Laboratory Testing for Endocrine Hypertension: Current and Future Perspectives.

Primary aldosteronism is the most common cause of secondary hypertension, accounting for about 10% of all forms of high blood pressure. Life-time pharmacological therapy is the treatment of choice for primary aldosteronism due to idiopathic adrenal hyperplasia (IHA), while adrenalectomy is effective in curing most patients with an aldosterone producing adenoma (APA). Far from being a benign form of hypertension, primary aldosteronism is characterized by the development of cardiovascular renal and metabolic complications, including left ventricular hypertrophy, myocardial infarction, atrial fibrillation and stroke, microalbuminuria, renal cysts as well as metabolic syndrome, glucose impairment and diabetes mellitus. We review recent clinical experience with the above mentioned complications and long-term outcomes of blood pressure normalization and cardiac, renal and gluco-metabolic complications in patients with primary aldosteronism, after medical treatment with mineralocorticoid receptor antagonists and surgical treatment. We conclude that removal of adrenal adenoma results in normalization of the renin-angiotensin-aldosterone system (RAAS) and of kalaemia and improvement of blood pressure levels in all patients. Complete resolution of hypertension is achieved in nearly half of treated patients. Moreover, unilateral adrenalectomy is the best treatment to have the regression of cardiovascular, renal and metabolic complications in patients with APA. On the other hand, targeted medical treatment with aldosterone antagonists improves blood pressure control and appears able to prevent the progression of cardiac and metabolic complications in patients with IHA.

Secondary hypertension: Evaluation and treatment

Secondary hypertension diagnosis and management among pregnant patients: a review.

Disclosure: M.A. Grytaas: None. P. Methlie: None. I. Marinelli: None. E. Zavala: None. M. Øksnes: None. T. Upton: None. K. Simunkova: None. D.A. Vassiliadi: None. K. Løvås: None. S. Bensing: None. I. Botusan: None. K. Berinder: None. G.M. Russell: None. G. Ueland: None. O. Kampe: None. S. Tsagarakis: None. S.L. Lightman: None. E.S. Husebye: None. Background: Primary aldosteronism (PA) is the most common cause of secondary hypertension but is grossly underdiagnosed. Early detection, accurate discrimination between unilateral and bilateral PA and appropriate treatment are vital to prevent cardiovascular and renal complications. The current workup however is a cumbersome, multistep process that may not detect dynamic aldosterone variability or nocturnal hypersecretion. Furthermore, subtype determination with adrenal venous sampling is invasive and technically challenging. Novel dynamic 24-hour steroid profiling may represent a major step forward in the diagnostics and subtyping of PA. Aim: To assess 24-hour rhythmicity of aldosterone and metabolites in PA, and to develop a novel dynamic diagnostic tool to discriminate PA from healthy subjects (HS), using tissue microdialysis. Material and methods: Twenty-minute frequency microdialysis fractions were collected over 24 hours from 64 ambulatory patients with PA (26 bilateral, 24 unilateral, 14 with undetermined subtype) using the U-Rhythm sampler followed by multiplex hormone assay liquid chromatography tandem mass spectrometry (LC-MS/MS). Sixteen patients subsequently treated with adrenalectomy for unilateral PA had additional postoperative samplings. Microdialysis samplings from 214 HS were used as controls. We calculated statistical distributions of dynamic biomarkers of abnormality, and developed a machine learning classifier that discriminates PA from HS. Results: Although there were large interindividual variations, PA patients did show a disturbed circadian rhythmicity of aldosterone compared with HS, including some with multiple very high ultradian spikes. Unilateral PA had higher aldosterone spikes and more disturbed rhythmicity compared with bilateral PA. A profound reduction of aldosterone levels and normalisation of rhythmicity was seen post adrenalectomy. Applying a Random Forest classifier in a subgroup of 20 PA patients, 82% specificity and 85% sensibility were achieved to discriminate PA from HS. Our analysis also suggests 18-hydroxycortisol as the most discriminative dynamic biomarker. Conclusions: We demonstrate for the first time circadian and ultradian rhythms of aldosterone in a large cohort of PA compared with HS. Based on our preliminary results, dynamic 24-hour samplings may provide a novel method for diagnosing and subtyping PA, and assess biochemical cure after adrenalectomy. Presentation: Thursday, June 15, 2023

