Graeme Eisenhofer (Presenter)
Technische Universität Dresden
Bio: Graeme Eisenhofer received his PhD in 1983 from the University of Otago, New Zealand, with clinical research on autonomic and neuroendocrine systems. He moved to the NIH in 1985, followed by the Baker Research Institute (Melbourne) in 1988, before returning to the NIH in 1991. At the NIH he developed measurements of plasma free metanephrines as a biochemical test for diagnosis of pheochromocytoma and was responsible the first ever synthesis of 18F-fluorodopamine as a PET imaging agent for localizing catecholamine-producing tumors. In 2007 he took up a Professorship at the University Hospital Dresden, where he is the coordinator of a Clinical Research Unit focusing on adrenal hypertension and disorders of adrenal function.
Authorship: Graeme Eisenhofer, Tracy A. Williams, Tanja Dekkers, Mirko Peitzsch, Anna S. Dietz, Marcus Treitl, Martin Bidlingmaier, Stefan R. Bornstein, Lars C. Rump, Holger S. Willenberg, Felix Beuschlein, Jaap Deinum, Jacques W.M. Lenders and Martin Reincke
Technische Universität Dresden, Dresden, Germany; Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany; University of Turin, Turin, Italy Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; University of Dusseldorf, Dusseldorf, Germany
Identification of patients with primary aldosteronism due to unilateral versus bilateral adrenal aldosterone production is crucial for choice of therapeutic intervention, but depends on measurements of aldosterone and cortisol in adrenal venous plasma. LC-MS/MS-based assessments of the plasma steroid metabolome provide advantages over conventional immunoassay measurements of aldosterone and cortisol for discrimination of bilateral from unilateral disease. In particular, measurements in peripheral plasma enable stratification of disease according to underlying mutations and therapeutic outcome. By using the peripheral venous steroid metabolome to identify patients with bilateral disease it is potentially possible to reduce requirements for adrenal venous sampling by up to 43%.
Background: Identification of patients with primary aldosteronism (PA) due to unilateral versus bilateral adrenal aldosterone production is crucial for choice of therapeutic intervention. For those patients with unilateral aldosterone-producing adenomas (APAs), for whom adrenalectomy is indicated, the nature of disease can vary depending on the presence of somatic mutations in several genes. We assessed the utility of the plasma steroid metabolome as a diagnostic tool to stratify patients with primary aldosteronism according to unilateral versus bilateral disease and underlying mutation.
Methods: Fifteen adrenal steroids were measured by liquid chromatograpy with tandem mass spectrometry (LC-MS/MS) in peripheral and adrenal venous plasma from 216 patients with PA who underwent adrenal venous sampling (AVS) studies at three tertiary referral centers. Ninety patients were diagnosed with bilateral disease and 126 with APAs based on immunoassay-derived adrenal venous aldosterone lateralization ratios. Among patients with APAs, mutations of KCNJ5 and other genes were identified in 43 adenomas from 79 patients tested.
Results: Alternative steroids to cortisol (e.g., dehydroepiandrosterone and androstenedione) were identified to provide vastly improved assessment of AVS selectivity and appropriate utility for assessment of lateralized aldosterone secretion. Among patients with APAs, LC-MS/MS-derived lateralization ratios were higher than immunoassay-derived ratios. The hybrid steroids, 18-oxocortisol and 18-hydroxycortisol, also showed lateralized secretion in 76% and 35% of patients with APAs, with the former steroid indicative of underlying KCNJ5 mutations. Adrenal venous concentrations of glucocorticoids and androgens were bilaterally higher in patients with bilateral than unilateral disease and among patients with APAs also showed different patterns according to the underlying mutation. The distinct steroid metabolome patterns in adrenal venous plasma translated to differences in peripheral plasma that correctly classified 80% of cases of unilateral versus bilateral disease and also enabled correct classification of underlying mutations in all except one of the APAs with identified mutations. Seven patients who showed treatment failure in response to adrenalectomy indicated by immunoassay-based lateralization of aldosterone secretion were correctly classified to this group based on the peripheral plasma steroid metabolome.
Conclusions: LC-MS/MS-based assessments of the plasma steroid metabolome not only provides advantages over conventional immunoassay measurements of aldosterone and cortisol for AVS-based discrimination of bilateral from unilateral disease, but with simpler measurements in peripheral plasma also enables stratification of disease according to underlying mutations and therapeutic outcome. By using the peripheral venous steroid metabolome to identify patients with bilateral disease it is possible to reduce requirements for AVS by up to 43%.
References & Acknowledgements:
IP Royalty: no
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