MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of primary aldosteronism: the Endocrine Society guideline 2016 revisited.
Williams Tracy Ann,Reincke Martin
European journal of endocrinology
The syndrome of primary aldosteronism (PA) is characterized by hypertension with excessive, autonomous aldosterone production and is usually caused by either a unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. The diagnostic workup of PA is a sequence of three phases comprising screening tests, confirmatory tests and the differentiation of unilateral from bilateral forms. The latter step is necessary to determine the optimal treatment approach of unilateral laparoscopic adrenalectomy (for patients with unilateral PA) or medical treatment with a mineralocorticoid receptor antagonist (for patients with bilateral PA). Since the publication of the revised Endocrine Society guideline 2016, a number of key studies have been published. They challenge the recommendations of the guideline in some areas and confirm current practice in others. Herein, we present the recent developments and current approaches to the medical management of PA.
Primary aldosteronism is highly prevalent in patients with hypertension and moderate to severe obstructive sleep apnea.
Dobrowolski Piotr,Kołodziejczyk-Kruk Sylwia,Warchoł-Celińska Ewa,Kabat Marek,Ambroziak Urszula,Wróbel Aleksandra,Piekarczyk Piotr,Ostrowska Aleksandra,Januszewicz Magdalena,Śliwiński Paweł,Lenders Jacques W M,Januszewicz Andrzej,Prejbisz Aleksander
Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine
STUDY OBJECTIVES:It has been suggested that there might be a pathophysiological link and overlap between primary aldosteronism (PA) and obstructive sleep apnea (OSA). Therefore, in a prospective study we evaluated the frequency of PA in hypertensive patients suspected of OSA. METHODS:We included 207 consecutive hypertensive patients (mean age 53.2±12.1 years, 133 M, 74 F) referred for polysomnography on the basis of one or more of the following clinical features: typical OSA symptoms, resistant or difficult-to-treat HT, diabetes or cardiovascular disease. PA was diagnosed based on saline infusion test. RESULTS:Moderate-to-severe OSA was diagnosed in 94 patients (45.4% of the whole group). PA was diagnosed in 20 patients with OSA (21.3%) as compared to 9 patients in the group without OSA (8.0%; p=0.006). PA was also frequent in patients in whom symptoms of OSA was a sole indication for PA screening (15.4%) and in patients with and without resistant hypertension (24.5 and 17.8% respectively). Most patients with PA and OSA were diagnosed with bilateral adrenal hyperplasia (18 patients, 90%). There were no major differences in clinical characteristics between patients with OSA with PA and those without PA. In multivariate models moderate-to-severe OSA predicted presence of PA (OR 2.89, p=0.018). CONCLUSIONS:Patients with clinically important moderate-to-severe OSA are characterized by relatively high frequency of PA. Our results support the recommendations to screen patients with moderate-to-severe OSA for PA regardless of the presence of other indication for PA screening.
Classification of microadenomas in patients with primary aldosteronism by steroid profiling.
Yang Yuhong,Burrello Jacopo,Burrello Alessio,Eisenhofer Graeme,Peitzsch Mirko,Tetti Martina,Knösel Thomas,Beuschlein Felix,Lenders Jacques W M,Mulatero Paolo,Reincke Martin,Williams Tracy Ann
The Journal of steroid biochemistry and molecular biology
In primary aldosteronism (PA) the differentiation of unilateral aldosterone-producing adenomas (APA) from bilateral adrenal hyperplasia (BAH) is usually performed by adrenal venous sampling (AVS) and/or computed tomography (CT). CT alone often lacks the sensitivity to identify micro-APAs. Our objectives were to establish if steroid profiling could be useful for the identification of patients with micro-APAs and for the development of an online tool to differentiate micro-APAs, macro-APAs and BAH. The study included patients with PA (n = 197) from Munich (n = 124) and Torino (n = 73) and comprised 33 patients with micro-APAs, 95 with macro-APAs, and 69 with BAH. Subtype differentiation was by AVS, and micro- and macro-APAs were selected according to pathology reports. Steroid concentrations in peripheral venous plasma were measured by liquid chromatography-tandem mass spectrometry. An online tool using a random forest model was built for the classification of micro-APA, macro-APA and BAH. Micro-APA were classified with low specificity (33%) but macro-APA and BAH were correctly classified with high specificity (93%). Improved classification of micro-APAs was achieved using a diagnostic algorithm integrating steroid profiling, CT scanning and AVS procedures limited to patients with discordant steroid and CT results. This would have increased the correct classification of micro-APAs to 68% and improved the overall classification to 92%. Such an approach could be useful to select patients with CT-undetectable micro-APAs in whom AVS should be considered mandatory.
Aldosterone Reduction Rate After Saline Infusion Test May Be a Novel Prediction in Patients With Primary Aldosteronism.
Nagano Hidekazu,Kono Takashi,Saiga Atsushi,Kubota Yoshihiro,Fujimoto Masanori,Felizola Saulo J A,Ishiwata Kazuki,Tamura Ai,Higuchi Seiichiro,Sakuma Ikki,Hashimoto Naoko,Suzuki Sawako,Koide Hisashi,Takeshita Nobushige,Sakamoto Shinichi,Ban Toshiaki,Yokote Koutaro,Nakamura Yasuhiro,Ichikawa Tomohiko,Uno Takashi,Tanaka Tomoaki
The Journal of clinical endocrinology and metabolism
OBJECTIVE:Accurate assessment and localization of aldosterone-producing adenomas (APAs) are essential for the treatment of primary aldosteronism (PA). Although adrenal venous sampling (AVS) is the standard method of reference for subtype diagnosis in PA, controversy exists concerning the criteria for its interpretation. This study aims to determine better indicators that can reliably predict subtypes of PA. METHOD:Retrospective, single-cohort analysis including 209 patients with PA who were subjected to AVS. Eighty-two patients whose plasma aldosterone concentrations (PAC) were normalized after surgery were histopathologically or genetically diagnosed with APA. The accuracy of image findings was compared to AVS results. Receiver operating characteristic (ROC) curve analysis between the operated and the no-apparent laterality groups was performed using AVS parameters and loading test for diagnosis of PA. RESULT:Agreement between image findings and AVS results was 56.3%. ROC curve analysis revealed that the lateralization index (LI) after adrenocorticotropin stimulation cutoff was 2.40, with 98.8% sensitivity and 97.1% specificity. The contralateral suppression index (CSI) cutoff value was 1.19, with 98.0% sensitivity and 93.9% specificity. All patients over the LI and CSI cutoff values exhibited unilateral subtypes. Among the loading test, the best classification accuracy was achieved using the PAC reduction rate after a saline infusion test (SIT) >33.8%, which yielded 87.2% sensitivity or a PAC after a SIT <87.9 pg/mL with 86.2% specificity for predicting bilateral PA. CONCLUSION:The combined criteria of the PAC reduction rate and PAC after the SIT can determine which subset of patients with APA who should be performed AVS for validation.
Subtype Diagnosis of Primary Aldosteronism: Approach to Different Clinical Scenarios.
Burrello J,Monticone S,Tetti M,Rossato D,Versace K,Castellano I,Williams T A,Veglio F,Mulatero P
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
Identification and management of patients with primary aldosteronism are of utmost importance because it is a frequent cause of endocrine hypertension, and affected patients display an increase of cardio- and cerebro-vascular events, compared to essential hypertensives. Distinction of primary aldosteronism subtypes is of particular relevance to allocate the patients to the appropriate treatment, represented by mineralocorticoid receptor antagonists for bilateral forms and unilateral adrenalectomy for patients with unilateral aldosterone secretion. Subtype differentiation of confirmed hyperaldosteronism comprises adrenal CT scanning and adrenal venous sampling. In this review, we will discuss different clinical scenarios where execution, interpretation of adrenal vein sampling and subsequent patient management might be challenging, providing the clinician with useful information to help the interpretation of controversial procedures.
A subtype prediction score for primary aldosteronism.
Nanba K,Tsuiki M,Nakao K,Nanba A,Usui T,Tagami T,Hirokawa Y,Okuno H,Suzuki T,Shimbo T,Shimatsu A,Naruse M
Journal of human hypertension
Primary aldosteronism (PA) is the most common cause of endocrine hypertension. Although adrenal venous sampling (AVS) is recommended as the gold standard procedure for subtype classification in PA, it is a specialized technique with limited availability. The objective of this study was to develop a scoring system that predicted PA subtype using clinical characteristics. Seventy-one patients with PA were studied. The subjects were diagnosed as having either unilateral (n=32) or bilateral disease (n=39) based on AVS, surgery and/or the postoperative clinical course. Variables associated with laterality in the univariate analysis were entered into multivariable logistic regression models and the regression coefficients were used to construct a subtype prediction score. The diagnostic significance of the score was then evaluated using receiver operating characteristic (ROC) curve analysis. The subtype prediction score was calculated as follows: serum potassium ⩽3.4 mEq l(-1), 2 points; plasma aldosterone concentration ⩾165 pg ml(-1), 3 points; and aldosterone to renin ratio ⩾1000 in a post-captopril challenge test (plasma renin activity in ng ml(-1) h(-1)), 3 points. ROC curve analysis for the ability to discriminate between unilateral and bilateral PA showed that a score of 5 points had 75% sensitivity and 95% specificity, and a score of 3 points had a sensitivity of 97% and a specificity of 59%. The area under the ROC curve was 0.920 (95% confidence interval, 0.859-0.979). Our subtype prediction score could discriminate between unilateral and bilateral PA and is useful for selecting patients who should undergo AVS before surgery.
Accuracy of adrenal computed tomography in predicting the unilateral subtype in young patients with hypokalaemia and elevation of aldosterone in primary aldosteronism.
Umakoshi Hironobu,Ogasawara Tatsuki,Takeda Yoshiyu,Kurihara Isao,Itoh Hiroshi,Katabami Takuyuki,Ichijo Takamasa,Wada Norio,Shibayama Yui,Yoshimoto Takanobu,Ogawa Yoshihiro,Kawashima Junji,Sone Masakatsu,Inagaki Nobuya,Takahashi Katsutoshi,Watanabe Minemori,Matsuda Yuichi,Kobayashi Hiroki,Shibata Hirotaka,Kamemura Kohei,Otsuki Michio,Fujii Yuichi,Yamamto Koichi,Ogo Atsushi,Yanase Toshihiko,Okamura Shintaro,Miyauchi Shozo,Suzuki Tomoko,Tsuiki Mika,Naruse Mitsuhide
CONTEXT:The current Endocrine Society Guideline suggests that patients aged <35 years with marked primary aldosteronism (PA) and unilateral adrenal lesions on adrenal computed tomography (CT) scan may not need adrenal vein sampling (AVS) before proceeding to unilateral adrenalectomy. This suggestion is, however, based on the data from only one report in the literature. OBJECTIVE:We sought to determine the accuracy of CT findings in young PA patients who had unilateral adrenal disease on CT with hypokalaemia and elevation of aldosterone. DESIGN AND PATIENTS:We retrospectively studied 358 PA patients (n = 30, aged <35 years; n = 39, aged 35-40 years; n = 289, aged ≥40 years) with hypokalaemia and elevation of aldosterone and unilateral disease on CT who had successful AVS. MAIN OUTCOME MEASURE:Accuracy of CT findings is determined by AVS findings and/or surgical outcomes in patients aged <35 years. RESULTS:Concordance of the diagnosis between CT and AVS was 90% (27/30) in patients aged <35 years, 79% (31/39) in patients aged 35-40 years and 69% (198/289) in those aged ≥40 years (trend for P < .01). Surgical benefit was confirmed in three patients aged <35 years and in three patients aged 35-40 years with the available surgical data who had discordance between CT and AVS findings. Collectively, the diagnostic accuracy of CT findings was 100% (30/30) if aged <35 years and 87% (34/39) if aged 35-40 years. CONCLUSION:Primary aldosteronism patients aged <35 years with hypokalaemia and elevation of aldosterone and unilateral disease on adrenal CT could be spared AVS.
Seated saline infusion test in predicting subtype diagnosis of primary aldosteronism.
Kaneko Hiroki,Umakoshi Hironobu,Ishihara Yuki,Sugawa Taku,Nanba Kazutaka,Tsuiki Mika,Kusakabe Toru,Satoh-Asahara Noriko,Yasoda Akihiro,Tagami Tetsuya
CONTEXT:Although saline infusion test is widely used as a confirmatory test for primary aldosteronism (PA), it is reportedly less sensitive in patients in whom aldosterone is responsive to the upright position by performing it in recumbent position. Based on a single-centre experience, seated saline infusion test (SSIT) has been reported to be highly sensitive and superior to recumbent testing in identifying both unilateral and bilateral forms of PA. However, due to limited participants number, the utility of SSIT needs to be validated in other series. OBJECTIVE:This study aimed to evaluate the accuracy of SSIT in determining the PA subtypes compared with adrenocorticotropic hormone stimulation test under dexamethasone suppression (Dex-AT). PATIENTS AND SETTING:Sixty-four patients with PA who underwent both SSIT and Dex-AT were included. Subtype diagnosis of PA was determined by adrenal venous sampling (AVS) (16 unilateral and 48 bilateral forms). MAIN OUTCOME MEASURE:Plasma aldosterone concentrations (PACs) were measured after SSIT and Dex-AT. RESULTS:The area under the receiver operating characteristic (ROC) curve for diagnosing unilateral PA was greater in SSIT than that in Dex-AT (0.907 vs. 0.755; P = .023). ROC curve analysis predicted optimal cut-off PACs of 13.1 ng/dL (sensitivity, 93.8%; specificity, 79.2%) for SSIT and 34.2 ng/dL (sensitivity, 75.0%; specificity, 68.8%) for Dex-AT. CONCLUSIONS:Seated saline infusion test has superior accuracy in subtype diagnosis of PA compared with Dex-AT. SSIT can be a sensitive test for determining patients who require AVS prior to surgery.
