Kosuke Inoue1,2, Yuto Yamazaki3, Takumi Kitamoto4,5, Rei Hirose2, Jun Saito2, Masao Omura2, Hironobu Sasano3, Tetsuo Nishikawa2. 1. Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California. 2. Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Yokohama, Japan. 3. Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan. 4. Division of Endocrinology, Department of Medicine, Columbia University, New York, New York. 5. Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba, Japan.
Abstract
Context: Aldosterone biosynthesis is regulated principally by ACTH and gene mutations as well as by angiotensin II and serum potassium. In addition, previous studies have reported the potential effects of KCNJ5 mutations in aldosterone-producing adenoma (APA) on cardiovascular diseases. However, responsiveness to ACTH in APAs according to potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5) mutations remains unknown. Objective: To investigate KCNJ5 genotype-specific differences in aldosterone biosynthesis in response to ACTH stimulation. Design and Setting: A cross-sectional study through retrieval of clinical records. Participants: One hundred forty-one patients aged ≥20 years with APA were examined. Main Outcome Measures: Associations between KCNJ5 mutations and clinical parameters reflecting the renin-angiotensin system [saline infusion test (SIT)] and ACTH pathways [dexamethasone suppression test (DST)]. Results: KCNJ5 mutations were detected in 107 cases. In the crude comparison, patients with mutations in KCNJ5 had higher plasma aldosterone concentrations (PACs) both at baseline and after the SIT. PAC after the DST showed a significant inverse association with KCNJ5 genotypes after controlling for age, sex, tumor size, and PAC after the SIT. Immunohistochemical analysis of 101 cases revealed more abundant immunoreactivity of CYP11B1 and CYP17 in the KCNJ5-mutated group than in the KCNJ5 wild-type group. Conclusion: This report of marked suppression of PAC by dexamethasone in patients with KCNJ5-mutated APAs indicates that such APAs respond to endogenous ACTH more readily than APAs in nonmutated cases. Further molecular and epidemiologic studies are required to validate our results and clarify the clinical effectiveness of the DST for predicting KCNJ5 mutations before adrenalectomy.
Context:Aldosterone biosynthesis is regulated principally by ACTH and gene mutations as well as by angiotensin II and serum potassium. In addition, previous studies have reported the potential effects of KCNJ5 mutations in aldosterone-producing adenoma (APA) on cardiovascular diseases. However, responsiveness to ACTH in APAs according to potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5) mutations remains unknown. Objective: To investigate KCNJ5 genotype-specific differences in aldosterone biosynthesis in response to ACTH stimulation. Design and Setting: A cross-sectional study through retrieval of clinical records. Participants: One hundred forty-one patients aged ≥20 years with APA were examined. Main Outcome Measures: Associations between KCNJ5 mutations and clinical parameters reflecting the renin-angiotensin system [saline infusion test (SIT)] and ACTH pathways [dexamethasone suppression test (DST)]. Results:KCNJ5 mutations were detected in 107 cases. In the crude comparison, patients with mutations in KCNJ5 had higher plasma aldosterone concentrations (PACs) both at baseline and after the SIT. PAC after the DST showed a significant inverse association with KCNJ5 genotypes after controlling for age, sex, tumor size, and PAC after the SIT. Immunohistochemical analysis of 101 cases revealed more abundant immunoreactivity of CYP11B1 and CYP17 in the KCNJ5-mutated group than in the KCNJ5 wild-type group. Conclusion: This report of marked suppression of PAC by dexamethasone in patients with KCNJ5-mutated APAs indicates that such APAs respond to endogenous ACTH more readily than APAs in nonmutated cases. Further molecular and epidemiologic studies are required to validate our results and clarify the clinical effectiveness of the DST for predicting KCNJ5 mutations before adrenalectomy.
Authors: Taweesak Wannachalee; Lili Zhao; Kazutaka Nanba; Aya T Nanba; James J Shields; William E Rainey; Richard J Auchus; Adina F Turcu Journal: J Clin Endocrinol Metab Date: 2019-12-01 Impact factor: 5.958
Authors: Christina Tatsi; Andrea G Maria; Cole Malloy; Lin Lin; Edra London; Nick Settas; Chelsi Flippo; Meg Keil; Fady Hannah-Shmouni; Dax A Hoffman; Constantine A Stratakis Journal: J Clin Endocrinol Metab Date: 2021-05-13 Impact factor: 5.958
Authors: Minna Soinio; Anna-Kaarina Luukkonen; Marko Seppänen; Jukka Kemppainen; Janne Seppänen; Juha-Pekka Pienimäki; Helena Leijon; Tiina Vesterinen; Johanna Arola; Eila Lantto; Semi Helin; Ilkka Tikkanen; Saara Metso; Tuomas Mirtti; Ilkka Heiskanen; Leena Norvio; Mirja Tiikkainen; Tuula Tikkanen; Timo Sane; Matti Välimäki; Celso E Gomez-Sanchez; Ilkka Pörsti; Pirjo Nuutila; Pasi I Nevalainen; Niina Matikainen Journal: Eur J Endocrinol Date: 2021-03 Impact factor: 6.664