Introduction: In this context, secondary arterial hypertension (SH) is defined as an increase in systemic arterial pressure (SAP) due to an identifiable cause. Only 5 to 10% of patients suffering from hypertension have a secondary form, while the vast majorities have essential hypertension. Objective: This study aimed to describe, through a systematic review, the main considerations on secondary hypertension, presenting its clinical data and main causes, as well as presenting the types of treatments according to the literary results. Methods: Following the criteria of literary search with the use of the Mesh Terms that were cited in the item below on Search strategies, the total of 76 papers that were submitted to the eligibility analysis were collated and, after that, 23 studies were selected, following the rules of systematic review-PRISMA. In general, as an example, the search strategy in MEDLINE / Pubmed, Web of Science, ScienceDirect Journals (Elsevier), Scopus (Elsevier), OneFile (Gale). Major findings: According to epidemiological data, secondary hypertension (SH) presents an incidence of 5.0 to 10.0% of the world population. In this context, since SH cases are difficult to screen and expensive, only patients with clinical suspicion should be examined. In recent years, some new aspects have gained importance in relation to this screening. Thus, increasing evidence suggests that 24-hour ambulatory blood pressure monitoring plays a central role. The prevalence of SH is related to age and clinical characteristics. In addition, some residual hypertension remains after the pathogenic cause of secondary hypertension has been identified and removed because of the existence of essential hypertension. Conclusion:It was concluded with the present study that secondary hypertension effects on average 7.5% of hypertensive patients. Screening in the diagnosis of secondary hypertension is expensive and laborious and should be performed only in patients with high clinical suspicion.

Hypertension artérielle endocrine

Hypertension is a common disease and a crucial predisposing factor of cardiovascular diseases. Approximately 10% of hypertensive patients are secondary hypertension, a pathogenetic factor of which can be identified. Secondary hypertension consists of endocrine, renal, and other diseases. Primary aldosteronism, Cushing's syndrome, pheochromocytoma, hyperthyroidism, and hypothyroidism result in endocrine hypertension. Renal parenchymal hypertension and renovascular hypertension result in renal hypertension. Other diseases such as obstructive sleep apnea syndrome are also very prevalent in secondary hypertension. It is very crucial to find and treat secondary hypertension at earlier stages since most secondary hypertension is curable or can be dramatically improved by specific treatment. One should keep in mind that screening of secondary hypertension should be done at least once in a daily clinical practice.