Significance of Computed Tomography and Serum Potassium in Predicting Subtype Diagnosis of Primary Aldosteronism.
Umakoshi Hironobu,Tsuiki Mika,Takeda Yoshiyu,Kurihara Isao,Itoh Hiroshi,Katabami Takuyuki,Ichijo Takamasa,Wada Norio,Yoshimoto Takanobu,Ogawa Yoshihiro,Kawashima Junji,Sone Masakatsu,Inagaki Nobuya,Takahashi Katsutoshi,Watanabe Minemori,Matsuda Yuichi,Kobayashi Hiroki,Shibata Hirotaka,Kamemura Kohei,Otsuki Michio,Fujii Yuichi,Yamamto Koichi,Ogo Atsushi,Yanase Toshihiko,Suzuki Tomoko,Naruse Mitsuhide,
The Journal of clinical endocrinology and metabolism
Context:The number of centers with established adrenal venous sampling (AVS) programs for the subtype diagnosis of primary aldosteronism (PA) is limited. Objective:Aim was to develop an algorithm for AVS based on subtype prediction by computed tomography (CT) and serum potassium. Design:A multi-institutional retrospective cohort study in Japan. Patients:A total of 1591 patients with PA were classified into four groups according to CT findings and potassium status. Subtype diagnosis of PA was determined by AVS. Main Outcome Measure:Prediction value of the combination of CT findings and potassium status for subtype diagnosis. Results:The percentages of unilateral hyperaldosteronism on AVS were higher in patients with unilateral disease on CT than those with bilateral normal results on CT (50.8% vs 14.6%, P < 0.01), and these percentages were higher in those with hypokalemia than those with normokalemia (58.4% vs 11.5%, P < 0.01). The prevalence and odds ratio for unilateral hyperaldosteronism on AVS were as follows: bilateral normal on CT with normokalemia, 6.2% (reference); unilateral disease on CT with normokalemia, 23.8% and 4.8 [95% confidence interval (CI), 3.1 to 7.2]; bilateral normal on CT with hypokalemia, 38.1% and 9.4 (95% CI, 6.2 to 14.1), and unilateral disease on CT with hypokalemia, 70.6% and 36.4 (95% CI, 24.7 to 53.5). Conclusions:Patients with PA with bilateral normal results on CT and normokalemia likely have a low prior probability of a lateralized form of AVS and could be treated medically, whereas those with unilateral disease on CT and hypokalemia have a high probability of a lateralized form of AVS.
Aldosterone-potassium ratio predicts primary aldosteronism subtype.
Puar Troy H,Loh Wann J,Lim Dawn St,Loh Lih M,Zhang Meifen,Foo Roger S,Lee Lynette,Swee Du S,Khoo Joan,Tay Donovan,Kam Jia W,Dekkers Tanja,Velema Marieke,Deinum Jaap,Kek Peng C
Journal of hypertension
OBJECTIVE:Prediction models have been developed to predict either unilateral or bilateral primary aldosteronism, and these have not been validated externally. We aimed to develop a simplified score to predict both subtypes and validate this externally. METHODS:Our development cohort was taken from 165 patients who underwent adrenal vein sampling (AVS) in two Asian tertiary centres. Unilateral disease was determined using both AVS and postoperative outcome. Multivariable analysis was used to construct prediction models. We validated our tool in a European cohort of 97 patients enrolled in the SPARTACUS trial who underwent AVS. Previously published prediction models were also tested in our cohorts. RESULTS:Backward stepwise logistic regression analysis yielded a final tool using baseline aldosterone-to-lowest-potassium ratio (APR, ng/dl/mmol/l), with an area under receiver-operating characteristic curve of 0.80 (95% CI 0.70-0.89). In the Asian development cohort, probability of bilateral disease was 90.0% (with APR <5) and probability of unilateral disease was 91.4% (with APR >15). Similar results were seen in the European validation cohort. Combining both cohorts, probability of bilateral disease was 76.7% (with APR <5), and probability for unilateral was 91.7% (with APR >15). Other models had similar predictive ability but required more variables, and were less sensitive for identifying bilateral PA. CONCLUSION:The novel aldosterone-to-lowest-potassium ratio is a convenient score to guide clinicians and patients of various ethnicities on the probability of primary aldosteronism subtype. Using APR to identify patients more likely to benefit from AVS may be a cost-effective strategy to manage this common condition.
Subtype diagnosis, treatment, complications and outcomes of primary aldosteronism and future direction of research: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension.
Mulatero Paolo,Sechi Leonardo A,Williams Tracy Ann,Lenders Jacques W M,Reincke Martin,Satoh Fumitoshi,Januszewicz Andrzej,Naruse Mitsuhide,Doumas Michael,Veglio Franco,Wu Vin Cent,Widimsky Jiri
Journal of hypertension
: Primary aldosteronism is a frequent cause of secondary hypertension requiring a specific pharmacological treatment with mineralocorticoid receptor antagonist or with unilateral adrenalectomy. These treatments have shown to reduce the excess of cardiovascular risk characteristically associated with this disease. In part I of this consensus, we discussed the procedures for the diagnosis of primary aldosteronism. In the present part II, we address the strategies for the differential diagnosis of primary aldosteronism subtypes and therapy. We also discuss the evaluation of outcomes and provide suggestions for follow-up as well as cardiovascular and metabolic complications specifically associated with primary aldosteronism. Finally, we analyse the principal gaps of knowledge and future challenges for research in this field.
Development and Validation of Prediction Models for Subtype Diagnosis of Patients With Primary Aldosteronism.
Burrello Jacopo,Burrello Alessio,Pieroni Jacopo,Sconfienza Elisa,Forestiero Vittorio,Rabbia Paola,Adolf Christian,Reincke Martin,Veglio Franco,Williams Tracy Ann,Monticone Silvia,Mulatero Paolo
The Journal of clinical endocrinology and metabolism
CONTEXT:Primary aldosteronism (PA) comprises unilateral (lateralized [LPA]) and bilateral disease (BPA). The identification of LPA is important to recommend potentially curative adrenalectomy. Adrenal venous sampling (AVS) is considered the gold standard for PA subtyping, but the procedure is available in few referral centers. OBJECTIVE:To develop prediction models for subtype diagnosis of PA using patient clinical and biochemical characteristics. DESIGN, PATIENTS AND SETTING:Patients referred to a tertiary hypertension unit. Diagnostic algorithms were built and tested in a training (N = 150) and in an internal validation cohort (N = 65), respectively. The models were validated in an external independent cohort (N = 118). MAIN OUTCOME MEASURE:Regression analyses and supervised machine learning algorithms were used to develop and validate 2 diagnostic models and a 20-point score to classify patients with PA according to subtype diagnosis. RESULTS:Six parameters were associated with a diagnosis of LPA (aldosterone at screening and after confirmatory testing, lowest potassium value, presence/absence of nodules, nodule diameter, and computed tomography results) and were included in the diagnostic models. Machine learning algorithms displayed high accuracy at training and internal validation (79.1%-93%), whereas a 20-point score reached an area under the curve of 0.896, and a sensitivity/specificity of 91.7/79.3%. An integrated flowchart correctly addressed 96.3% of patients to surgery and would have avoided AVS in 43.7% of patients. The external validation on an independent cohort confirmed a similar diagnostic performance. CONCLUSIONS:Diagnostic modelling techniques can be used for subtype diagnosis and guide surgical decision in patients with PA in centers where AVS is unavailable.
Sex Difference in the Association Between Subtype Distribution and Age at Diagnosis in Patients With Primary Aldosteronism.
Akasaka Hiroshi,Yamamoto Koichi,Rakugi Hiromi,Nagasawa Motonori,Nakamaru Ryo,Ichijo Takamasa,Takeda Yoshiyu,Kurihara Isao,Katabami Takuyuki,Tsuiki Mika,Wada Norio,Ogawa Yoshihiro,Kawashima Junji,Sone Masakatsu,Kamemura Kohei,Yoshimoto Takanobu,Matsuda Yuichi,Fujita Megumi,Kobayashi Hiroki,Watanabe Minemori,Tamura Kouichi,Okamura Shintaro,Miyauchi Shozo,Izawa Shoichiro,Chiba Yoshiro,Tanabe Akiyo,Naruse Mitsuhide,
Hypertension (Dallas, Tex. : 1979)
Primary aldosteronism (PA) is the most frequent cause of secondary hypertension. Adrenal vein sampling (AVS) is an established method for finding patients with the unilateral subtype of PA, for which adrenalectomy is an applicable treatment. In this study, we analyzed a large database of patients with PA who underwent adrenal vein sampling, to investigate the sex differences in the impact of age at diagnosis on the subtype and cause of PA. In 2122 patients, women with the unilateral subtype were younger than men with the same subtype and women with the bilateral subtype. Younger age and older age were associated with unilateral PA in women and men, respectively. After stratification by tertiles of age, there was a trend of decreased and increased incidence of unilateral PA with aging in women and men, respectively. Male sex was a predictor of unilateral PA in middle-aged and older patients but not in younger patients. We also found that obesity, a known factor associated with idiopathic hyperaldosteronism, was positively associated with bilateral PA in younger patients but not in older patients. These findings suggest that the proportion of operable patients with unilateral PA differs depending on the combination of sex and age, and that other than obesity, the cause of PA is also associated with the bilateral subtype in older patients.
Primary aldosteronism subtype discordance between computed tomography and adrenal venous sampling.
Aono Daisuke,Kometani Mitsuhiro,Karashima Shigehiro,Usukura Mikiya,Gondo Yuko,Hashimoto Atsushi,Demura Masashi,Furukawa Kenji,Takeda Yoshiyu,Kawashiri Masaaki,Yoneda Takashi
Hypertension research : official journal of the Japanese Society of Hypertension
The primary aldosteronism (PA) subtype is usually confirmed by CT and adrenal venous sampling (AVS). However, the subtype diagnosis by AVS is not necessarily consistent with the subtype diagnosis by CT. Patients with PA who show bilateral lesions (normal-appearing adrenals or bilateral adrenal nodules) on CT but unilateral disease on AVS are often found. The aim of this study was to evaluate whether patients with PA subtype discordance between CT and AVS obtain benefits from unilateral adrenalectomy. We retrospectively analyzed 362 consecutive patients with PA who underwent both CT and adrenocorticotropic hormone-unstimulated AVS at Kanazawa University Hospital. Surgical outcomes for unilateral PA were evaluated according to the criteria of the Primary Aldosteronism Surgical Outcome study. In our study, the success rate of AVS in patients with bilateral lesions on CT was 89% (191/214). Furthermore, the discordance rate between CT and AVS in patients with bilateral lesions on CT was 39% (74/191). After surgery, patients with bilateral lesions on CT but unilateral disease on AVS (n = 17) had a lower complete biochemical success rate than those with unilateral lesions on CT and ipsilateral disease on AVS (n = 30) (41% vs. 80%, p = 0.01), but clinical and biochemical benefits (the complete and partial success combined) were not significantly different between them (76% vs. 93% (p = 0.11) and 70% vs. 90% (p = 0.10), respectively). In conclusion, patients with bilateral lesions on CT but unilateral disease on AVS benefited from surgery, and AVS should be performed for patients who pursue surgical management when the CT findings suggest bilateral lesions.
Use of Steroid Profiling Combined With Machine Learning for Identification and Subtype Classification in Primary Aldosteronism.
Eisenhofer Graeme,Durán Claudio,Cannistraci Carlo Vittorio,Peitzsch Mirko,Williams Tracy Ann,Riester Anna,Burrello Jacopo,Buffolo Fabrizio,Prejbisz Aleksander,Beuschlein Felix,Januszewicz Andrzej,Mulatero Paolo,Lenders Jacques W M,Reincke Martin
JAMA network open
Importance:Most patients with primary aldosteronism, a major cause of secondary hypertension, are not identified or appropriately treated because of difficulties in diagnosis and subtype classification. Applications of artificial intelligence combined with mass spectrometry-based steroid profiling could address this problem. Objective:To assess whether plasma steroid profiling combined with machine learning might facilitate diagnosis and treatment stratification of primary aldosteronism, particularly for patients with unilateral adenomas due to pathogenic KCNJ5 sequence variants. Design, Setting, and Participants:This diagnostic study was conducted at multiple tertiary care referral centers. Steroid profiles were measured from June 2013 to March 2017 in 462 patients tested for primary aldosteronism and 201 patients with hypertension. Data analyses were performed from September 2018 to August 2019. Main Outcomes and Measures:The aldosterone to renin ratio and saline infusion tests were used to diagnose primary aldosteronism. Subtyping was done by adrenal venous sampling and follow-up of patients who underwent adrenalectomy. Statistical tests and machine-learning algorithms were applied to plasma steroid profiles. Areas under receiver operating characteristic curves, sensitivity, specificity, and other diagnostic performance measures were calculated. Results:Primary aldosteronism was confirmed in 273 patients (165 men [60%]; mean [SD] age, 51  years), including 134 with bilateral disease and 139 with unilateral adenomas (58 with and 81 without somatic KCNJ5 sequence variants). Plasma steroid profiles varied according to disease subtype and were particularly distinctive in patients with adenomas due to KCNJ5 variants, who showed better rates of biochemical cure after adrenalectomy than other patients. Among patients tested for primary aldosteronism, a selection of 8 steroids in combination with the aldosterone to renin ratio showed improved effectiveness for diagnosis over either strategy alone. In contrast, the steroid profile alone showed superior performance over the aldosterone to renin ratio for identifying unilateral disease, particularly adenomas due to KCNJ5 variants. Among 632 patients included in the analysis, machine learning-designed combinatorial marker profiles of 7 steroids alone both predicted primary aldosteronism in 1 step and subtyped patients with unilateral adenomas due to KCNJ5 variants at diagnostic sensitivities of 69% (95% CI, 68%-71%) and 85% (95% CI, 81%-88%), respectively, and at specificities of 94% (95% CI, 93%-94%) and 97% (95% CI, 97%-98%), respectively. The validation series yielded comparable diagnostic performance. Conclusions and Relevance:Machine learning-designed combinatorial plasma steroid profiles may facilitate both screening for primary aldosteronism and identification of patients with unilateral adenomas due to pathogenic KCNJ5 variants, who are most likely to show benefit from surgical intervention.
