Diagnostic Workup For Primary Aldosteronism Research Articles

A new LC-MS/MS method for simultaneous determination of six steroids in urine for the diagnostic workup of primary aldosteronism

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

EFFECTS OF MINERALOCORTICOID RECEPTOR ANTAGONISTS ON ALDOSTERONE TO RENIN RATIO IN PATIENTS WITH PRIMARY ALDOSTERONISM

Objective: Current guidelines recommend to withdraw interfering antihypertensive drugs before to perform a screening test for primary aldosteronism (PA). Recent studies suggested that diagnostic work-up of PA might be performed without withdrawing mineralocorticoid receptor antagonist (MRA) treatment in selected patients, especially when severe hypertension and hypokalemia are difficult to control. We designed a prospective study to evaluate the effects of MRA treatment on aldosterone to renin ratio (ARR) in patients with PA. Design and method: We prospectively recruited 121 patients with confirmed PA and started on canrenone treatment. Eighteen patients were enrolled in a short-term treatment cohort to assess the effects of MRA on aldosterone to renin ratio (ARR) and potassium after 2 and 8 weeks of canrenone therapy. One hundred and two patients were recruited in the long-term treatment cohort to evaluate the effects of canrenone on ARR after 2 to 12 months of MRA therapy. Results: Plasma renin activity and potassium displayed a significant increase, and ARR showed a significant reduction compared with baseline in patients with PA after MRA initiation. These effects were observed both after a short- and a long-term treatment with canrenone, and were progressively more significant after longer periods of therapy and with greater doses of MRA. We demonstrated that canrenone assumption severely impacts on the rate of false-negative screening tests for PA, which raised from 16.7% to 72.5% after 2 weeks and 7–12 months of MRA treatment, respectively. Conclusions: ARR testing for PA screening should not be performed under MRA therapy.

Adrenal venous sampling in the diagnostic workup of primary aldosteronism.

Primary aldosteronism (PA) is the primary cause of secondary hypertension. The prevalence of PA has probably been underestimated in the past and recent studies suggest that PA could be present in up to 10% of patients suffering from hypertension. Aldosterone excess in PA can be caused by unilateral adrenal disease, usually adrenal adenoma, or bilateral adrenal hyperplasia. Differentiation between unilateral and bilateral disease is clinically important as the former can effectively be treated by removal of the affected adrenal. CT or MRI cannot reliably distinguish unilateral from bilateral disease. Therefore, adrenal vein sampling (AVS) is an important step of the diagnostic work-up in patients with PA. Current guidelines recommend PA in virtually all patients with biochemically diagnosed PA who would undergo adrenal surgery if unilateral PA was diagnosed. In this narrative review, we give an overview of the current technique used for AVS with a focus on the experience with this technique at the University Hospital Basel, Switzerland.

Primary aldosteronism: from diagnosis to therapy in clinical practice

Primary aldosteronism (PA) is the single most common cause of secondary hypertension and is associated with increased target organ injury. It can be can either surgically cured or treated with targeted pharmacotherapy. PA is frequently undiagnosed and untreated, leading to aldosterone-specific cardiovascular morbidity and nephrotoxicity. Thus, clinicians should perform case detection testing for PA at least once in all patients with hypertension. The diagnostic work-up of PA is a sequence of three phases comprising screening tests, confirmatory tests and the differentiation of unilateral from bilateral forms. With appropriate surgical expertise, laparoscopic unilateral adrenalectomy is safe, efficient and curative in patients with unilateral adrenal disease. In patients who have bilateral aldosterone hypersecretion, the optimal management is a low sodium diet and lifelong treatment with a mineralocorticoid receptor antagonist administered at a dosage to maintain a high-normal serum potassium concentration without the aid of oral potassium supplements. In patients with PA, 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.

Aldosterone-producing adenoma associated with non-suppressed renin: a case series.

