Detection of the major urinary metabolite of prostaglandin D2 in the circulation: Demonstration of elevated levels in patients with disorders of systemic mast cell activation

doi:10.1016/0091-6749(94)90371-9

Journal of Allergy and Clinical Immunology

Volume 93, Issue 5, May 1994, Pages 817-824

https://doi.org/10.1016/0091-6749(94)90371-9 Get rights and content

Abstract

The symptoms and hemodynamic alterations that accompany episodes of systemic mast cell activation have been largely attributed to excessive prostaglandin(PG)D₂ release. Quantification of the major urinary metabolite of PGD₂ has been invaluable in elucidating a role for PGD₂ in these clinical entities and in the biochemical evaluation of systemic mastocytosis. With the use of a modified mass spectrometric assay for the major urinary metabolite of PGD₂, this metabolite was detected in plasma from 10 normal volunteers (3.5 ± 1.4 pg/ml). Ingestion of niacin, which induces endogenous release of PGD₂, increased plasma levels of this metabolite 6.3 to 33 times above the upper limit of normal by 2 hours. Thereafter, levels declined gradually but remained elevated for up to 6 to 8 hours. In contrast, circulating levels of 9α;11β-PGF₂, the initial metabolite of PGD₂, peaked by 30 minutes and returned to baseline by 2 hours. The clinical utility of measuring the major urinary metabolite in the circulation was demonstrated by detection of markedly increased levels in plasma and serum from patients with systemic inastocytosis and a patient with a severe type I allergic reaction. Thus in the biochemical evaluation of episodes of systemic mast cell activation and endeavors to further elucidate the role of PGD₂ in human disease there are kinetic advantages of measuring the major urinary metabolite of PGD₂ in the circulation. One particular advantage is the evaluation of clinical events, which only in retrospect are suspected to be associated with excessive release of PGD₂, yet plasma or serum was obtained proximate to the event.

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Cited by (60)