Development and validation of subtype prediction scores for the workup of primary aldosteronism.
Kobayashi Hiroki,Abe Masanori,Soma Masayoshi,Takeda Yoshiyu,Kurihara Isao,Itoh Hiroshi,Umakoshi Hironobu,Tsuiki Mika,Katabami Takuyuki,Ichijo Takamasa,Wada Norio,Yoshimoto Takanobu,Ogawa Yoshihiro,Kawashima Junji,Sone Masakatsu,Inagaki Nobuya,Takahashi Katsutoshi,Watanabe Minemori,Matsuda Yuichi,Shibata Hirotaka,Kamemura Kohei,Yanase Toshihiko,Otsuki Michio,Fujii Yuichi,Yamamoto Koichi,Ogo Atsushi,Nanba Kazutaka,Tanabe Akiyo,Suzuki Tomoko,Naruse Mitsuhide,
Journal of hypertension
OBJECTIVES:A subtype prediction score for primary aldosteronism has not yet been developed and validated using a large dataset. This study aimed to develop and validate a new subtype prediction score and to compare it with existing scores using a large multicenter database. METHODS:In total, 1936 patients with primary aldosteronism were randomly assigned to the development and validation datasets, constituting 1290 and 646 patients, respectively. Three prediction scores were generated with or without confirmatory tests, using logistic regression analysis. In the validation dataset, new and existing prediction scores were compared using receiver operating characteristic curve, net reclassification improvement, and integrated discrimination improvement analyses. RESULTS:The new prediction score is simply calculated using serum potassium levels [>3.9 mmol/l (four points); 3.5-3.9 mmol/l (three points)], the absence of adrenal nodules during computed tomography (three points), a baseline plasma aldosterone concentration of <210.0 pg/ml (two points), a baseline aldosterone/renin ratio of less than 620 (two points), and female sex (one point). Using the validation dataset, we found that a new subtype prediction score of at least 8 had a positive predictive value of 93.5% for bilateral hyperaldosteronism. The new prediction score for bilateral hyperaldosteronism was better than the existing prediction scores in the receiver operating characteristic curve and net reclassification improvement analyses. CONCLUSION:The new prediction score has clear advantages over the existing prediction scores in terms of diagnostic accuracy, feasibility, and the potential for generalization in a large population. These data will help healthcare professionals to better select patients who require adrenal venous sampling.
Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study.
Hundemer Gregory L,Curhan Gary C,Yozamp Nicholas,Wang Molin,Vaidya Anand
The lancet. Diabetes & endocrinology
BACKGROUND:Mineralocorticoid receptor (MR) antagonists are the recommended medical therapy for primary aldosteronism. Whether this recommendation effectively reduces cardiometabolic risk is not well understood. We aimed to investigate the risk of incident cardiovascular events in patients with primary aldosteronism treated with MR antagonists compared with patients with essential hypertension. METHODS:We did a cohort study using patients from a research registry from Brigham and Women's Hospital, Massachusetts General Hospital, and their affiliated partner hospitals. We identified patients with primary aldosteronism using International Classification of Disease, 9th and 10th Revision codes, who were assessed between the years 1991-2016 and were at least 18 years of age. We excluded patients who underwent surgical adrenalectomy, had a previous cardiovascular event, were not treated with MR antagonists, or had no follow-up visits after study entry. From the same registry, we identified a population with essential hypertension that was frequency matched by decade of age at study entry. We extracted patient cohort data and collated it into a de-identified database. The primary outcome was an incident cardiovascular event, defined as a composite of incident myocardial infarction or coronary revascularisation, hospital admission with congestive heart failure, or stroke, which was assessed using adjusted Cox regression models. Secondary outcomes were the individual components of the composite cardiovascular outcome, as well as incident atrial fibrillation, incident diabetes, and death. FINDINGS:We identified 602 eligible patients with primary aldosteronism treated with MR antagonists and 41 853 age-matched patients with essential hypertension from the registry. The two groups of patients had comparable cardiovascular risk profiles and blood pressure throughout the study. The incidence of cardiovascular events was higher in patients with primary aldosteronism on MR antagonists than in patients with essential hypertension (56·3 [95% CI 48·8-64·7] vs 26·6 [26·1-27·2] events per 1000 person-years, adjusted hazard ratio 1·91 [95% CI 1·63-2·25]; adjusted 10-year cumulative incidence difference 14·1 [95% CI 10·1-18·0] excess events per 100 people). Patients with primary aldosteronism also had higher adjusted risks for incident mortality (hazard ratio [HR] 1·34 [95% CI 1·06-1·71]), diabetes (1·26 [1·01-1·57]), and atrial fibrillation (1·93 [1·54-2·42]). Compared with essential hypertension, the excess risk for cardiovascular events and mortality was limited to patients with primary aldosteronism whose renin activity remained suppressed (<1 μg/L per h) on MR antagonists (adjusted HR [2·83 [95% CI 2·11-3·80], and 1·79 [1·14-2·80], respectively) whereas patients who were treated with higher MR antagonist doses and had unsuppressed renin (≥1 μg/L per h) had no significant excess risk. INTERPRETATION:The current practice of MR antagonist therapy in primary aldosteronism is associated with significantly higher risk for incident cardiometabolic events and death, independent of blood pressure control, than for patients with essential hypertension. Titration of MR antagonist therapy to raise renin might mitigate this excess risk. FUNDING:US National Institutes of Health.
Does ACTH improve the diagnostic performance of adrenal vein sampling for subtyping primary aldosteronism?
Wolley Martin J,Ahmed Ashraf H,Gordon Richard D,Stowasser Michael
OBJECTIVE:Adrenal vein sampling (AVS) is used for determining treatment options for primary aldosteronism (PA), but is a difficult procedure. Adrenocorticotropic hormone (ACTH) infusion or bolus has been reported to improve AVS success rates by increasing cortisol secretion, but effects on lateralization are controversial. We therefore assessed the effects of ACTH in regard to AVS success and lateralization in our unit, after a change in protocol to ACTH-stimulated AVS. SETTING:AVS was performed after overnight recumbency in patients with PA confirmed by fludrocortisone suppression testing. Bilateral sequential sampling was performed before and after an intravenous bolus of 250 mcg of ACTH. Lateralization was defined as an aldosterone/cortisol ratio in one adrenal vein at least twice peripheral, combined with a contralateral adrenal ratio no higher than peripheral (contralateral suppression). RESULTS:In 47 AVS procedures, the median adrenal/peripheral cortisol gradient increased on the left (11·6 vs 18·2 μg/100 ml, P < 0·001) and right (15·6 vs 31·5 μg/100 ml, P < 0·001) after ACTH. A total of 34 of 47 studies were diagnostic pre-ACTH (six failing because of low aldosterone levels bilaterally and seven failing to cannulate one or both sides) vs 44 of 47 (P = 0·011) studies diagnostic post-ACTH (failure to cannulate one or both sides in 3). Concordance between diagnostic studies pre- and post-ACTH was 91%, but two bilateral cases became unilateral after ACTH and one unilateral case before ACTH was bilateral afterwards. CONCLUSIONS:ACTH improved cortisol gradients and aldosterone secretion, resulting in a reduction in the proportion of nondiagnostic studies. There was a low proportion of discordance between pre- and post-ACTH diagnoses, the significance of which is unclear.
Comparison between adrenal venous sampling and computed tomography in the diagnosis of primary aldosteronism and in the guidance of adrenalectomy.
Zhu Limin,Zhang Ying,Zhang Hua,Zhou Wenlong,Shen Zhoujun,Zheng Fangfang,Tang Xiaofeng,Tao Bo,Zhang Jin,Lu Xiaohong,Xu Jianzhong,Chu Shaoli,Zhu Dingliang,Gao Pingjin,Wang Ji-Guang
In our series of patients with primary aldosteronism, we compared diagnostic concordance and clinical outcomes after adrenalectomy between adrenal venous sampling (AVS) and computed tomography (CT) imaging.Our retrospective analysis included 886 patients with primary aldosteronism diagnosed in our hospital between 2005 and 2014. Of them, 269 patients with CT unilateral adrenal disease were included in the analysis on the diagnostic concordance and 126 patients with follow-up data in the analysis on clinical outcomes after adrenalectomy. Hypertension was considered cured if systolic/diastolic blood pressure (BP) was controlled (<140/90 mm Hg) without medication and improved if BP was controlled with a reduced number of antihypertensive drugs.In 269 patients with CT unilateral adrenal disease, the overall concordance rate between AVS and CT was 50.5% for lateralization on the same side. The concordance rate decreased with increasing age, with highest rate of 61% in patients aged <30 years (n = 16). In 126 patients with follow-up data after adrenalectomy, the AVS- (n = 96) and CT-guided patients (n = 30) had similar characteristics before adrenalectomy. After andrenalectomy, the AVS-guided patients had a significantly higher serum potassium concentration (4.3 ± 0.3 vs 4.0 ± 0.5 mmol/L, P = 0.04) and rate of cured and improved hypertension (98% vs 87%, P = 0.03). The AVS-guided patients (n = 50) had slightly higher cured rate than the CT-guided patients (n = 11) in those older than 50 years (26.0% vs 18.2%, P = 0.72). The age below which the cured rate in the CT-guided patients was 100% was 30 years.AVS guidance had moderate concordance with CT and slightly improved clinical outcomes after adrenalectomy. The age below which CT unilateralization achieved 100% cured rate was approximately 30 years.
Obesity and the diagnostic accuracy for primary aldosteronism.
Tirosh Amit,Hannah-Shmouni Fady,Lyssikatos Charalampos,Belyavskaya Elena,Zilbermint Mihail,Abraham Smita B,Lodish Maya B,Stratakis Constantine A
Journal of clinical hypertension (Greenwich, Conn.)
The effects of body mass index on the diagnostic accuracy of primary aldosteronism (PA) are inconsistent and yet important considering the high prevalence and frequent co-occurrence of obesity and hypertension. The current study included 59 adult patients who underwent a stepwise evaluation for PA, using aldosterone to renin ratio for case detection and plasma aldosterone concentration after saline suppression test and/or 24-hour urinary aldosterone after oral sodium loading for case confirmation. Body mass index had a quadratic (U-shaped) correlation with plasma aldosterone concentration, plasma renin activity, aldosterone to renin ratio, and plasma aldosterone concentration after saline suppression test. Among patients with a body mass index ≥30 kg/m , the aldosterone to renin ratio yielded lower case detection accuracy of PA. We conclude that obesity results in a nonlinear correlation with plasma aldosterone concentration, plasma renin activity, and aldosterone to renin ratio, which affects the accuracy of case detection for PA. Patients with a body mass index ≥30 kg/m are less accurately identified as having PA when saline suppression and/or oral salt loading tests are used for case confirmation.
Treatment of primary aldosteronism is associated with a reduction in the severity of obstructive sleep apnoea.
Wolley M J,Pimenta E,Calhoun D,Gordon R D,Cowley D,Stowasser M
Journal of human hypertension
Obstructive sleep apnoea (OSA) is known to commonly co-exist with primary aldosteronism (PA), but it is unknown if treatment of PA improves sleep apnoea parameters in these patients. We therefore aimed to determine whether specific medical or surgical treatment of PA improves OSA, as measured by the apnoea-hypopnoea index (AHI). We recruited patients undergoing diagnostic workup for PA if they had symptoms suggestive of OSA. Patients with confirmed PA underwent polysomnography (PSG) at baseline and again at least 3 months after specific treatment for PA. Of 34 patients with PA, 7 (21%) had no evidence of OSA (AHI <5), 9 (26%) had mild (AHI ⩾5 and <15), 8 (24%) moderate (AHI ⩾15 and <30) and 10 (29%) severe OSA (AHI ⩾30). Body mass index tertile, neck circumference and 24 h urinary sodium correlated with the AHI. Twenty patients had repeat PSG performed after treatment for PA (mineralocorticoid receptor antagonists in 13 with bilateral PA and adrenalectomy in 7 with unilateral PA). In this group the median (s.d.) AHI reduced from 22.5 (14.7) to 12.3 (12.1) (P=0.02). Neck circumference reduced with PA treatment (41.6 vs 41.2 cm, P=0.012). OSA is common in patients with primary aldosteronism and may improve with specific therapy for this disease. Aldosterone and sodium-mediated fluid retention in the upper airways and neck region may be a potential mechanism for this relationship.
Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial.
Dekkers Tanja,Prejbisz Aleksander,Kool Leo J Schultze,Groenewoud Hans J M M,Velema Marieke,Spiering Wilko,Kołodziejczyk-Kruk Sylwia,Arntz Mark,Kądziela Jacek,Langenhuijsen Johannes F,Kerstens Michiel N,van den Meiracker Anton H,van den Born Bert-Jan,Sweep Fred C G J,Hermus Ad R M M,Januszewicz Andrzej,Ligthart-Naber Alike F,Makai Peter,van der Wilt Gert-Jan,Lenders Jacques W M,Deinum Jaap,
The lancet. Diabetes & endocrinology
BACKGROUND:The distinction between unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia as causes of primary aldosteronism is usually made by adrenal CT or by adrenal vein sampling (AVS). Whether CT or AVS represents the best test for diagnosis remains unknown. We aimed to compare the outcome of CT-based management with AVS-based management for patients with primary aldosteronism. METHODS:In a randomised controlled trial, we randomly assigned patients with aldosteronism to undergo either adrenal CT or AVS to determine the presence of aldosterone-producing adenoma (with subsequent treatment consisting of adrenalectomy) or bilateral adrenal hyperplasia (subsequent treatment with mineralocorticoid receptor antagonists). The primary endpoint was the intensity of drug treatment for obtaining target blood pressure after 1 year of follow-up, in the intention-to-diagnose population. Intensity of drug treatment was expressed as daily defined doses. Key secondary endpoints included biochemical outcome in patients who received adrenalectomy, health-related quality of life, cost-effectiveness, and adverse events. This trial is registered with ClinicalTrials.gov, number NCT01096654. FINDINGS:We recruited 200 patients between July 6, 2010, and May 30, 2013. Of the 184 patients that completed follow-up, 92 received CT-based treatment (46 adrenalectomy and 46 mineralocorticoid receptor antagonist) and 92 received AVS-based treatment (46 adrenalectomy and 46 mineralocorticoid receptor antagonist). We found no differences in the intensity of antihypertensive medication required to control blood pressure between patients with CT-based treatment and those with AVS-based treatment (median daily defined doses 3·0 [IQR 1·0-5·0] vs 3·0 [1·1-5·9], p=0·52; median number of drugs 2 [IQR 1-3] vs 2 [1-3], p=0·87). Target blood pressure was reached in 39 (42%) patients and 41 (45%) patients, respectively (p=0·82). On secondary endpoints we found no differences in health-related quality of life (median RAND-36 physical scores 52·7 [IQR 43·9-56·8] vs 53·2 [44·0-56·8], p=0·83; RAND-36 mental scores 49·8 [43·1-54·6] vs 52·7 [44·9-55·5], p=0·17) for CT-based and AVS-based treatment. Biochemically, 37 (80%) of patients with CT-based adrenalectomy and 41 (89%) of those with AVS-based adrenalectomy had resolved hyperaldosteronism (p=0·25). A non-significant mean difference of 0·05 (95% CI -0·04 to 0·13) in quality-adjusted life-years (QALYs) was found to the advantage of the AVS group, associated with a significant increase in mean health-care costs of €2285 per patient (95% CI 1323-3248). At a willingness-to-pay value of €30 000 per QALY, the probability that AVS compared with CT constitutes an efficient use of health-care resources in the diagnostic work-up of patients with primary aldosteronism is less than 0·2. There was no difference in adverse events between groups (159 events of which nine were serious vs 187 events of which 12 were serious) for CT-based and AVS-based treatment. INTERPRETATION:Treatment of primary aldosteronism based on CT or AVS did not show significant differences in intensity of antihypertensive medication or clinical benefits for patients after 1 year of follow-up. This finding challenges the current recommendation to perform AVS in all patients with primary aldosteronism. FUNDING:Netherlands Organisation for Health Research and Development-Medical Sciences, Institute of Cardiology, Warsaw.
Primary aldosteronism in patients with adrenal incidentaloma: Is screening appropriate for everyone?
Stavropoulos Konstantinos,Imprialos Konstantinos P,Katsiki Niki,Petidis Konstantinos,Kamparoudis Apostolos,Petras Panagiotis,Georgopoulou Vasiliki,Finitsis Stefanos,Papadopoulos Christodoulos,Athyros Vasilios G,Doumas Michael,Karagiannis Asterios
Journal of clinical hypertension (Greenwich, Conn.)
Primary aldosteronism (PA) is a common form of secondary hypertension. Several guidelines recommend that patients with adrenal incidentaloma have a high probability of suffering from PA. We conducted a prospective study of 269 consecutive adults with adrenal incidentaloma to investigate the prevalence and clinical characteristics of PA. In total, 9 participants were detected with PA, suggesting a prevalence of 3.35% among the study population. PA participants had a higher blood pressure level by 14/20.8 mm Hg and a lower serum potassium level by 0.8 mmol/L (P < .05). Importantly, all patients with PA presented with concurrent indications (hypertension with or without hypokalemia) for screening of the disease, but they have not undergone relative screening by the referring physician, thus casting doubts about the appropriate implementation of current guidelines in real-life practice. Intense efforts are needed to familiarize physicians with recommendations for PA to minimize undiagnosed cases and the detrimental sequelae of this endocrine form of hypertension.
Plasma Aldosterone After Seated Saline Infusion Test Outperforms Captopril Test at Predicting Clinical Outcomes After Adrenalectomy for Primary Aldosteronism.
Wu Che-Hsiung,Wu Vincent,Yang Ya-Wen,Lin Yen-Hung,Yang Shao-Yu,Lin Po-Chih,Chang Chin-Chen,Tsai Yao-Chou,Wang Shuo-Meng,
American journal of hypertension
OBJECTIVE:The saline infusion test (SIT) and the captopril test (CT) are widely used as confirmatory tests for primary aldosteronism (PA). We hypothesized that post-SIT and post-CT plasma aldosterone concentrations (PAC) indicate the severity of aldosterone-producing adenoma (APA) and might predict clinical outcome. METHODS:We recruited 216 patients with APA in the Taiwan Primary Aldosteronism Investigation (TAIPAI) registry who received both seated SIT and CT as confirmatory tests. The data of 143 patients who underwent adrenalectomy with complete follow-up after diagnosis were included in the final analysis. We determined the proportion of patients achieving clinical success in accordance with the Primary Aldosteronism Surgical Outcome consensus. Logistic regression analysis was conducted to identify preoperative factors associated with cure of hypertension. RESULTS:Complete clinical success was achieved in 48 (33.6%) patients and partial clinical success in 59 (41.2%) patients; absent clinical success was seen in 36 (25.2%) of 143 patients. Post-SIT PAC but not post-CT PAC was independently associated with clinical outcome. Higher levels of post-SIT PAC had a higher likelihood of clinical benefit (complete plus partial clinical success; odds ratio = 1.04 per ng/dl increase, 95% confidence interval = 1.01, 1.06; P = 0.004). Patients with post-SIT PAC > 25 ng/dl were more likely to have a favorable clinical outcome after adrenalectomy. This cutoff value translated into a positive predictive value of 86.0%. CONCLUSIONS:We suggest that post-SIT PAC is a better predictor than post-CT PAC for clinical success in PA post adrenalectomy.
Clinical and biochemical outcomes after adrenalectomy and medical treatment in patients with unilateral primary aldosteronism.
Katabami Takuyuki,Fukuda Hisashi,Tsukiyama Hidekazu,Tanaka Yasushi,Takeda Yoshiyu,Kurihara Isao,Ito Hiroshi,Tsuiki Mika,Ichijo Takamasa,Wada Norio,Shibayama Yui,Yoshimoto Takanobu,Ogawa Yoshihiro,Kawashima Junji,Sone Masakatsu,Inagaki Nobuya,Takahashi Katsutoshi,Fujita Megumi,Watanabe Minemori,Matsuda Yuichi,Kobayashi Hiroki,Shibata Hirotaka,Kamemura Kohei,Otsuki Michio,Fujii Yuichi,Yamamoto Koichi,Ogo Atsushi,Yanase Toshihiko,Suzuki Tomoko,Naruse Mitsuhide,
Journal of hypertension
OBJECTIVES:Current clinical guidelines of primary aldosteronism recommend adrenalectomy (AdX) for unilateral primary aldosteronism based on the studies showing the potential superiority of AdX over the medical treatment. However, since most medically treated cases consisted of bilateral primary aldosteronism and all surgically treated cases consisted of unilateral primary aldosteronism, the different subtype of primary aldosteronism could be a bias for their effects. This study compared the effects of AdX and medical therapy in patients with unilateral primary aldosteronism confirmed by adrenal vein sampling. METHODS:Of the 339 patients with unilateral primary aldosteronism in the Japan Primary Pldosteronism Study data base, unilateral AdX and treatment with mineral corticoid receptor antagonists (MRAs) was done in 276 patients (AdX group) and in 63 patients (MRAs group), respectively. The effects were compared by the clinical (improvement of blood pressure) and biochemical outcomes (improvement of hypokalemia). RESULTS:At baseline, use of potassium replacement, plasma aldosterone concentration, aldosterone-to-renin ratio, estimated glomerular filtration rate, and prevalence of adrenal mass on imaging were higher in the AdX group than in the MRAs group. At 6 months after commencement of specific treatment for primary aldosteronism, clinical outcome and biochemical outcome in the AdX group were superior than those in the MRAs group. The difference of the outcome between the two groups were the case even after adjusting for the different clinical backgrounds in the two groups before the specific treatment. CONCLUSION:Our study provides evidence that AdX is the first choice of treatment in the patients with unilateral primary aldosteronism in terms of clinical and biochemical outcome.
Cardiovascular risk in primary aldosteronism: A systematic review and meta-analysis.
Wu Xueyi,Yu Jie,Tian Haoming
AIM:This study aimed to evaluate whether the increased cardiovascular risk and the incidence of cerebrovascular (CCV) events in hypertensive patients were related to primary aldosteronism (PA). METHODS:The PubMed, EmBase, and the Cochrane Central Register of Controlled Trials were searched to evaluate the risk of CCV in PA patients and compared to essential hypertension (EH) patients. The mean differences (MD) and the risk ratios (RR) were calculated to assess the risk of main outcomes, such as stroke, coronary artery disease, left ventricular hypertrophy (LVH), levels of systolic blood pressure (SBP), diastolic blood pressure (DBP), blood glucose, and urinary potassium. RESULTS:We identified 31 individual studies including 4546 patients in PA group and 52,284 patients in EH group. Our results revealed that PA was significantly associated with increased risk of stroke (RR=2.03, 95% CI = 1.71-2.39, Pheterogeneity = .331, I = 12.7%), coronary artery disease (RR = 1.67, 95% CI = 1.23-2.25, Pheterogeneity = .043, I = 48.3%), and LVH (RR = 1.54, 95% CI = 1.29-1.83, Pheterogeneity = .004, I = 62.6%) when compared with those in the EH group. Moreover, PA group had significantly increased levels of SBP (WMD = 4.14, 95% CI = 2.60-5.68, Pheterogeneity < .001, I = 84.3%), DBP (WMD = 2.65, 95% CI = 1.83-3.47, Pheterogeneity < .001, I = 77.7%), and urinary potassium (SMD = 0.04, 95% CI = -0.03-0.11, Pheterogeneity = .827, I = 0%) when compared to EH group. However, no significant difference was observed in the levels of blood glucose between the groups. CONCLUSIONS:These findings suggested that PA significantly increased the risk of cardiac and cerebrovascular complications. In addition, patients with PA might benefit from a periodic assessment of CCV risk.
Aldosterone/direct renin concentration ratio as a screening test for primary aldosteronism: A meta-analysis.
Li Xiyue,Goswami Richa,Yang Shumin,Li Qifu
Journal of the renin-angiotensin-aldosterone system : JRAAS
OBJECTIVE:The accuracy of aldosterone/direct renin concentration ratio (ADRR) as a screening test in patients with primary aldosteronism (PA) varies widely across the studies. Therefore, we conducted a meta-analysis to assess the accuracy of ADRR. METHODS:A literature search was performed in PubMed, Embase, and the Cochrane library published between April 1971-February 2016. Studies focusing on the accuracy of ADRR for PA screening were included. Two authors independently extracted information regarding patient characteristics, antihypertensives status, true positives, true negatives, false positives, and false negatives. The random-effects model was used for statistical analysis. Heterogeneity was explored by subgroup analysis and meta-regression. RESULTS:Nine studies involving 974 patients were included. The overall sensitivity, specificity, area under the curve, and diagnostic odds ratio of ADRR were 0.89 (95% confidence interval (CI) 0.84-0.93), 0.96 (95% CI 0.95-0.98), 0.985 and 324 respectively, with substantial heterogeneity. Meta-regression showed that antihypertensive status affects the ADRR and may account for the heterogeneity (p=0.03). Subgroup analysis of patients who discontinued the antihypertensives revealed a sensitivity of 0.99 (95% CI, 0.95-1.00) and a specificity of 0.98 (95% CI, 0.96-0.99). CONCLUSIONS:This study demonstrates the efficacy of ADRR as a screening test for PA. However, as antihypertensive drugs can interfere with the interpretation of ADRR, it is recommended to interrupt therapy or at least replace with analogues that do not significantly affect the ADRR value.