Although the aldosterone/renin ratio (ARR) is the preferred screening test for primary aldosteronism (PA), patients with non-suppressed renin and a falsely negative ARR on non-interfering medications have occasionally been reported. This report describes the clinical characteristics and outcomes of seven patients with proven aldosterone-producing adenoma (APA) and non-suppressed renin.Chart review of seven PA patients with an APA and a non-suppressed plasma renin concentration (PRC > 8.4 mU/L) was undertaken to collect data on anthropometric and biochemical characteristics, diagnostic evaluation and postsurgical outcomes.Seven patients (two women and five men) with a proven APA had median (range) PRC, plasma aldosterone and ARR of 20 (9-43) mU/L, 750 (270-1940) pmol/L and 45 (8-62, normal <70), respectively, on non-interfering medications. Six patients had two consecutive ARR measurements and in five of them both were normal. Renal artery stenosis was carefully excluded in all patients. Further evaluation for PA was pursued because of high clinical suspicion (either hypokalaemia and/or a known adrenal mass lesion on imaging). All underwent adrenal vein sampling confirming unilateral PA which was managed by unilateral adrenalectomy. Postsurgical follow-up data either confirmed or were highly suggestive of cure of PA.Strict control of factors known to influence the ARR is crucial to avoid false-negative results. Other causes that could explain a non-suppressed renin should be excluded. In patients with a consistently non-suppressed renin further diagnostic workup for PA should be considered if clinical suspicion remains high.

Development of a Prediction Score to Avoid Confirmatory Testing in Patients With Suspected Primary Aldosteronism.

The diagnostic work-up of primary aldosteronism (PA) includes screening and confirmation steps. Case confirmation is time-consuming, expensive, and there is no consensus on tests and thresholds to be used. Diagnostic algorithms to avoid confirmatory testing may be useful for the management of patients with PA. Development and validation of diagnostic models to confirm or exclude PA diagnosis in patients with a positive screening test. We evaluated 1024 patients who underwent confirmatory testing for PA. The diagnostic models were developed in a training cohort (n = 522), and then tested on an internal validation cohort (n = 174) and on an independent external prospective cohort (n = 328). Different diagnostic models and a 16-point score were developed by machine learning and regression analysis to discriminate patients with a confirmed diagnosis of PA. Male sex, antihypertensive medication, plasma renin activity, aldosterone, potassium levels, and the presence of organ damage were associated with a confirmed diagnosis of PA. Machine learning-based models displayed an accuracy of 72.9%-83.9%. The Primary Aldosteronism Confirmatory Testing (PACT) score correctly classified 84.1% at training and 83.9% or 81.1% at internal and external validation, respectively. A flow chart employing the PACT score to select patients for confirmatory testing correctly managed all patients and resulted in a 22.8% reduction in the number of confirmatory tests. The integration of diagnostic modeling algorithms in clinical practice may improve the management of patients with PA by circumventing unnecessary confirmatory testing.

Safety of medical adjustment and confirmatory testing in the diagnostic work-up of primary aldosteronism.

Saline infusion test (SIT) and captopril challenge test (CCT) are standard confirmatory procedures routinely used in the diagnostic work-up of primary aldosteronism (PA). However, side effects and complications during testing have not been systematically studied. We performed a cohort study with patients undergoing SIT and/or CCT in two centers from 2016 until 2018. We studied 272 study participants with suspected PA enrolled at two outpatient centers in Germany. We assessed the frequency and severity of side effects during adjustment of blood pressure medication and during SIT and CCT. During the adjustment phase prior confirmatory testing, side effects including palpitations, headaches, edema and hypertensive episodes occurred in 18.4% of study participants. Side effects were associated with higher defined daily doses (DDD) (r = 0.25, P < 0.005), number of antihypertensive drugs (r = 0.285, P < 0.005) and higher blood pressure (r = 0.145, P = 0.019). During SIT, 17.5% of study participants had side effects, associated with higher blood pressure (systolic: r = 0.541, P < 0.0005; diastolic: r = 0.426, P < 0.0005) and DDDs (r = 0.727, P < 0.0005). During CCT, only 1.5% of study participants developed side effects. In contrast to the high rate of side effects during SIT, CCT appears to be the safer test with a very low event rate. This makes CCT especially suitable for severely hypertensive patients.

