Genotype-Specific Steroid Profiles Associated With Aldosterone-Producing Adenomas

Primary aldosteronism comprises 2 main subtypes: unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia. Somatic KCNJ5 mutations are found in APA at a prevalence of around 40% that drive and sustain aldosterone excess. Somatic APA mutations have been described in other genes (CACNA1D, ATP1A1, and ATP2B3) albeit at a lower frequency. Our objective was to identify genotype-specific steroid profiles in adrenal venous (AV) and peripheral venous (PV) plasma in patients with APAs. We measured the concentrations of 15 steroids in AV and PV plasma samples by liquid chromatography–tandem mass spectrometry from 79 patients with confirmed unilateral primary aldosteronism. AV sampling lateralization ratios of steroids normalized either to cortisol or to DHEA+androstenedione were also calculated. The hybrid steroid 18-oxocortisol exhibited 18- and 16-fold higher concentrations in lateralized AV and PV plasma, respectively, from APA with KCNJ5 mutations compared with all other APA combined together (P<0.001). Lateralization ratios for the KCNJ5 group were also generally higher. Strikingly, we demonstrate that a distinct steroid signature can differentiate APA genotype in AV and PV plasma. Notably, a 7-steroid fingerprint in PV plasma correctly classified 92% of the APA according to genotype. Prospective studies are necessary to translate these findings into clinical practice and determine if steroid fingerprinting could be of value to select patients with primary aldosteronism who are particularly suitable candidates for adrenal venous sampling because of a high probability of having an APA.

[1]  Xiangjun Lyu,et al.  Prevalence and Characterization of Somatic Mutations in Chinese Aldosterone-Producing Adenoma Patients , 2015, Medicine.

[2]  P. Milliez,et al.  Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. , 2005, Journal of the American College of Cardiology.

[3]  F. Veglio,et al.  Visinin-Like 1 Is Upregulated in Aldosterone-Producing Adenomas With KCNJ5 Mutations and Protects From Calcium-Induced Apoptosis , 2012, Hypertension.

[4]  M. Reiser,et al.  Age below 40 or a recently proposed clinical prediction score cannot bypass adrenal venous sampling in primary aldosteronism. , 2014, The Journal of clinical endocrinology and metabolism.

[5]  R. Holle,et al.  Risk factors associated with a low glomerular filtration rate in primary aldosteronism. , 2009, The Journal of clinical endocrinology and metabolism.

[6]  M. Reincke,et al.  Primary aldosteronism: current knowledge and controversies in Conn's syndrome , 2007, Nature Clinical Practice Endocrinology &Metabolism.

[7]  Ji-Guang Wang,et al.  Clinical Characteristics of Somatic Mutations in Chinese Patients With Aldosterone-Producing Adenoma , 2015, Hypertension.

[8]  S. Ito,et al.  18-oxocortisol measurement in adrenal vein sampling as a biomarker for subclassifying primary aldosteronism. , 2011, The Journal of clinical endocrinology and metabolism.

[9]  M. Mori,et al.  Expression and mutations of KCNJ5 mRNA in Japanese patients with aldosterone-producing adenomas. , 2012, The Journal of clinical endocrinology and metabolism.

[10]  R. Kuick,et al.  Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands , 2015, Proceedings of the National Academy of Sciences.

[11]  S. Ito,et al.  Measurement of Peripheral Plasma 18-Oxocortisol Can Discriminate Unilateral Adenoma From Bilateral Diseases in Patients With Primary Aldosteronism , 2015, Hypertension.

[12]  P. Plouin,et al.  Cardiovascular Complications Associated With Primary Aldosteronism: A Controlled Cross-Sectional Study , 2013, Hypertension.

[13]  D. Miotto,et al.  Somatic mutations in the KCNJ5 gene raise the lateralization index: implications for the diagnosis of primary aldosteronism by adrenal vein sampling. , 2012, The Journal of clinical endocrinology and metabolism.

[14]  M. Omura,et al.  Comparison of cardiovascular complications in patients with and without KCNJ5 gene mutations harboring aldosterone-producing adenomas. , 2015, Journal of atherosclerosis and thrombosis.

[15]  C. Gomez-Sanchez,et al.  Potassium channel mutant KCNJ5 T158A expression in HAC-15 cells increases aldosterone synthesis. , 2012, Endocrinology.

[16]  C. Gomez-Sanchez,et al.  Immunohistochemical, genetic and clinical characterization of sporadic aldosterone-producing adenomas , 2015, Molecular and Cellular Endocrinology.

[17]  P. Mulatero,et al.  Understanding primary aldosteronism: impact of next generation sequencing and expression profiling , 2015, Molecular and Cellular Endocrinology.

[18]  X. Jeunemaître,et al.  Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. , 1998, The Journal of clinical endocrinology and metabolism.

[19]  James Hadfield,et al.  Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension , 2013, Nature Genetics.

[20]  T. Strom,et al.  Genetic Spectrum and Clinical Correlates of Somatic Mutations in Aldosterone-Producing Adenoma , 2014, Hypertension.

[21]  W. Young,et al.  Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. , 2008, The Journal of clinical endocrinology and metabolism.

[22]  F. Beuschlein,et al.  Cardiovascular and cerebrovascular comorbidities of hypokalemic and normokalemic primary aldosteronism: results of the German Conn's Registry. , 2009, The Journal of clinical endocrinology and metabolism.

[23]  B. Tops,et al.  Adrenal nodularity and somatic mutations in primary aldosteronism: one node is the culprit? , 2014, The Journal of clinical endocrinology and metabolism.

[24]  Gabriele Siegert,et al.  An LC–MS/MS method for steroid profiling during adrenal venous sampling for investigation of primary aldosteronism , 2015, The Journal of Steroid Biochemistry and Molecular Biology.

[25]  J. Funder,et al.  A Meta-Analysis of Somatic KCNJ5 K(+) Channel Mutations In 1636 Patients With an Aldosterone-Producing Adenoma. , 2015, The Journal of clinical endocrinology and metabolism.

[26]  F. Veglio,et al.  Long-term cardio- and cerebrovascular events in patients with primary aldosteronism. , 2013, The Journal of clinical endocrinology and metabolism.

[27]  M. Bäckdahl,et al.  Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas. , 2015, Endocrine-related cancer.

[28]  C. Gomez-Sanchez,et al.  18-hydroxycorticosterone, 18-hydroxycortisol, and 18-oxocortisol in the diagnosis of primary aldosteronism and its subtypes. , 2012, The Journal of clinical endocrinology and metabolism.

[29]  R. Bollag,et al.  Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells. , 2012, The Journal of clinical endocrinology and metabolism.

[30]  Annabelle L. Fonseca,et al.  Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype , 2015, Clinical endocrinology.

[31]  Morris J. Brown,et al.  Microarray, qPCR, and KCNJ5 sequencing of aldosterone-producing adenomas reveal differences in genotype and phenotype between zona glomerulosa- and zona fasciculata-like tumors. , 2012, The Journal of clinical endocrinology and metabolism.

[32]  H. Wallaschofski,et al.  Prevalence of Primary Aldosteronism in Patient’s Cohorts and in Population-based Studies – A Review of the Current Literature , 2011, Hormone and Metabolic Research.