SummaryBackgroundArterial hypertension is a major cardiovascular risk factor. Identification of secondary hypertension in its various forms is key to preventing and targeting treatment of cardiovascular complications. Simplified diagnostic tests are urgently required to distinguish primary and secondary hypertension to address the current underdiagnosis of the latter.MethodsThis study uses Machine Learning (ML) to classify subtypes of endocrine hypertension (EHT) in a large cohort of hypertensive patients using multidimensional omics analysis of plasma and urine samples. We measured 409 multi-omics (MOmics) features including plasma miRNAs (PmiRNA: 173), plasma catechol O-methylated metabolites (PMetas: 4), plasma steroids (PSteroids: 16), urinary steroid metabolites (USteroids: 27), and plasma small metabolites (PSmallMB: 189) in primary hypertension (PHT) patients, EHT patients with either primary aldosteronism (PA), pheochromocytoma/functional paraganglioma (PPGL) or Cushing syndrome (CS) and normotensive volunteers (NV). Biomarker discovery involved selection of disease combination, outlier handling, feature reduction, 8 ML classifiers, class balancing and consideration of different age- and sex-based scenarios. Classifications were evaluated using balanced accuracy, sensitivity, specificity, AUC, F1, and Kappa score.FindingsComplete clinical and biological datasets were generated from 307 subjects (PA=113, PPGL=88, CS=41 and PHT=112). The random forest classifier provided ∼92% balanced accuracy (∼11% improvement on the best mono-omics classifier), with 96% specificity and 0.95 AUC to distinguish one of the four conditions in multi-class ALL-ALL comparisons (PPGL vs PA vs CS vs PHT) on an unseen test set, using 57 MOmics features. For discrimination of EHT (PA + PPGL + CS) vs PHT, the simple logistic classifier achieved 0.96 AUC with 90% sensitivity, and ∼86% specificity, using 37 MOmics features. One PmiRNA (hsa-miR-15a-5p) and two PSmallMB (C9 and PC ae C38:1) features were found to be most discriminating for all disease combinations. Overall, the MOmics-based classifiers were able to provide better classification performance in comparison to mono-omics classifiers.InterpretationWe have developed a ML pipeline to distinguish different EHT subtypes from PHT using multi-omics data. This innovative approach to stratification is an advancement towards the development of a diagnostic tool for EHT patients, significantly increasing testing throughput and accelerating administration of appropriate treatment.FundingEuropean Union's Horizon 2020 Research and Innovation Programme under Grant Agreement No. 633983, Clinical Research Priority Program of the University of Zurich for the CRPP HYRENE (to Z.E. and F.B.), and Deutsche Forschungsgemeinschaft (CRC/Transregio 205/1).

Caution About the Overdiagnosis of Primary Aldosteronism

Coexistence of two causes of secondary hypertension in a single patient

Background and Aims Primary aldosteronism (PA) is one of the most frequent causes of secondary hypertension. Patients with PA are at higher risk for cardiovascular and renal complications than those with essential hypertension. Screening for PA is rarely considered in the assessment of a hypertensive patient, in part because of difficulties in the diagnostic process. Nevertheless, identification of PA is crucial to guide patients towards optimal management, either by mineralocorticoid receptor blockade or by unilateral adrenalectomy, with the latter offering potential cure for patients with aldosterone-producing adenomas (APAs). Numerous studies show inadequate diagnostic accuracy of the aldosterone:renin ratio (ARR) for screening for PA, particularly in females, who have higher ARR variability and lower renin compared to males. Women have a higher risk of false-positive screening results leading to unnecessary confirmatory tests. Use of oral contraception (OC) or hormone replacement therapy (HRT) may also confound the ARR. The aim of this study was to develop improved screening tools for PA, including adjustments for sex-specific differences. Method PROSALDO is a multicenter prospective cohort study designed to test new diagnostic procedures for patients with suspected PA. Medication that interfere with the renin-angiotensin-aldosterone system are withdrawn before laboratory measurements. For screening, the routine ARR is calculated along with additional probability scores based on a peripheral venous steroid hormone profile (PVSP). The latter allows for identification of potentially false-negative ARR results. After a positive screening result of the ARR and/or a high probability score based on the PVSP, PA is confirmed or excluded with a saline infusion test (SIT). PA confirmation is followed by adrenal venous sampling (AVS) to identify patients with unilateral PA. We compared aldosterone, renin and ARR levels between females and males with and without PA. Renin- and sex dependent formulas for aldosterone screening cut-offs were derived from the study population. Logistic regression and the corresponding receiver operating characteristic (ROC) curves were used to determine and compare diagnostic accuracies. Results PA was confirmed in 159 (24.5%) of 649 (328 (50.5%) females and 321 (49.5%) males). Lateralization was shown in 58 out of 117 patients who underwent AVS. In hypertensive patients without PA, ARR was higher in females vs. males (26.4 vs. 11.7 pmol/mU, P < 0.0001), mainly due to a lower renin (9.2 vs. 16.2 mU/L, P < 0.0001). Furthermore, ARRs in patients with vs. without PA showed more overlap in females compared to males. Areas under ROC curves (AUROCs) for the ARR were 0.857 (CI 95%: 0.797-0.902) vs. 0.912 (CI 95%: 0.876-0.938) for females and males respectively. Using liquid chromatography mass spectrometry measurements (LC-MS/MS) of aldosterone, an ARR cut-off of 21.75 pmol/L yielded a sensitivity of 93% with only 45% specificity in females, while for males, a specificity of 66% was obtained for a sensitivity of 97.7%. This meant for females having a higher risk of false-positive screening results (OR 2.36 (CI 95%: 1.65-3.41)), even after excluding patients on OC or HRT (OR 2.17 (CI 95%: 1.5-3.17)). We derived a renin- and sex-dependent formula for the calculation of aldosterone cut-offs, which improved diagnostic accuracy for both males and females (ΔAUROC = 0.05 and 0.045, P < 0.0001 and 0.02 respectively): for a diagnostic sensitivity of 94-95%, specificity was improved to 61% in females and 82% in males. Conclusion Lower renin in females without PA leads to higher ARRs and thus a higher risk of false-positive screening results. Higher overlap of the ARR between females with and without PA compared to their male counterparts weakens utility of the ARR for discrimination of patients with and without PA. Sex- and renin-specific aldosterone cut-offs for screening for PA offer improved diagnostic accuracy. Diagnostic accuracy remains however superior in males, which highlights the need for further optimization of diagnostic procedures specifically in women.