Evaluation of Biochemical Conditions Allowing Bypass of Confirmatory Testing in The Workup of Primary Aldosteronism: A Retrospective Study in a French Hypertensive Population.

The diagnostic workup for primary aldosteronism includes a screening step using the aldosterone-to-renin ratio (ARR) and a confirmatory step based on dynamic testing of aldosterone secretion autonomy. International guidelines suggest that precise clinical and biochemical conditions may allow the bypassing of the confirmatory step, however, data which validate hormone thresholds defining such conditions are lacking. At our tertiary center, we retrospectively examined a cohort of 173 hypertensive patients screened for PA by the ARR, of whom 120 had positive screening and passed a saline infusion test (SIT) or a captopril challenge test (CCT). Fifty-nine had PA, including 34 Conn adenomas and 25 with idiopathic aldosteronism (IA). Using a threshold of 160 pmol/l, post-SIT plasma aldosterone concentration (PAC) identified PA with 86.4% sensitivity, 94.7% specificity, and a negative predictive value of 92.3%. Of those subjects with a high ARR and a PAC above 550 pmol/l, 93% had a positive SIT, while 100% of subjects with a high ARR, but a PAC under 240 pmol/l had a negative SIT. Our results thus validate the biochemical conditions defined in the French and US guidelines for bypassing the confirmatory step in the workup for PA diagnosis.

The Biology of Normal Zona Glomerulosa and Aldosterone-Producing Adenoma: Pathological Implications.

The identification of several germline and somatic ion channel mutations in aldosterone-producing adenomas (APAs) and detection of cell clusters that can be responsible for excess aldosterone production, as well as the isolation of autoantibodies activating the angiotensin II type 1 receptor, have rapidly advanced the understanding of the biology of primary aldosteronism (PA), particularly that of APA. Hence, the main purpose of this review is to discuss how discoveries of the last decade could affect histopathology analysis and clinical practice. The structural remodeling through development and aging of the human adrenal cortex, particularly of the zona glomerulosa, and the complex regulation of aldosterone, with emphasis on the concepts of zonation and channelopathies, will be addressed. Finally, the diagnostic workup for PA and its subtyping to optimize treatment are reviewed.

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of primary aldosteronism: the Endocrine Society guideline 2016 revisited.

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.

New Advances in the Diagnostic Workup of Primary Aldosteronism.

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.

Is steroid profiling using LC-MS/MS useful in the diagnostic work-up of primary aldosteronism?

Is steroid profiling using LC-MS/MS useful in the diagnostic work-up of primary aldosteronism?

Urine steroid metabolomics as a diagnostic tool in primary aldosteronism

Introduction: The regular diagnostic workup for primary aldosteronism (PA) can be very demanding and involves multiple invasive as well as time and cost intensive diagnostic tests. Here we have explored the value of urinary steroid metabolome analysis in the diagnosis and differential diagnosis of PA. Previously, urinary 3α,5β-tetrahydroaldosterone (THAldo) has been suggested as a reliable screening test for PA and serum 18-oxocortisol and 18-hydroxycortisol have been reported as diagnostic markers with the potential to distinguish unilateral aldosterone-producing adenomas (APA) from bilateral adrenal hyperplasia (BAH). Patients and methods: We studied 180 PA patients (103 APA, 71 BAH) in whom PA had been confirmed by saline infusion test followed by adrenal vein sampling for subtype differentiation. We carried out targeted sequencing for disease-causing somatic mutations in the KCNJ5, CACNA1D, ATP1A1 and ATP2B3 genes in tumour tissue obtained by unilateral adrenalectomy, which was available in 75/103 APA patients. The urine steroid metabolome was analysed by gas chromatography-mass spectrometry comprising the quantification of 38 distinct steroids including metabolites of aldosterone, deoxycorticosterone, corticosterone as well as 18OH-cortisol (18OH-F) and 18-oxo-tetrahydrocortisol (18oxo-THF). Results: As expected, urinary excretion of mineralocorticoids (p 69 μg/24h, with significantly higher THAldo in APAs compared to BAH (p=0.0082). Similarly, APAs had significantly higher excretion of 18OH-F (p=0.0171) and 18oxo-THF (p=0.0005). Genetic analysis of APA tissue revealed mutations in KCNJ5 (n=29), ATPases (n=12) and CACNA1D (n=6) while in 28 patients no known mutation was identified. Patients with KCNJ5 mutations had significantly increased excretion of both 18OH-F (p=0.0002) and 18oxo-THF (p<0.0001) as compared to the other mutation groups. Conclusion: Urine steroid metabolomics is a promising approach for the diagnosis and differential diagnosis of PA.

