Clinical, Biochemical, and Genetic Characteristics of “Nonclassic” Apparent Mineralocorticoid Excess Syndrome

• Published in: The journal of clinical endocrinology and metabolism Vol. 104; no. 2; pp. 595 - 603
• Main Authors: Tapia-Castillo, Alejandra, Baudrand, Rene, Vaidya, Anand, Campino, Carmen, Allende, Fidel, Valdivia, Carolina, Vecchiola, Andrea, Lagos, Carlos F, Fuentes, Cristóbal A, Solari, Sandra, Martínez-Aguayo, Alejandro, García, Hernán, Carvajal, Cristian A, Fardella, Carlos E
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.02.2019; Copyright Oxford University Press; Oxford University Press
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 2 - genetics; 11β-Hydroxysteroid dehydrogenase; Adolescent; Adult; Angiotensin II; Antagonists; Biochemistry; Biomarkers - blood; Blood pressure; Body mass index; C-reactive protein; Cardiovascular diseases; Chile; Cortisol; Cortisone; Cortisone - blood; Cross-Sectional Studies; Endocrine disorders; Enzymes; Excretion; Female; Genes; Genotypes; Hereditary diseases; HSD11B2 gene; Humans; Hypertension; Hypokalemia; Inflammation; Male; Middle Aged; Mineralocorticoid Excess Syndrome, Apparent - blood; Mineralocorticoid Excess Syndrome, Apparent - diagnosis; Mineralocorticoid Excess Syndrome, Apparent - genetics; Pediatrics; Phenotype; Phenotypes; Plasminogen activator inhibitors; Potassium; Primary care; Renin; Young Adult; Youth; Chile
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2018-01197

Abstract Context Classical apparent mineralocorticoid excess (AME) is a rare recessive disorder, caused by severe 11β-hydroxysteroid dehydrogenase type 2 enzyme (11β-HSD2) deficiency. AME manifests as low-renin pediatric hypertension, hypokalemia and high cortisol/cortisone (F/E) ratio. Objective To evaluate nonclassic AME (NC-AME) due to partial 11β-HSD2 insufficiency and its association with hypertension, mineralocorticoid receptor (MR) activation, and inflammatory parameters. Design Cross-sectional study. Setting Primary care cohort. Participants We recruited 127 adolescents and adults. Subjects with secondary hypertension were excluded. We measured clinical, biochemical, renal, vascular, and inflammatory variables. Sequencing of HSD11B2 gene was performed in all subjects. Main Outcome Measure NC-AME. Results Serum F/E ratio was positively associated with systolic blood pressure (BP), microalbuminuria, and high-sensitivity C-reactive protein (hs-CRP). Serum cortisone correlated with MR activation parameters even when adjusted for age, body mass index, and sex: lower cortisone with higher potassium excretion (partial r = −0.29, P = 0.002) and with lower plasma renin activity (PRA) (partial r = 0.29, P = 0.001). Consistently, we identified 9 in 127 subjects (7.1%) with high F/E ratios (first quartile) and low cortisone (last quartile), suggestive of NC-AME. These subjects had higher systolic BP, 141.4 ± 25.7 mm Hg vs 127.3 ± 18.1 mm Hg, P = 0.03; lower PRA, 0.36 ± 0.19 ng/L*s vs 0.64 ± 0.47 ng/L*s, P < 0.0001; and greater potassium excretion, microalbuminuria, hs-CRP, and plasminogen activator inhibitor. We only found in 2 out of 9 subjects with NC-AME heterozygous mutations in the HSD11B2 gene. Conclusions These findings suggest a spectrum of partial 11β-HSD2 insufficiency in a primary care cohort without the classic phenotype and genotype of AME. NC-AME may represent a phenotype of MR activation and cardiovascular risk, suggesting that these subjects could be treated with MR antagonists. Our findings demonstrate that nonclassic AME may represent a currently unrecognized phenotype of excess MR activation and cardiovascular risk that may be specifically targeted with MR antagonists.