Introduction: Primary aldosteronism (PA), the most common endocrine cause of secondary hypertension, is generally under diagnosed using current diagnostic tests. Objective: To present our findings, based on studies using modified diagnostic tests, on the diagnosis, prevalence and treatment of PA. Design and Methods: We prospectively studied 992 hypertensive patients and 278 matched controls. Participants underwent conventional confirmatory tests for the diagnosis of PA modified by the addition of dexamethasone including the Fludrocortisone Dexamethasone Suppression Test (FDST), the Dexamethasone Captopril Valsartan Test (DCVT) and the Dexamethasone Saline Infusion Test (DSIT). Normal cut-offs of basal aldosterone-to-renin ratio and post-test (FDST, DCVT and DSIT) aldosterone levels and aldosterone-to-renin ratio were calculated from the control groups, who had normal adrenal imaging. Results: Hypertensive patients had significantly higher baseline blood pressure and lower serum potassium levels compared to controls. Using the basal aldosterone-to-renin ratio as screening test, the prevalence of PA was 17.8%. After applying the modified tests to all patients, the prevalence of PA was 33.4%. Targeted treatment with Mineralocorticoid Receptor Antagonists was administered in 252 hypertensives, with bilateral PA; 188 (74.6%) of them obtained a biochemical response and normalization of blood pressure. Unilateral disease had 48 patients who underwent laparoscopic adrenalectomy obtaining a biochemical success rate was 94%. Conclusion: Our modified methodology and the use of normotensive controls for calculation of normal cut-offs of aldosterone suppression, significantly improves the sensitivity and specificity of the existing tests on the diagnosis of PA, allowing the detection of milder forms.