Bone health among patients with primary aldosteronism: a systematic review and meta-analysis.
Loh Huai H,Yee Anne,Loh Huai S
INTRODUCTION:Recent studies showed a possible association between hyperaldosteronism and secondary hyperparathyroidism leading to reduced bone health, however results are conflicting. EVIDENCE ACQUISITION:We conducted a meta-analysis to evaluate the relationship between primary aldosteronism (PA) with bone biochemical markers and to assess bone mineral density in patients with primary aldosteronism. EVIDENCE SYNTHESIS:A total of 939 subjects were examined (37.5% with PA). Patients with PA had significantly higher serum parathyroid hormone, lower serum calcium, higher urine calcium excretion and higher serum alkaline phosphatase compared to patients without PA, with no significant difference in serum vitamin D between both groups. Bone mineral density of lumbar spine, femoral neck and total neck of femur were similar between two groups. With PA treatment, there was a significant increment in serum calcium and reduction in serum parathyroid hormone. CONCLUSIONS:PA is associated with hypercalciuria with subsequent secondary hyperparathyroidism. This potentially affects bone health. We recommend this to be part of complication screening among patients with PA.
Confirmatory tests for the diagnosis of primary aldosteronism: A systematic review and meta-analysis.
Wu Sicen,Yang Jun,Hu Jinbo,Song Ying,He Wenwen,Yang Shumin,Luo Rong,Li Qifu
OBJECTIVE:Saline infusion test (SIT), captopril challenge test (CCT), fludrocortisone suppression test (FST) and oral sodium loading test (SLT) are recommended by the Endocrine Society's Clinical Practice Guidelines to diagnose primary aldosteronism, but which one is the best remains controversial. We aimed to summarize the available comparative data and evaluate the diagnostic accuracy of these four tests. DESIGN:We searched PubMed, Embase and the Cochrane Library for relevant studies published between January 1980 and January 2018. PATIENTS:Eligible studies reported on the accuracy of one or more of the four confirmatory tests in patients suspected of PA. MEASUREMENTS:Two reviewers independently conducted the data extraction of all selected studies, which consisted of study characteristics and data to estimate the summary receiver operating characteristic (SROC) curve and the corresponding summary area under the curve (SAUC), pooled sensitivity and specificity, diagnostic odds ratios (DOR) with 95% confidence interval (CI). RESULTS:We identified 26 articles including 3686 patients. Fifteen articles evaluated the diagnostic accuracy of CCT, 10 of SIT, 1 of FST and none of SLT. For CCT, the SAUC was 0.9207, and the pooled sensitivity and specificity were 0.87 (95% CI: 0.84-0.89) and 0.84 (95% CI: 0.81-0.86), respectively. For SIT, the SAUC was 0.9232, and the pooled sensitivity and specificity were 0.85 (95% CI: 0.82-0.87) and 0.87 (95% CI: 0.85-0.89), respectively. For FST, the pooled sensitivity and specificity were 0.87 (95% CI: 0.66-0.97) and 0.95 (95% CI: 0.82-0.99), respectively. Overall, we found no significant differences in the diagnostic accuracy of CCT and SIT. CONCLUSIONS:CCT and SIT exhibit high and comparable accuracy for diagnosing PA. CCT may be a more feasible alternative as it is safe and much easier to perform.
Evaluation of bone health in patients with adrenal tumors.
Athimulam Shobana,Bancos Irina
Current opinion in endocrinology, diabetes, and obesity
PURPOSE OF REVIEW:Adrenal tumors occur in 5% of population with higher prevalence in elderly. Patients with adrenal tumors present with overt hormonal excess in up to 15% of cases, and mild autonomous cortisol secretion in 30-40% of cases. Overt Cushing syndrome, mild autonomous cortisol secretion, pheochromocytoma, and primary aldosteronism have been associated with higher cardiovascular morbidity and mortality. Increasing experimental and clinical evidence also suggests that adrenal hormone excess is detrimental to bone health. This review aims to discuss the effect of cortisol, aldosterone, and catecholamine excess on bone metabolism, secondary osteoporosis, and fragility fractures. RECENT FINDINGS:Several studies have reported that patients with hormonally active adrenal tumors demonstrate increased prevalence of fragility fractures incongruous to bone density scan findings. The utility of dual absorptiometry X-ray (DXA) in diagnosing secondary osteoporosis is unclear in patients with cortisol, aldosterone, and catecholamine excess. Trabecular bone score and bone turn over markers could serve as potential diagnostic tools in assessment of severity of bone disease in patients with hormonally active adrenal tumors. SUMMARY:Adrenalectomy is the mainstay of therapy in patients with overt hormone production. Appropriate case detection strategies to identify patients at risk of fragility fractures are needed in patients not treated with adrenalectomy, such as bilateral primary aldosteronism and mild autonomous cortisol secretion.
Targeted Molecular Imaging in Adrenal Disease-An Emerging Role for Metomidate PET-CT.
Mendichovszky Iosif A,Powlson Andrew S,Manavaki Roido,Aigbirhio Franklin I,Cheow Heok,Buscombe John R,Gurnell Mark,Gilbert Fiona J
Diagnostics (Basel, Switzerland)
Adrenal lesions present a significant diagnostic burden for both radiologists and endocrinologists, especially with the increasing number of adrenal 'incidentalomas' detected on modern computed tomography (CT) or magnetic resonance imaging (MRI). A key objective is the reliable distinction of benign disease from either primary adrenal malignancy (e.g., adrenocortical carcinoma or malignant forms of pheochromocytoma/paraganglioma (PPGL)) or metastases (e.g., bronchial, renal). Benign lesions may still be associated with adverse sequelae through autonomous hormone hypersecretion (e.g., primary aldosteronism, Cushing's syndrome, phaeochromocytoma). Here, identifying a causative lesion, or lateralising the disease to a single adrenal gland, is key to effective management, as unilateral adrenalectomy may offer the potential for curing conditions that are typically associated with significant excess morbidity and mortality. This review considers the evolving role of positron emission tomography (PET) imaging in addressing the limitations of traditional cross-sectional imaging and adjunctive techniques, such as venous sampling, in the management of adrenal disorders. We review the development of targeted molecular imaging to the adrenocortical enzymes CYP11B1 and CYP11B2 with different radiolabeled metomidate compounds. Particular consideration is given to iodo-metomidate PET tracers for the diagnosis and management of adrenocortical carcinoma, and the increasingly recognized utility of C-metomidate PET-CT in primary aldosteronism.
DIAGNOSIS OF ENDOCRINE DISEASE: 18-Oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids?
Lenders Jacques W M,Williams Tracy Ann,Reincke Martin,Gomez-Sanchez Celso E
European journal of endocrinology
Since the early 1980s 18-hydroxycortisol and 18-oxocortisol have attracted attention when it was shown that the urinary excretion of these hybrid steroids was increased in primary aldosteronism. The development and more widespread use of specific assays has improved the understanding of their role in the (patho)physiology of adrenal disorders. The adrenal site of synthesis is not fully understood although it is clear that for the synthesis of 18-hydroxycortisol and 18-oxocortisol the action of both aldosterone synthase (zona glomerulosa) and 17α-hydroxylase (zona fasciculata) is required with cortisol as main substrate. The major physiological regulator is ACTH and the biological activity of both steroids is very low and therefore only very high concentrations might be effective In healthy subjects, the secretion of both steroids is low with 18-hydroxycortisol being substantially higher than that of 18-oxocortisol. The highest secretion of both steroids has been found in familial hyperaldosteronism type 1 (glucocorticoid-remediable aldosteronism) and in familial hyperaldosteronism type 3. Lower but yet substantially increased secretion is found in patients with aldosterone-producing adenomas in contrast to bilateral hyperplasia in whom the levels are similar to patients with hypertension. Several studies have attempted to show that these steroids, in particular, peripheral venous plasma 18-oxocortisol, might be a useful discriminatory biomarker for subtyping PA patients. The current available limited evidence precludes the use of these steroids for subtyping. We review the biosynthesis, regulation and function of 18-hydroxycortisol and 18-oxocortisol and their potential utility for the diagnosis and differential diagnosis of patients with primary aldosteronism.
Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney.
Stowasser Michael,Gordon Richard D
In the 60 years that have passed since the discovery of the mineralocorticoid hormone aldosterone, much has been learned about its synthesis (both adrenal and extra-adrenal), regulation (by renin-angiotensin II, potassium, adrenocorticotrophin, and other factors), and effects (on both epithelial and nonepithelial tissues). Once thought to be rare, primary aldosteronism (PA, in which aldosterone secretion by the adrenal is excessive and autonomous of its principal regulator, angiotensin II) is now known to be the most common specifically treatable and potentially curable form of hypertension, with most patients lacking the clinical feature of hypokalemia, the presence of which was previously considered to be necessary to warrant further efforts towards confirming a diagnosis of PA. This, and the appreciation that aldosterone excess leads to adverse cardiovascular, renal, central nervous, and psychological effects, that are at least partly independent of its effects on blood pressure, have had a profound influence on raising clinical and research interest in PA. Such research on patients with PA has, in turn, furthered knowledge regarding aldosterone synthesis, regulation, and effects. This review summarizes current progress in our understanding of the physiology of aldosterone, and towards defining the causes (including genetic bases), epidemiology, outcomes, and clinical approaches to diagnostic workup (including screening, diagnostic confirmation, and subtype differentiation) and treatment of PA.
MANAGEMENT OF ENDOCRINE DISEASE: The role of confirmatory tests in the diagnosis of primary aldosteronism.
Morera Julia,Reznik Yves
European journal of endocrinology
The strategy for diagnosis of primary aldosteronism (PA) in the hypertensive population includes firstly a screening step, based on the measurement of plasma aldosterone-to-renin ratio (ARR), a test which must have high sensitivity, and secondly a confirmatory step based on the demonstration of excessive aldosterone production independent of the renin-angiotensin-aldosterone system (RAAS) activity. The high proportion of false-positive ARR results and conversely of actual PA without a persistent elevation in baseline plasma aldosterone concentration necessitates the addition of a confirmatory step in the work-up of PA diagnosis. The present review focuses on the description of the different dynamic tests available for demonstrating autonomy of aldosterone secretion, on the performance and limitations of confirmatory tests and on possible strategies for PA diagnosis which may either include or avoid the confirmatory step for PA diagnosis. Large prospective studies comparing different strategies with and without dynamic testing are mandatory to delineate clearly the role and limits of confirmatory tests in the work-up of PA.
Cardiovascular risk markers in patients with primary aldosteronism: A systematic review and meta-analysis of literature studies.
Ambrosino Pasquale,Lupoli Roberta,Tortora Anna,Cacciapuoti Marianna,Lupoli Gelsy Arianna,Tarantino Paolo,Nasto Aurelio,Di Minno Matteo Nicola Dario
International journal of cardiology
BACKGROUND/OBJECTIVES:Several studies reported an increased cardiovascular (CV) morbidity and mortality in patients with primary aldosteronism (PA). We performed a meta-analysis on the impact of PA on major markers of CV risk. METHODS:Studies on the relationship between PA and common carotid artery intima-media thickness (CCA-IMT), prevalence of carotid plaques, flow-mediated dilation (FMD), nitrate-mediated dilation (NMD), pulse-wave velocity (PWV), augmentation index (AIx), and ankle-brachial index (ABI) were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. RESULTS:12 case-control studies (445 cases, 472 controls) were included. Compared to subjects with essential hypertension (EH), PA patients showed a higher CCA-IMT (MD: 0.12 mm; 95% CI: 0.09, 0.16; P<0.00001), and a higher aortic-PWV (272 cases and 240 controls, MD: 1.39 m/s; 95% CI: 0.90, 1.87; P<0.00001). In contrast, non-significant differences were found in AIx and AIx normalized to a heart rate of 75 beats per minute (AIx@75). When compared to normotensive subjects, PA patients showed significantly higher CCA-IMT (MD: 0.16 mm; 95% CI: 0.05, 0.27; P=0.004), aortic-PWV (MD: 3.74 m/s; 95% CI: 3.43, 4.05; P<0.00001), AIx@75 (MD: 8.59%; 95% CI: 0.69, 16.50; P=0.03), and a significantly lower FMD (MD: -2.52%; 95% CI: -3.64, -1.40; P<0.0001). Sensitivity and subgroup analyses substantially confirmed our results. Metaregression models showed that male gender, diabetes, and smoking habit impact on the observed results. CONCLUSIONS:PA appears significantly associated with markers of subclinical atherosclerosis and CV risk. These findings could help establish more specific CV prevention strategies in this clinical setting.
Role of ACTH and Other Hormones in the Regulation of Aldosterone Production in Primary Aldosteronism.