Aldosterone excess and resistant hypertension: investigation and treatment.

Among patients with resistant hypertension, primary aldosteronism (PA) is worth detecting as it appears to be particularly common in this cohort. It is associated with excessive cardiovascular morbidity in relation to the degree of hypertension and reduced quality of life, both of which can be abrogated with specific surgical or medical treatment. Knowledge concerning factors (including medications) which can influence the results of screening by aldosterone/renin ratio (ARR) testing is expanding, and is important to appreciate, particularly in patients with resistant hypertension, in whom the need for multiple medications can render interpretation challenging. Advances in approaches to confirmatory testing, subtype differentiation and assay methodology are helping to improve feasibility and reliability of the diagnostic workup for PA and new treatment approaches are emerging. Major developments in understanding the genetic bases for PA hold promise towards further improvements and options in diagnosis and therapy.

Effects of female sex hormones and contraceptive pill on the diagnostic work-up for primary aldosteronism

Due to the widespread use of the aldosterone to renin ratio (ARR), primary aldosteronism is currently recognized as a frequent cause of secondary hypertension. After a positive screening, primary aldosteronism diagnosis needs confirmation by an inhibitory test such as intravenous saline load (ivSLT). The aim of the present study was to investigate the role of female hormones in primary aldosteronism diagnosis, by evaluating possible differences by sex on ARR screening, on the rate of ivSLT response and analyzing the influence of free and oral contraceptive-induced menstrual cycle on ARR. We examined ARR in 103 healthy normotensive volunteers, 81 hypertensive patients who underwent ivSLT, 33 healthy women during free menstrual cycle and after oral contraceptive therapy. A significantly higher proportion of normotensive women than men had an elevated ARR (13.6 versus 2.3%, P < 0.05). In 44 out of 81 hypertensive patients, diagnosis of primary aldosteronism was confirmed by ivSLT. Patients with positive and negative ivSLT differed only for sex distribution: 85.2% of men had the primary aldosteronism diagnosis confirmed, compared with 38.9% of women. In healthy women, renin and aldosterone concentrations increased from the follicular to luteal phase of menstrual period, with unchanged ARR. By contrast, renin nearly halved, aldosterone slightly decreased and ARR doubled after oral contraceptive therapy. ARR screening fails to predict positive ivSLT in most (60.2%) hypertensive women as compared with 14.8% of hypertensive men. ARR is more often increased in normotensive women than men. Oral contraceptive may affect ARR contributing to the diagnostic inaccuracy in women.

Controversies on the Diagnosis of Primary Aldosteronism

Primary aldosteronism (PA) is the most common secondary form of hypertension. The diagnosis of PA is of particular importance since aldosterone has been shown to play a pathological role in target organs that is partly independent from effects on blood pressure levels and electrolyte balance. Patients with PA display a higher rate of target organ damage than patients with essential hypertension. As a consequence, PA patients experience a higher rate of cardiovascular events such as stroke and myocardial infarction. The diagnosis of PA is also important as one subgroup of PA should be treated with specific medical therapy, whereas the other can be cured or considerably ameliorated by adrenalectomy. In this review we discuss the current controversies on the diagnostic work-up of PA and its subtypes.

Prevalence and diagnostic workup of primary aldosteronism: new knowledge and new approaches

Prevalence and diagnostic workup of primary aldosteronism: new knowledge and new approaches