Background: nowadays, primary aldosteronism (PA) is suggested to be the most frequent cause of secondary hypertension and it reaches 10% of whole hypertensive population. The CYP11B2 promoter polymorphism might cause aldosterone overproduction. The aim of this study was to establish whether the polymorphism CYP11B2 promoter has a significant impact on diagnostic of PA. Material and Methods: study group consisted of 239 hypertensive patients previously diagnosed with adrenal incidentaloma. For diagnose of PA were performed: screening test–aldosterone-renin ratio (ARR) and saline suppression test (SIT) as a confirmatory test. Genotyping was carried out by the real time PCR method. The significance of differences between the groups was evaluated through Student’s t-test. Results: our study revealed that genotype TT had plasma aldosterone concentration (PAC), ARR and SIT significantly higher in comparison with CC patients. The mean PAC in CC was 12.71 ng/dL vs. 20.55 ng/dL in TT patients (p = 0.037), which consequently gave a higher ARR in TT patients (119 vs. 44, p = 0.034). Mean aldosterone concentration in SIT was 2.40 ng/dL in CC patients and 9.99 ng/dL in TT patients (p = 0.046). Patients with CC genotype required less hypotensive drugs in comparison with TT genotype (p = 0.044). PA was recognized in 16 patients. Nine patients had TC genotype, six TT, and one with CC genotype. Conclusion: our study revealed predisposing TT genotype to PA. Additionally, patients with TT genotype, regardless of the PA presence, had more severe hypertension. The determination of the CYP11B2 promoter polymorphism seems to be useful in the diagnosis of PA, especially in cases where it is difficult to properly prepare patients for hormonal tests or even results of the hormonal test are incoherent.

Disclosure: K. Zekarias: None. J. Kohlenberg: None. M. Xu: None. S. Ma: None.Background: Primary aldosteronism (PA) is a leading, often undiagnosed cause of secondary hypertension. Objective: This study aimed to develop an electronic-health-record (EHR) based machine learning model to predict PA in people with hypertension. Methods: We conducted a retrospective cohort study utilizing EHR data from 1,649 people screened for PA between April 13, 2018, and May 2, 2023 at an academic health system in the upper Midwest, USA. PA screening was conducted using standardized guideline recommended risk factor assessment. PA diagnosis was defined as 1) urine aldosterone > 12 µg/24h after oral salt loading or 2) PAC > 10 ng/dL 4 hours after saline infusion or 3) plasma aldosterone concentration (PAC) > 20 ng/dL with renin < 1 ng/mL/h or 4) Aldosterone to Renin Ratio (ARR) > 50 with PAC ≥ 10 ng/dL. We extracted 74 potential PA predictor variables from EHR data and applied various feature selection and classification methods to develop predictive models. Results: Among 1,649 people screened for primary aldosteronism (PA), 166 (10%) were diagnosed with PA. Compared to people without PA, those with PA were older (mean age 61 ± 13 years vs. 56 ± 17 years, p=0.001). There was no difference in gender (48% male, 52% female, p=0.7). The prevalence of PA among those screened was higher in Black patients (20%) compared to White patients (7%) and other racial groups (5%), with a statistically significant difference (p < 0.001). Those with PA exhibited increased end organ damage (48%) compared to those people without PA (37%, p=0.02).The model selection procedure resulted in a logistic regression model with 13 predictors, with cross validated area under the receiver operating characteristic curve (AUC) 0.7+/-0.021. Key risk factors predicting PA diagnosis were age, race, body mass index, hypokalemia, sodium and bicarbonate concentrations, high-density lipoprotein levels, obstructive sleep apnea, end stage renal disease, uncontrolled blood pressure (B/P >130/80), and prescription of > 4 blood pressure medications, diastolic blood pressure > 80, and Glomerular Filtration Rate (GFR).Discussion/Conclusion: We have developed a predictive model with moderate performance designed to optimize PA screening through risk stratification. Notably, the cohort in this study was screened for PA following current clinical guideline recommendations. The fact that our model achieved AUC=0.7 indicates that additional clinical information not currently included in the screening guideline can enhance screening performance. Following rigorous validation with prospective data, we aim to integrate this prediction tool directly into the clinical workflow as a decision support tool for PA screening. The clinical significance of this approach lies in its potential to enhance targeted screening for PA and to improve screening rates by leveraging a clinical workflow decision support tool.Presentation: Sunday, July 13, 2025

Endocrine Causes of Hypertension in Children