Global Classification of Mast Cell Activation Disorders: An ICD-10-CM–Adjusted Proposal of the ECNM-AIM Consortium
2022, Journal of Allergy and Clinical Immunology: In Practice
Citation Excerpt :
It is also appropriate to ask for other MC mediators in these patients. Some of these patients can be reclassified as suffering from MCAS when tryptase and/or other MC-related mediators increase substantially during an attack in a subsequent investigation.57-60 In some of the patients, the levels of urinary PGD2 metabolites may increase substantially but serum tryptase levels increase only slightly.
Mast cell activation (MCA) is common and occurs in a number of pathologic conditions, including IgE-dependent and independent allergic reactions, atopic disorders, autoimmune processes, and mastocytosis. In a subset of patients, no underlying disease and no known trigger of MCA are found. When the symptoms are severe, systemic, and recurrent, and accompanied by a diagnostic increase in the serum tryptase level or other mast cell mediators, an MCA syndrome (MCAS) may be diagnosed. In these patients, the symptoms typically respond to drugs suppressing MCA, mediator production in mast cells, or mediator effects. In each case, diagnostic consensus criteria must be fulfilled to diagnose MCAS. In other patients, MCA may be local, less severe, or less acute, or may be suspected but not confirmed, so that the diagnostic criteria of MCAS are not fulfilled. In these patients, it may be difficult to prove MCA, for example, by measuring multiple mast cell mediators or basophil activation, the latter as a surrogate of IgE-dependent hypersensitivity. However, validated diagnostic criteria for implicating suspected MCA behind such conditions are lacking, even if some of these conditions have recently been assigned to an International Classification of Diseases-10-Clinical Modification code (ICD-10-CM). In this article, we discuss diagnostic features and criteria and propose a ICD-10-CM–adjusted classification for disorders associated with MCA, herein referred to as MCA disorders (MCADs), with special emphasis on the delineation between confirmed MCAS, MCAD not fulfilling MCAS criteria, and suspected MCAD that is not present. In addition, we discuss the discrimination between overt MCAD and predisposing conditions, such as atopic states, mastocytosis, and hereditary alpha tryptasemia.
Nontryptase Urinary and Hematologic Biomarkers of Mast Cell Expansion and Mast Cell Activation: Status 2022
2022, Journal of Allergy and Clinical Immunology: In Practice
Citation Excerpt :
In contrast, measurement of baseline urinary N-MH excretion has not been helpful to identify patients with MCAS or with MCA. In a series of 25 patients, only 2 had increased N-MH excretion.55 Likewise, in a second report of MC mediator levels from patients presenting with symptoms of MCA, among 52 patients who were found to have a single mediator increased, only 2 had increased excretion of N-MH.54
Quantitation of urinary metabolites of histamine, prostaglandin D₂, and leukotriene E₄ can fill the gap in our current efforts to improve diagnosis and management of symptomatic patients with systemic mastocytosis, and/or mast cell activation syndrome, In addition, patients symptomatic due to mast cell activation but who do not meet all the criteria for mast cell activation syndrome can have elevated baseline mediator metabolites. Serum tryptase levels have been the workhorse in diagnosing these disorders, but it has several drawbacks including the need to obtain acute and baseline samples, which require 2 visits to health care facilities and 2 venipunctures. Recently, increased baseline tryptase level has been reported in hereditary alpha tryptasemia, complicating diagnostic possibilities of an increased baseline tryptase level. Furthermore, no treatment can specifically be targeted at tryptase itself. In contrast, the finding of 1 or more elevated urinary levels of histamine, prostaglandin D₂, and/or leukotriene E₄ metabolites (1) greatly narrows diagnostic possibilities for causes of symptoms; (2) informs the practitioner what specific metabolic pathways are involved; and (3) targets the treatment in a specific, direct fashion. As a bonus, baseline spot/random urine samples can be obtained by the patients themselves and repeated at exactly the correct time when symptoms occur.
Evaluation and diagnosis of mast cell–associated disorders
2022, Allergic and Immunologic Diseases: A Practical Guide to the Evaluation, Diagnosis and Management of Allergic and Immunologic Diseases
Mast cells likely evolved to promote health and survival of their hosts, but these pathways and mechanisms have facilitated the development of immediate hypersensitivity reactions in humans. Holistically, mast cell activation is best conceived of as summative event having multiple inputs, with antigen-dependent immunoglobulin E (IgE)-mediated hypersensitivity being an important component. Patients with inappropriate mast cell activation, frequently independent of classical IgE-mediated allergic disease(s), are said to have mast cell–associated disorders (MCADs), that in some individuals result from clonal expansion of mast cells. A number of biomarkers and genetic tests have been developed that aid in confirmation of these clinical diagnoses. However, significant limitations remain in diagnostic modalities and management options for patients with suspected MCADs. Here we discuss human mast cells in an historical and evolutionary context and provide a clinical and genetic background for MCADs, as well as a practical approach for their evaluation and diagnosis.