El Ghorayeb Nada,Bourdeau Isabelle,Lacroix André
Frontiers in endocrinology
The major physiological regulators of aldosterone production from the adrenal zona glomerulosa are potassium and angiotensin II; other acute regulators include adrenocorticotropic hormone (ACTH) and serotonin. Their interactions with G-protein coupled hormone receptors activate cAMP/PKA pathway thereby regulating intracellular calcium flux and CYP11B2 transcription, which is the specific steroidogenic enzyme of aldosterone synthesis. In primary aldosteronism (PA), the increased production of aldosterone and resultant relative hypervolemia inhibits the renin and angiotensin system; aldosterone secretion is mostly independent from the suppressed renin-angiotensin system, but is not autonomous, as it is regulated by a diversity of other ligands of various eutopic or ectopic receptors, in addition to activation of calcium flux resulting from mutations of various ion channels. Among the abnormalities in various hormone receptors, an overexpression of the melanocortin type 2 receptor (MC2R) could be responsible for aldosterone hypersecretion in aldosteronomas. An exaggerated increase in plasma aldosterone concentration (PAC) is found in patients with PA secondary either to unilateral aldosteronomas or bilateral adrenal hyperplasia (BAH) following acute ACTH administration compared to normal individuals. A diurnal increase in PAC in early morning and its suppression by dexamethasone confirms the increased role of endogenous ACTH as an important aldosterone secretagogue in PA. Screening using a combination of dexamethasone and fludrocortisone test reveals a higher prevalence of PA in hypertensive populations compared to the aldosterone to renin ratio. The variable level of MC2R overexpression in each aldosteronomas or in the adjacent zona glomerulosa hyperplasia may explain the inconsistent results of adrenal vein sampling between basal levels and post ACTH administration in the determination of source of aldosterone excess. In the rare cases of glucocorticoid remediable aldosteronism, a chimeric CYP11B2 becomes regulated by ACTH activating its chimeric CYP11B1 promoter of aldosterone synthase in bilateral adrenal fasciculate-like hyperplasia. This review will focus on the role of ACTH on excess aldosterone secretion in PA with particular focus on the aberrant expression of MC2R in comparison with other aberrant ligands and their GPCRs in this frequent pathology.
Molecular Mechanisms of Primary Aldosteronism.
Tevosian Sergei G,Fox Shawna C,Ghayee Hans K
Endocrinology and metabolism (Seoul, Korea)
Primary aldosteronism (PA) results from excess production of mineralocorticoid hormone aldosterone by the adrenal cortex. It is normally caused either by unilateral aldosterone-producing adenoma (APA) or by bilateral aldosterone excess as a result of bilateral adrenal hyperplasia. PA is the most common cause of secondary hypertension and associated morbidity and mortality. While most cases of PA are sporadic, an important insight into this debilitating disease has been derived through investigating the familial forms of the disease that affect only a minor fraction of PA patients. The advent of gene expression profiling has shed light on the genes and intracellular signaling pathways that may play a role in the pathogenesis of these tumors. The genetic basis for several forms of familial PA has been uncovered in recent years although the list is likely to expand. Recently, the work from several laboratories provided evidence for the involvement of mammalian target of rapamycin pathway and inflammatory cytokines in APAs; however, their mechanism of action in tumor development and pathophysiology remains to be understood.
Primary aldosteronism and pregnancy.
Landau Ester,Amar Laurence
Hypertension (HT) is a complication of 8% of all pregnancies and 10% of HT cases are due to primary aldosteronism (PA). There is very little data on PA and pregnancy. Given the changes in the renin angiotensin system during pregnancy, the diagnosis of PA is difficult to establish during gestation. It may be suspected in hypertensive patients with hypokalemia. A comprehensive literature review identified reports covering 40 pregnancies in patients suffering from PA. Analysis of these cases shows them to be high-risk pregnancies leading to maternal and fetal complications. Pregnancy must be programmed, and if the patient has a unilateral form of PA, adrenalectomy should be performed prior to conception. It is customary to stop spironolactone prior to conception and introduce antihypertensive drugs that present no risk of teratogenicity. When conventional antihypertensive drugs used during pregnancy fail to control high blood pressure, diuretics, including potassium-sparing diuretics may be prescribed. Adrenalectomy can be considered during the second trimester of pregnancy exclusively in cases of refractory hypertension. A European retrospective study is currently underway to collect a larger number of cases.
Associations between primary aldosteronism and diabetes, poor bone health, and sleep apnea-what do we know so far?
Loh Huai Heng,Sukor Norlela
Journal of human hypertension
Primary aldosteronism (PA), the most common cause of secondary hypertension, is a well-recognized condition that can lead to cardiovascular and renal complications. PA is frequently left undiagnosed and untreated, leading to aldosterone-specific morbidity and mortality. In this review we highlight the evidence linking PA with other conditions such as (i) diabetes mellitus, (ii) obstructive sleep apnea, and (iii) bone health, along with clinical implications and proposed underlying mechanisms.
Genetic causes of primary aldosteronism.
Seidel Eric,Schewe Julia,Scholl Ute I
Experimental & molecular medicine
Primary aldosteronism is characterized by at least partially autonomous production of the adrenal steroid hormone aldosterone and is the most common cause of secondary hypertension. The most frequent subforms are idiopathic hyperaldosteronism and aldosterone-producing adenoma. Rare causes include unilateral hyperplasia, adrenocortical carcinoma and Mendelian forms (familial hyperaldosteronism). Studies conducted in the last eight years have identified somatic driver mutations in a substantial portion of aldosterone-producing adenomas, including the genes KCNJ5 (encoding inwardly rectifying potassium channel GIRK4), CACNA1D (encoding a subunit of L-type voltage-gated calcium channel Ca1.3), ATP1A1 (encoding a subunit of Na/K-ATPase), ATP2B3 (encoding a Ca-ATPase), and CTNNB1 (encoding ß-catenin). In addition, aldosterone-producing cells were recently reported to form small clusters (aldosterone-producing cell clusters) beneath the adrenal capsule. Such clusters accumulate with age and appear to be more frequent in individuals with idiopathic hyperaldosteronism. The fact that they are associated with somatic mutations implicated in aldosterone-producing adenomas also suggests a precursor function for adenomas. Rare germline variants of CYP11B2 (encoding aldosterone synthase), CLCN2 (encoding voltage-gated chloride channel ClC-2), KCNJ5, CACNA1H (encoding a subunit of T-type voltage-gated calcium channel Ca3.2), and CACNA1D have been reported in different subtypes of familial hyperaldosteronism. Collectively, these studies suggest that primary aldosteronism is largely due to genetic mutations in single genes, with potential implications for diagnosis and therapy.
Adrenal venous sampling for primary aldosteronism: laboratory medicine best practice.
Kline Gregory,Holmes Daniel T
Journal of clinical pathology
Primary aldosteronism (PA) is the most common form of secondary hypertension and is critical to identify because when caused by an aldosterone-producing adenoma (APA) or another unilateral form, it is potentially curable, and even when caused by bilateral disease, antihypertensives more specific to PA treatment can be employed (ie, aldosterone antagonists). Identification of unilateral forms is not generally accomplished with imaging because APAs may be small and elude detection, and coincidental identification of a non-functioning incidentaloma contralateral to an APA may lead to removal of an incorrect gland. For this reason, the method of choice for identifying unilateral forms of PA is selective adrenal venous sampling (AVS) followed by aldosterone and cortisol analysis on collected samples. This procedure is technically difficult from a radiological standpoint and, from the laboratory perspective, is fraught with opportunities for preanalytical, analytical and postanalytical error. We review the process of AVS collection, analysis and reporting. Suggestions are made for patient preparation, specimen labelling practices and nomenclature, analytical dilution protocols, which numerical results to report, and the necessary subsequent calculations. We also identify and explain frequent sources of confusion in the aldosterone and cortisol results and provide an example of tabular reporting to facilitate interpretation and communication between laboratorian, radiologist and clinician.
Subtyping of Patients with Primary Aldosteronism: An Update.
Lenders Jacques W M,Eisenhofer Graeme,Reincke Martin
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
Primary aldosteronism (PA) comprises two main subtypes: unilateral aldosteronism, mainly caused by aldosterone-producing adenoma; and bilateral adrenal hyperplasia. Establishing the correct subtype in patients with PA is indispensible for choice of treatment. In addition to established methods, alternative tests are evolving for subtyping. Computed tomography (CT) and adrenal venous sampling (AVS) are currently recommended in the guidelines for the diagnostic work-up of patients with PA. CT cannot be used as a stand-alone test for subtyping because of its limited accuracy but may be used in combination with other tests such as AVS or functional imaging. Nevertheless CT remains mandatory to exclude adrenocortical carcinoma. AVS provides the most accurate test to detect excessive secretion of aldosterone from an adrenal mass but has several practical limitations and disadvantages. Therefore, alternative non-invasive and patient-friendly methods are required to determine the need for adrenalectomy. Functional imaging with specific molecular positron emission tomographic ligands is a potential alternative method that may replace AVS for subclassifying patients with PA. The results of preliminary studies of C-metomidate are promising but ligands incorporating radionuclides with longer half-lives that selectively bind to CYP11B2 are needed. Steroid profiling provides another method for subtyping and selecting patients for adrenalectomy, but this technology is in its infancy and prospective outcome-based studies are required to determine if this technique may provide an alternative to AVS.
Primary Aldosteronism and Obstructive Sleep Apnea: Is This A Bidirectional Relationship?
Prejbisz Aleksander,Kołodziejczyk-Kruk Sylwia,Lenders Jacques W M,Januszewicz Andrzej
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
It has been suggested that the high prevalence of obstructive sleep apnea (OSA) in resistant hypertension (RHT) may be related to the high prevalence of primary aldosteronism (PA) in patients with RHT. It has been also hypothesized that the relationship between aldosterone and OSA might be bidirectional. In patients with RHT, it has been shown that aldosterone levels correlate with severity of OSA and that blockade of aldosterone reduces the severity of OSA. It has been postulated that aldosterone worsens OSA by promoting accumulation of fluid, which shifted in the supine position to the neck, contributes to increased upper airway resistance. Also there is growing data that PA is more frequent in patients with OSA and that the treatment of PA positively influences OSA course. Also in some studies it has been shown that patients with OSA are characterized by higher aldosterone levels and higher prevalence of PA than patients without OSA and that causal treatment of OSA might decrease aldosterone levels. Moreover, the recent guideline of the Endocrine Society on management of PA recommends to screen hypertensive patients with OSA for PA.
Primary aldosteronism: Treatment of the disease, and new therapeutic approaches.
Best practice & research. Clinical endocrinology & metabolism
Primary aldosteronism is currently considered to represent 5-13% of hypertension, yet fewer than 1% of patients with the disorder are ever diagnosed and treated. Current management of patients screened and confirmed positive for primary aldosteronism involves imaging, and with very few exceptions adrenal venous sampling to lateralize (or not) hyperaldosteronism. Unilateral disease is treated by adrenalectomy: bilateral disease by mineralocorticoid receptor antagonists and conventional antihypertensives as/if required. New therapeutic approaches include (i) routine screening on first presentation for hypertension; (ii) harmonisation of cut-offs for renin and aldosterone, plus use of 24-h urinary rather than spot plasma values for the latter; (iii) adoption of a dexamethasone enhanced seated saline suppression test for confirmation exclusion; (iv) enhanced imaging and steroid profiles as partial replacement for adrenal venous sampling; and finally (v), inclusion of low dose spironolactone in first-line therapy for hypertension.
Update in adrenal venous sampling for primary aldosteronism.
Rossi Gian Paolo
Current opinion in endocrinology, diabetes, and obesity
PURPOSE OF REVIEW:Current guidelines recommend adrenal venous sampling (AVS) to identify the surgically curable causes of hyperaldosteronism. In contrast with this recommendation, AVS remains markedly underutilized in clinical practice, which leads to deny curative adrenalectomy, to many patients with primary aldosteronism. The purpose of this review is to challenge the views that AVS is a technically challenging, invasive and risky procedure, which moreover, is difficult to interpret. RECENT FINDINGS:Several studies, including a large international survey on how AVS is being performed and used at major referral centres worldwide the AVIS-1 Study - and a randomized clinical trial comparing and AVS and a computed tomography based strategy, will be examined. SUMMARY:The results of these studies have sound implications for clinical practice in that they allow to define what to do and what not to do for proper performance and interpretation of AVS and avoidance of the main concern, for example the risk of adrenal vein rupture.
Primary Aldosteronism: Practical Approach to Diagnosis and Management.
Byrd James Brian,Turcu Adina F,Auchus Richard J
Primary aldosteronism (PA) is the most common form of secondary hypertension. In many cases, somatic mutations in ion channels and pumps within adrenal cells initiate the pathogenesis of PA, and this mechanism might explain why PA is so common and suggests that milder and evolving forms of PA must exist. Compared with primary hypertension, PA causes more end-organ damage and is associated with excess cardiovascular morbidity, including heart failure, stroke, nonfatal myocardial infarction, and atrial fibrillation. Screening is simple and readily available, and targeted therapy improves blood pressure control and mitigates cardiovascular morbidity. Despite these imperatives, screening rates for PA are low, and mineralocorticoid-receptor antagonists are underused for hypertension treatment. After the evidence for the prevalence of PA and its associated cardiovascular morbidity is summarized, a practical approach to PA screening, referral, and management is described. All physicians who treat hypertension should routinely screen appropriate patients for PA.
Steroid Profiling and Immunohistochemistry for Subtyping and Outcome Prediction in Primary Aldosteronism-a Review.
