ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2015) 38 OC1.6 | DOI: 10.1530/endoabs.38.OC1.6

Urine steroid metabolomics as a diagnostic tool in primary aldosteronism

Katharina Lang1, Felix Beuschlein2, Michael Biehl3, Anna Dietz2, Anna Riester2, Beverly A Hughes1, Donna M O’Neil1, Stefanie Hahner4, Marcus Quinkler5, Jacques W Lenders6, Cedric H L Shackleton1, Martin Reincke2 & Wiebke Arlt1

1Institute of Metabolism and Systems Research, University of Birmingham, and Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TT, UK; 2Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany; 3Johann-Bernoulli-Institute for Mathematics and Computer Science, University of Groningen, Groningen, The Netherlands; 4Department of Internal Medicine I, University Hospital Würzburg, 97080 Wuerzburg, Germany; 5Endocrinology in Charlottenburg, 10627 Berlin, Germany; 6Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.

Introduction: The regular diagnostic workup for primary aldosteronism (PA) can be very demanding and involves multiple invasive as well as time and cost intensive diagnostic tests. Here we have explored the value of urinary steroid metabolome analysis in the diagnosis and differential diagnosis of PA. Previously, urinary 3α,5β-tetrahydroaldosterone (THAldo) has been suggested as a reliable screening test for PA and serum 18-oxocortisol and 18-hydroxycortisol have been reported as diagnostic markers with the potential to distinguish unilateral aldosterone-producing adenomas (APA) from bilateral adrenal hyperplasia (BAH).

Patients and methods: We studied 180 PA patients (103 APA, 71 BAH) in whom PA had been confirmed by saline infusion test followed by adrenal vein sampling for subtype differentiation. We carried out targeted sequencing for disease-causing somatic mutations in the KCNJ5, CACNA1D, ATP1A1 and ATP2B3 genes in tumour tissue obtained by unilateral adrenalectomy, which was available in 75/103 APA patients. The urine steroid metabolome was analysed by gas chromatography-mass spectrometry comprising the quantification of 38 distinct steroids including metabolites of aldosterone, deoxycorticosterone, corticosterone as well as 18OH-cortisol (18OH-F) and 18-oxo-tetrahydrocortisol (18oxo-THF).

Results: As expected, urinary excretion of mineralocorticoids (p<0.0001) and mineralocorticoid precursors (p=0.002) was significantly higher in PA patients as compared to 89 sex- and age-matched controls. 65% of PA but none of the controls had a THAldo excretion >69 μg/24h, with significantly higher THAldo in APAs compared to BAH (p=0.0082). Similarly, APAs had significantly higher excretion of 18OH-F (p=0.0171) and 18oxo-THF (p=0.0005). Genetic analysis of APA tissue revealed mutations in KCNJ5 (n=29), ATPases (n=12) and CACNA1D (n=6) while in 28 patients no known mutation was identified. Patients with KCNJ5 mutations had significantly increased excretion of both 18OH-F (p=0.0002) and 18oxo-THF (p<0.0001) as compared to the other mutation groups.

Conclusion: Urine steroid metabolomics is a promising approach for the diagnosis and differential diagnosis of PA.