukotriene receptor antagonists has been shown to decrease production of LTE4.
Urinary LTE4 may be used together with serum tryptase, urinary 2,3-dinor 11 beta-prostaglandin F2 alpha, and/or urinary N-methyl histamine.
Patients taking 5-lipoxygenase inhibitor Zileuton/Zyflo may have decreased concentrations of leukotriene E4 (LTE4) if dosage has not been discontinued for 48 hours.
Systemic mastocytosis is a heterogenous disease and lack of elevated LTE4 does not exclude the diagnosis of mast cell disease.
Increased excretion of LTE4 has also been reported in the following conditions: asthma, eosinophilic pneumonia, respiratory syncytial virus infection, atopic dermatitis, Crohn disease, and rheumatoid arthritis.
This assay measures both LTE4 and the 11-trans-LTE4 as markers of mast cell release.
< or =104 pg/mg creatinine
1. Gotlib J, Pardanani A, Akin C, et al: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis. Blood 2013 Mar 28;121(13):2393-2401
2. Heide R, Riezebos P, van Toorenbergen AW, et al: Predictive value of urinary N-methylhistamine for bone marrow involvement in mastocytosis. J Invest Dermatol 2000;115(3):587
3. Van Gysel D, Oranje AP, Vermeiden I, et al: Value of urinary N-methylhistamine measurements in childhood mastocytosis. J Am Acad Derm 1996;35(4):556-558
4. Roberts LJ, Sweetman BJ, Lewis RA, et al: Increased production of prostaglandin D2 in patients with systemic mastocytosis. N Engl J Med 1980;303:1400-1404