Holler Finn,Heinrich Daniel A,Adolf Christian,Lechner Benjamin,Bidlingmaier Martin,Eisenhofer Graeme,Williams Tracy Ann,Reincke Martin
Current hypertension reports
PURPOSE OF REVIEW:Steroid profiling and immunohistochemistry are both promising new tools used to improve diagnostic accuracy in the work-up of primary aldosteronism (PA) and to predict treatment outcomes. Herein, we review the recent literature and present an outlook to the future of diagnostics and therapeutic decision-making in patients with PA. RECENT FINDING:PA is the most common endocrine cause of arterial hypertension and unilateral forms of the disease are potentially curable by surgical resection of the overactive adrenal. Recent studies have shown that adrenal steroid profiling by liquid chromatography-tandem mass spectrometry (LC-MS/MS) can be helpful for subtyping unilateral and bilateral forms of PA, classifying patients with a unilateral aldosterone-producing adenoma (APA) according to the presence of driver mutations of aldosterone production in APAs, and potentially predicting the outcomes of surgical treatment for unilateral PA. Following adrenalectomy, immunohistochemistry of aldosterone synthase (CYP11B2) in resected adrenals is a new tool to analyze "functional" histopathology and may be an indicator of biochemical outcomes after surgery. Biochemical and clinical outcomes of therapy in PA vary widely among patients. Peripheral venous steroid profiling at baseline could improve diagnostic accuracy and help in surgical decision-making in cases of a suspected APA; results of "functional" histopathology could help determine which patients are likely to need close post-surgical follow-up for persistent aldosteronism.
GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism.
Monticone Silvia,Buffolo Fabrizio,Tetti Martina,Veglio Franco,Pasini Barbara,Mulatero Paolo
European journal of endocrinology
Aldosterone is the main mineralocorticoid hormone in humans and plays a key role in maintaining water and electrolyte homeostasis. Primary aldosteronism (PA), characterized by autonomous aldosterone overproduction by the adrenal glands, affects 6% of the general hypertensive population and can be either sporadic or familial. Aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) are the two most frequent subtypes of sporadic PA and 4 forms of familial hyperaldosteronism (FH-I to FH-IV) have been identified. Over the last six years, the introduction of next-generation sequencing has significantly improved our understanding of the molecular mechanisms responsible for autonomous aldosterone overproduction in both sporadic and familial PA. Somatic mutations in four genes ( and ), differently implicated in intracellular ion homeostasis, have been identified in nearly 60% of the sporadic APAs. Germline mutations in and cause FH-III and FH-IV, respectively, while germline mutations in cause the rare PASNA syndrome, featuring primary aldosteronism seizures and neurological abnormalities. Further studies are warranted to identify the molecular mechanisms underlying BAH and FH-II, the most common forms of sporadic and familial PA whose molecular basis is yet to be uncovered.
Disordered CYP11B2 Expression in Primary Aldosteronism.
Gomez-Sanchez Celso E,Kuppusamy Maniselvan,Reincke Martin,Williams Tracy Ann
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
Primary aldosteronism is the most common type of secondary hypertension affecting 6-10% of patients with primary hypertension. PA is mainly caused by unilateral hyperaldosteronism due to an aldosterone-producing adenoma, unilateral hyperplasia with or without micronodules or bilateral zona glomerulosa hyperplasias with or without macro or micronodules. The development of antibodies against the terminal enzyme of aldosterone biosynthesis (CYP11B2) has permitted the further characterization of normal adrenals and resected adrenals from patients with primary aldosteronism. Normal adrenals exhibit two different patterns of cellular expression of CYP11B2: young individuals display a relatively uniform expression of the enzyme throughout the zona glomerulosa while the adrenals of older individuals have dispersed CYP11B2-expressing cells but have more groups of cells called aldosterone-producing cell clusters (APCC). APAs exhibit different patterns of CYP11B2 staining that vary from uniform to homogeneous. There are also a proportion of cells within the APA that co-express different enzymes that are not normally co-expressed in normal individuals. Approximately 30% of patients with unilateral hyperaldosteronism do not have an APA, but either have an increased number of CYP11B2 expressing micronodules or hyperplasia of the zona glomerulosa. In summary, the studies reported in this review are shedding new light on the pathophysiology of primary aldosteronism. The wide variation in histopathological features of the adenomas and concurrent presence of APCCs raises the possibility that most cases of unilateral production of aldosterone actually might represent bilateral asymmetric hyperplasia with nodules frequently due to the development of somatic aldosterone-driving mutations.
Primary Aldosteronism and Cerebrovascular Diseases.
Chen Zheng Wei,Hung Chi Sheng,Wu Vin Cent,Lin Yen Hung,
Endocrinology and metabolism (Seoul, Korea)
As diagnostic techniques have advanced, primary aldosteronism (PA) has emerged as the most common cause of secondary hypertension. The excess of aldosterone caused by PA resulted in not only cardiovascular complications, including coronary artery disease, myocardial infarction, arrhythmia, and heart failure, but also cerebrovascular complications, such as stroke and transient ischemic attack. Moreover, PA is associated more closely with these conditions than is essential hypertension. In this review, we present up-to-date findings on the association between PA and cerebrovascular diseases.
Regulation of aldosterone production by ion channels: From basal secretion to primary aldosteronism.
Yang Tingting,He Min,Hu Changlong
Biochimica et biophysica acta. Molecular basis of disease
Aldosterone is produced by zona glomerulosa (ZG) cells of the adrenal cortex and plays a key role in balancing water and electrolytes levels. Autonomous overproduction of aldosterone leads to primary aldosteronism (PA), which is the most common form of secondary endocrine hypertension. Recently, significant progress has been made towards understanding the genetic basis of PA, where increasing clinical evidence suggests that mutations in ion channels appear to be the major cause of aldosterone-producing adenomas. In this review, we focused on potassium and calcium channels that regulate aldosterone secretion, and their roles in the pathology of PA. Because potassium and calcium channels are differentially expressed in ZG cells in different species of mammals, the limitations of published studies are also discussed.
Primary Aldosteronism: JACC State-of-the-Art Review.
Rossi Gian Paolo
Journal of the American College of Cardiology
Primary aldosteronism (PA) is a common, but frequently overlooked, cause of arterial hypertension and excess cardiovascular events, particularly atrial fibrillation. As timely diagnosis and treatment can provide a cure of hyperaldosteronism and hypertension, even when the latter is resistant to drug treatment, strategies to screen patients for PA early with a simplified diagnostic algorithm are justified. They can be particularly beneficial in some subgroups of hypertensive patients, as those who are at highest cardiovascular risk. However, identification of the surgically curable cases of PA and achievement of optimal results require subtyping with adrenal vein sampling, which, as it is technically challenging and currently performed only in tertiary referral centers, represents the bottleneck in the work-up of PA. Measures aimed at improving the clinical use of adrenal vein sampling and at developing alternative techniques for subtyping, alongside recommendations for drug treatment, including new development in the field, and for follow-up are discussed.
THERAPY OF ENDOCRINE DISEASE: Medical treatment of primary aldosteronism.
Lechner Benjamin,Lechner Katharina,Heinrich Daniel,Adolf Christian,Holler Finn,Schneider Holger,Beuschlein Felix,Reincke Martin
European journal of endocrinology
In patients with primary aldosteronism, specific treatment provides prognostic benefit over optimal antihypertensive therapy and is therefore crucial to reduce mortality and morbidity in this subgroup of patients with hypertension. Prognostic relevance has been shown for adrenalectomy in unilateral disease and for medical treatment with mineralocorticoid receptor antagonists in bilateral adrenal hyperplasia. Collectively, evidence points to the superiority of surgical treatment compared to medical treatment. The causal approach of removing the mineralocorticoid excess, as well as the often-accompanying glucocorticoid excess, might provide one biologically plausible explanation for the observation of slightly better outcomes with surgical therapy. However, in patients living with primary aldosteronism, medical treatment is often insufficient for three major reasons. First and foremost, no marker of sufficient aldosterone blockade has yet been established and therefore adequate treatment of the aldosterone excess is often dismissed as a treatment goal. Second, side effects often limit patient compliance. Third, as recommendations differ from other indications like heart failure, drug dosing is often inadequate. The aim of this review is first to provide an overview over medical treatment options and second to review potential markers for treatment surveillance in patients with primary aldosteronism.
[Primary aldosteronism : Genetics and pathology].
BACKGROUND:Primary aldosteronism, the excessive production of the steroid hormone aldosterone, is the most common cause of secondary hypertension. Common subforms include bilateral adrenal hyperplasia and aldosterone-producing adenoma. OBJECTIVES:The goal of this review is to summarize important publications on the genetic basis of primary aldosteronism. RESULTS:Somatic mutations in the KCNJ5, CACNA1D, ATP1A1, and ATP2B3 genes have been described as causes of aldosterone-producing adenomas. They eventually all lead to increased cellular calcium influx and aldosterone production. The mechanisms of rare CTNNB1 mutations are less defined. Correlations between mutations and different histologic characteristics as well as gender and ethnicity remain unexplained. Recent publications suggest that bilateral hyperplasia is at least partially due to so-called aldosterone-producing cell clusters, often with mutations in CACNA1D. Rare familial forms show mutations in the CYP11B2, CLCN2, KCNJ5, CACNA1H, or CACNA1D genes. CONCLUSIONS:These results suggest that a significant fraction of primary aldosteronism is due to somatic mutations in single genes.
Primary Aldosteronism: Cardiovascular Risk, Diagnosis, and Management.
Pillai Padma Raghavan,Griffith Mindy,Schwarcz Monica D,Weiss Irene A
Cardiology in review
Primary aldosteronism remains a leading cause of secondary hypertension, and its diagnosis and management continue to pose a challenge for clinicians. In this article, we review the diagnosis of primary aldosteronism along with its cardiovascular manifestations. Treatment is described depending on the diagnostic outcome, focusing on medical management with mineralocorticoid receptor antagonists and unilateral adrenalectomy. Although screening and diagnosing hyperaldosteronism follows well-known algorithms, in practice, physicians may find difficulty establishing the best course of action due to complexity in testing and confirming laterality of aldosterone production by the adrenals. Recognizing and treating primary aldosteronism requires a multidisciplinary approach with primary care physicians, cardiologists, endocrinologists, and radiologists working collaboratively.
Primary aldosteronism and pregnancy.
Primary aldosteronism is the most common cause of secondary hypertension. Less than 50 cases of pregnancy in women with primary aldosteronism have been reported, suggesting the disorder is significantly underdiagnosed in confinement. Accurate diagnosis is complicated by physiological changes in the renin-angiotensin-aldosterone axis in pregnancy, leading to a risk of false negative results on screening tests. The course of primary aldosteronism during pregnancy is highly variable, although overall it is associated with a very high risk of fetal and maternal morbidity and mortality. The optimal management of primary aldosteronism during pregnancy is unclear, with uncertainty regarding the safety of mineralocorticoid antagonists and amiloride, their relative efficacy compared with the antihypertensive medications commonly used during pregnancy, and as to whether prognosis is improved by laparoscopic adrenalectomy where an adrenal adenoma can be demonstrated.
Controversies and advances in adrenal venous sampling in the diagnostic workup of primary aldosteronism.
Wolley Martin,Thuzar Moe,Stowasser Michael
Best practice & research. Clinical endocrinology & metabolism
Adrenal venous sampling (AVS) is a key part of the diagnostic workup of primary aldosteronism, distinguishing unilateral from bilateral disease and determining treatment options. Although AVS is a well-established procedure, many aspects remain controversial, including optimal patient selection for the procedure and exactly how AVS is performed and interpreted. Despite the controversies, a growing body of evidence supports the use of AVS in most patients with primary aldosteronism, though some specific patient groups may be able to forego AVS and proceed directly to treatment. Although AVS remains a difficult procedure, success rates may be improved with the use of advanced CT imaging techniques and/or rapid cortisol assays. New advances in nuclear imaging and steroid profiling may also offer alternatives or adjuncts to AVS in the future.
New Advances in the Diagnostic Workup of Primary Aldosteronism.
Wolley Martin J,Stowasser Michael
Journal of the Endocrine Society
Primary aldosteronism is an important and common cause of hypertension that carries a high burden of morbidity. Outcomes, however, are excellent if diagnosed and treated appropriately. The diagnostic workup for primary aldosteronism is complex and comprises three steps: (1) screening, (2) confirmatory testing, and (3) subtype differentiation. In this review, we discuss recent advances in the diagnostic workup for primary aldosteronism. The development of accurate mass spectroscopy-based assays for measuring aldosterone will lead to improved confidence in all diagnostic aspects involving measurement of aldosterone, and accurate measurement of angiotensin II may soon advance us beyond the measurement of renin. We now have a greater understanding of hormonal influences on the aldosterone/renin ratio, which are particularly important when screening premenopausal women or those taking estrogen-containing preparations. Confirmatory testing is important, but there are limitations to the commonly used methods that have recently become more apparent, with new approaches offering a way forward. Adrenal venous sampling (AVS) is a challenging procedure but is important for deciding on treatment options. Success rates may be improved by the use of Synacthen stimulation and of rapid intraprocedural measurement of cortisol. Better understanding of AVS interpretation criteria allows improved prognostication and aids treatment decisions. The use of labeled metomidate positron emission tomography computed tomography scanning may also offer an alternative to AVS in some units. Although the diagnostic approach to patients with primary aldosteronism remains a complex multistep process in which attention to detail is important, recent advances will improve patient care and outcomes.
Primary Aldosteronism Diagnosis and Management: A Clinical Approach.