Selecting the Right Criteria and Proper Classification to Diagnose Mast Cell Activation Syndromes: A Critical Review
2021, Journal of Allergy and Clinical Immunology: In Practice
In recent years, knowledge about mechanisms underlying mast cell activation (MCA) and accumulation in various pathologic conditions increased substantially. In addition, criteria and a classification of MCA syndromes (MCASs) have been set forth. MCAS is defined by typical clinical symptoms, a substantial increase in serum tryptase level during an attack over the patient's baseline tryptase, and a response of the symptoms to drugs targeting mast cells, mediator production, and/or mediator effects. Alternative diagnostic criteria of MCAS have also been suggested, but these alternative criteria often lack specificity and validation. In this report, we critically review the contemporary literature relating to MCAS and compare the specificity, sensitivity, and strength of MCAS-related parameters within proposals to diagnose and classify MCAS and its variants. Furthermore, we highlight the need to apply specific consensus criteria in the evaluation and classification of MCAS in individual patients. This is an urgent and important medical necessity because as an increasing number of patients are being given a misdiagnosis of MCAS based on nonspecific criteria, which contributes to confusion and frustration by patients and caregivers and sometimes may delay recognition and treatment of correct medical conditions that often turn out to be unrelated to MCA.
Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome
2019, Journal of Allergy and Clinical Immunology: In Practice
Citation Excerpt :
Additional mediators, when rising from baseline, may also serve as markers of MCA or even MCAS. These include, among others, histamine (plasma, urine), histamine metabolites (urine), and the 24-hour urine PGD2 metabolite, 11β-PGF2α, or the LTC4 metabolite, LTE4, level (urine).27,31,32,45-50 However, as noted, these mediators are less specific for MCA compared with tryptase.
Mast cell activation (MCA) accompanies diverse physiologic and pathologic processes and is one of the more frequently encountered conditions in medicine. MCA-related symptoms are usually mild and often transient. In such cases, histamine receptor blockers and other mediator-targeting drugs can usually control MCA. In severe cases, an MCA syndrome (MCAS) may be diagnosed. However, overt MCAS is an unusual condition, and many patients referred because of suspected MCAS are diagnosed with other diseases (autoimmune, neoplastic, or infectious) unrelated to MCA or suffer from MCA-related (eg, allergic) disorders and/or comorbidities without fulfilling criteria of an overt MCAS. These considerations are important as more and more patients are informed that they may have MCA or even MCAS without completing a thorough medical evaluation. In fact, in several instances, symptoms are misinterpreted as MCA/MCAS, and other clinically relevant conditions are not thoroughly pursued. The number of such referrals is increasing. To avoid such unnecessary referrals and to prevent misdiagnoses, we here propose a diagnostic algorithm through which a clinically relevant (systemic) MCA can be suspected and MCAS can subsequently be documented or excluded. In addition, the algorithm proposed should help guide the investigating care providers to consider the 2 principal diagnoses that may underlie MCAS, namely, severe allergy and systemic mastocytosis accompanied by severe MCA. Although validation is required, we anticipate that this algorithm will facilitate the management of patients with suspected MCAS.
Gastrointestinal Involvement in Mast Cell Activation Disorders
2018, Immunology and Allergy Clinics of North America
Citation Excerpt :
Multiple studies have suggested that patients with mastocytosis are at higher risk for gastroduodenal ulcers.7,8,11 The pathogenesis of diarrhea in mastocytosis is also unclear, with contributions from gastric hypersecretion or prostaglandin D2 overproduction postulated.7,20 Malabsorption in systemic mastocytosis is rare and is not associated with pancreatic abnormalities; it may be related to small intestinal dysfunction and, again, possibly gastric hyperacidity.6,22

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^☆: Supported by grants GM15431, GM42056, ES07028 and HL02499 from the National Institutes of Health. Dr. Morrow is a Howard Hughes Medical Institute Postdoctoral Physician Fellow and a recipient of an award from the International Life Sciences Institute.

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Detection of the major urinary metabolite of prostaglandin D2 in the circulation: Demonstration of elevated levels in patients with disorders of systemic mast cell activation☆

Abstract

Prostaglandins

J Biol Chem

Anal Biochem

Biochem Biophys Acta

Biochem Biophys Acta

J Biol Chem

Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE

J Immunol

Increased production of prostaglandin D2 in patients with systemic mastocytosis

N Engl J Med

Prostaglandins

Annu Rev Biochem

Detection of the major urinary metabolite of prostaglandin D₂ in the circulation: Demonstration of elevated levels in patients with disorders of systemic mast cell activation☆

Prostaglandin D₂ generation after activation of rat and human mast cells with anti-IgE

Increased production of prostaglandin D₂ in patients with systemic mastocytosis