Hundemer Gregory L,Vaidya Anand
Endocrinology and metabolism clinics of North America
Primary aldosteronism used to be considered a rare cause of secondary hypertension. However, accruing evidence indicates that primary aldosteronism is more common than previously recognized. The implications of this increased prevalence are important to public health because autonomous aldosterone production contributes to cardiovascular disease and can be treated in a targeted manner. This article focuses on clinical approaches for diagnosing primary aldosteronism more frequently and earlier in its course, as well as practical treatment objectives to reduce the risk for incident cardiovascular disease.
C-metomidate PET in the diagnosis of adrenal masses and primary aldosteronism: a review of the literature.
Chen Cardenas Stanley M,Santhanam Prasanna
BACKGROUND:Adrenal masses are commonly encountered in clinical practice, many of whom are incidental. Identifying malignancy, and excess hormone production is essential for appropriate management. Biochemical workup and imaging tests (dedicated adrenal CT and/or MRI) are used to determine the likelihood of excessive hormone function and malignancy, respectively. However, imaging cannot provide information about function and biochemical workup cannot localize the source. Furthermore, in primary aldosteronism, adrenal vein sampling, the gold standard for lateralization, has important limitations such as the technical expertise required, the elevated costs, and potential complications. Over the last decades, there has been a renewed interest in alternative noninvasive imaging techniques that provide information about adrenal function without the need for invasive procedures. In this review, we will evaluate the evidence and the potential role of C-metomidate as a promising positron emission tomography (PET) tracer in clinical practice. METHODS:A review of the English literature for articles describing the use of the tracer C-metomidate in adrenal disorders. RESULTS:A total of 12 studies were included in the systematic review, which altogether addressed the use of C-metomidate in adrenal masses and the application of this tracer in primary aldosteronism. CONCLUSIONS:C-metomidate, a selective inhibitor of 11-β-hydroxylase, demonstrated a high specificity for adrenocortical tissue. In addition, C-metomidate is correlated with this enzyme activity making it a potentially useful PET tracer for the identification primary aldosteronism, in addition to detection of adrenocortical masses.
Mineralocorticoid Receptor Antagonists in Primary Aldosteronism.
Stavropoulos Konstantinos,Papadopoulos Christodoulos,Koutsampasopoulos Konstantinos,Lales Georgios,Mitas Christos,Doumas Michael
Current pharmaceutical design
BACKGROUND:Primary aldosteronism is the most common causes of secondary hypertension. Patients suffering from this clinical syndrome have an increased cardiovascular risk and target organ damage. Mineralocorticoid receptor antagonists are the optimal pharmaceutical option for the management of such patients. OBJECTIVES:The study aimed to assess the effects of mineralocorticoid receptor antagonist in the treatment of patients with primary aldosteronism. METHOD:We conducted an in-depth review of the literature and comprehensive identification of the clinical studies investigating the efficacy of mineralocorticoid receptor antagonists in individuals with primary aldosteronism. RESULTS:Mineralocorticoid receptor antagonists result in significant improvement in blood pressure and serum potassium level among patients with primary aldosteronism. Moreover, mineralocorticoid receptor antagonists reverse left ventricular hypertrophy, albuminuria, and carotid intima-media thickness. However, a high risk for atrial fibrillation remains among subject with primary aldosteronism in such agents. CONCLUSION:Mineralocorticoid receptor antagonists are recommended as the first-line treatment in patients with bilateral primary aldosteronism. In patients with unilateral aldosterone-producing adenoma, adrenalectomy should be preferred. However, existing data presents significant limitations and is rather inconclusive. Future randomized control trials are required in order to illustrate the field.
MANAGEMENT OF ENDOCRINE DISEASE: The role of surgical adrenalectomy in primary aldosteronism.
Hundemer Gregory L,Vaidya Anand
European journal of endocrinology
Primary aldosteronism is common and contributes to adverse cardiovascular, kidney, and metabolic outcomes. When instituted early and effectively, targeted therapies can mitigate these adverse outcomes. Surgical adrenalectomy is among the most effective treatments because it has the potential to cure, or attenuate the severity of, pathologic aldosterone excess, resulting in a host of biochemical and clinical changes that improve health outcomes. Herein, we review the role of surgical adrenalectomy in primary aldosteronism while emphasizing the physiologic ramifications of surgical intervention, and compare these to other targeted medical therapies for primary aldosteronism. We specifically review the role of curative adrenalectomy for unilateral primary aldosteronism, the role of non-curative adrenalectomy for bilateral primary aldosteronism, and how these interventions influence biochemical and clinical outcomes in relation to medical therapies for primary aldosteronism.
Aldosterone level after saline infusion test could predict clinical outcome in primary aldosteronism after adrenalectomy.
Chan Chieh-Kai,Kim Jung-Hee,Chueh Eric,Chang Chin-Chen,Lin Yu-Feng,Lai Tai-Shuan,Huang Kuo-How,Lin Yen-Hung,Wu Vin-Cent,
BACKGROUND:The saline infusion test is widely used as a conﬁrmatory test for primary aldosteronism, and we hypothesized that post-saline-infusion test aldosterone levels might predict the clinical outcomes in primary aldosteronism patients after adrenalectomy. METHODS:An observational cohort study was performed. We included primary aldosteronism patients who had undergone adrenalectomy from the Taiwan Primary Aldosteronism Investigation database between 1995 and 2017. The patients were divided into the following 2 groups: the clinical success group and the resist hypertension group, according to the criteria from the Primary Aldosteronism Surgery Outcome consensus. RESULTS:We enrolled 236 patients with primary aldosteronism (male, 41.1%; mean age, 49.8 years). A total of 79.7% patients achieved clinical success after adrenalectomy after 12-month follow-up. The clinical success group had higher mean blood pressure, higher aldosterone-to-renin ratio, lower potassium, and lower renin levels than that of the resist hypertension group. In multivariate logistic regression analysis, post saline-infusion test aldosterone levels higher than 48 ng/dL (odds ratio, 2.51; 95% confidence interval, 1.04-6.06; P = .040), body mass index less than 25 kg/m (odds ratio, 2.22; 95% confidence interval, 1.12-4.40; P = .023) and mean blood pressure higher than 115 mmHg (odds ratio, 2.79; 95% confidence interval, 1.37-5.68; P = .005) could predict better clinical success rates after adrenalectomy in primary aldosteronism patients. CONCLUSION:Our study demonstrated that the post-saline-infusion test aldosterone level could not only confirm primary aldosteronism but also forecast clinical outcomes in primary aldosteronism patients after adrenalectomy.
A novel clinical nomogram to predict bilateral hyperaldosteronism in Chinese patients with primary aldosteronism.
Xiao Libin,Jiang Yiran,Zhang Cui,Jiang Lei,Zhou Weiwei,Su Tingwei,Ning Guang,Wang Weiqing
CONTEXT:Adrenal venous sampling (AVS) is recommended as the gold standard for subtype classification in primary aldosteronism (PA); however, this approach has limited availability. OBJECTIVE:We aimed to develop a novel clinical nomogram to predict PA subtype based on routine variables, thereby reducing the number of candidates for AVS. PATIENTS AND METHOD:Patients were randomly divided into a training set (n = 185) and a validation set (n = 79). Risk factors for idiopathic hyperaldosteronism (IHA) differentiating from aldosterone-producing adenoma (APA) were identified using logistic regression analysis. A nomogram was constructed to predict the probability of IHA. A receiver operating characteristic (ROC) curve and a calibration plot were applied to assess the predictive value. Then, 115 patients were prospectively enrolled, and a nomogram was used to predict the subtypes before AVS. RESULTS:Body mass index (BMI), serum potassium and computed tomography (CT) finding were adopted in the nomogram. The nomogram presented an area under the ROC (AUC) of 0.924 (95% CI: 0.875-0.957), sensitivity of 86.59% and specificity of 87.38% in the training set and an AUC of 0.894 (95% CI: 0.804-0.952), sensitivity of 82.86% and specificity of 84.09% in the validation set. Predicted probability and actual probability matched well in the nomogram (Hosmer-Lemeshow test: P > 0.05). Using the nomogram as a surrogate to predict IHA in the prospective set before AVS, the specificity reached 100% when we increased the threshold to a probability of 90%. CONCLUSION:We have developed a tool that is able to predict IHA in patients with PA and potentially avoid AVS.
Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis.
Monticone Silvia,D'Ascenzo Fabrizio,Moretti Claudio,Williams Tracy Ann,Veglio Franco,Gaita Fiorenzo,Mulatero Paolo
The lancet. Diabetes & endocrinology
BACKGROUND:There is conflicting evidence, relying on heterogeneous studies, as to whether aldosterone excess is responsible for an increased risk of cardiovascular and cerebrovascular complications in patients with primary aldosteronism. We aimed to assess the association between primary aldosteronism and adverse cardiac and cerebrovascular events, target organ damage, diabetes, and metabolic syndrome, compared with the association of essential hypertension and these cardiovascular and end organ events, by integrating results of previous studies. METHODS:We did a meta-analysis of prospective and retrospective observational studies that compared patients with primary aldosteronism and essential hypertension, to analyse the association between primary aldosteronism and stroke, coronary artery disease (as co-primary endpoints), atrial fibrillation and heart failure, target organ damage, metabolic syndrome, and diabetes (as secondary endpoints). We searched MEDLINE and Cochrane Library for articles published up to Feb 28, 2017, with no start date restriction. Eligible studies compared patients with primary aldosteronism with patients with essential hypertension (as a control group) and reported on the clinical events or endpoints of interest. We also compared primary aldosteronism subtypes, aldosterone-producing adenoma, and bilateral adrenal hyperplasia. FINDINGS:We identified 31 studies including 3838 patients with primary aldosteronism and 9284 patients with essential hypertension. After a median of 8·8 years (IQR 6·2-10·7) from the diagnosis of hypertension, compared with patients with essential hypertension, patients with primary aldosteronism had an increased risk of stroke (odds ratio [OR] 2·58, 95% CI 1·93-3·45), coronary artery disease (1·77, 1·10-2·83), atrial fibrillation (3·52, 2·06-5·99), and heart failure (2·05, 1·11-3·78). These results were consistent for patients with aldosterone-producing adenoma and bilateral adrenal hyperplasia, with no difference between these subgroups. Similarly, primary aldosteronism increased the risk of diabetes (OR 1·33, 95% CI 1·01-1·74), metabolic syndrome (1·53, 1·22-1·91), and left ventricular hypertrophy (2·29, 1·65-3·17). INTERPRETATION:Diagnosing primary aldosteronism in the early stages of disease, with early initiation of specific treatment, is important because affected patients display an increased cardiovascular risk compared with patients with essential hypertension. FUNDING:None.
Pathogenesis and treatment of primary aldosteronism.
Zennaro Maria-Christina,Boulkroun Sheerazed,Fernandes-Rosa Fabio L
Nature reviews. Endocrinology
Early diagnosis and appropriate treatment of primary aldosteronism, the most frequent cause of secondary hypertension, are crucial to prevent deleterious cardiovascular outcomes. In the past decade, the discovery of genetic abnormalities responsible for sporadic and familial forms of primary aldosteronism has improved the knowledge of the pathogenesis of this disorder. Mutations in genes encoding ion channels and pumps lead to increased cytosolic concentrations of calcium in zona glomerulosa cells, which triggers CYP11B2 expression and autonomous aldosterone production. Improved understanding of the mechanisms underlying the disease is key to improving diagnostics and to developing and implementing targeted treatments. This Review provides an update on the genetic abnormalities associated with sporadic and familial forms of primary aldosteronism, their frequency among different populations and the mechanisms explaining excessive aldosterone production and adrenal nodule development. The possible effects and uses of these findings for improving the diagnostics for primary aldosteronism are discussed. Furthermore, current treatment options of primary aldosteronism are reviewed, with particular attention to the latest studies on blood pressure and cardiovascular outcomes following medical or surgical treatment. The new perspectives regarding the use of targeted drug therapy for aldosterone-producing adenomas with specific somatic mutations are also addressed.
The Expanding Spectrum of Primary Aldosteronism: Implications for Diagnosis, Pathogenesis, and Treatment.
Vaidya Anand,Mulatero Paolo,Baudrand Rene,Adler Gail K
Primary aldosteronism is characterized by aldosterone secretion that is independent of renin and angiotensin II and sodium status. The deleterious effects of primary aldosteronism are mediated by excessive activation of the mineralocorticoid receptor that results in the well-known consequences of volume expansion, hypertension, hypokalemia, and metabolic alkalosis, but it also increases the risk for cardiovascular and kidney disease, as well as death. For decades, the approaches to defining, diagnosing, and treating primary aldosteronism have been relatively constant and generally focused on detecting and treating the more severe presentations of the disease. However, emerging evidence suggests that the prevalence of primary aldosteronism is much greater than previously recognized, and that milder and nonclassical forms of renin-independent aldosterone secretion that impart heightened cardiovascular risk may be common. Public health efforts to prevent aldosterone-mediated end-organ disease will require improved capabilities to diagnose all forms of primary aldosteronism while optimizing the treatment approaches such that the excess risk for cardiovascular and kidney disease is adequately mitigated. In this review, we present a physiologic approach to considering the diagnosis, pathogenesis, and treatment of primary aldosteronism. We review evidence suggesting that primary aldosteronism manifests across a wide spectrum of severity, ranging from mild to overt, that correlates with cardiovascular risk. Furthermore, we review emerging evidence from genetic studies that begin to provide a theoretical explanation for the pathogenesis of primary aldosteronism and a link to its phenotypic severity spectrum and prevalence. Finally, we review human studies that provide insights into the optimal approach toward the treatment of primary aldosteronism.