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

in European Journal of Endocrinology
View More View Less
  • 1 Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, Munich, Germany
  • 2 Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Turin, Turin, Italy

Correspondence should be addressed to M Reincke; Email: Martin.Reincke@med.uni-muenchen.de

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.

Abstract

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.

Invited Author’s profile

Prof. Dr med. Martin Reincke is the Director of the Medizinische Klinik and Poliklinik IV, Ludwig-Maximilians University in Munich and Chair of the Department of Endocrinology and Diabetology. His research focus includes adrenal physiology and pathophysiology, endocrine hypertension, pituitary disease, mineralocorticoid and glucocorticoid action and stress research. Prof. Reincke is heading a research team specifically exploring the prevalence and relevance of mineralocorticoid excess in resistant hypertension on the epidemiological, clinical, genetic and molecular levels.

Introduction

Primary aldosteronism (PA), first described by Jerome W. Conn in 1955, was once thought to be a rare condition of hypertension characterized by hypokalemia and excess aldosterone production relative to suppressed plasma renin (1). The application of the current screening method of an elevated plasma aldosterone-to-renin ratio (ARR) to a wider target population (instead of restricted to patients with hypokalemia) accounting for up to 50% of the population with hypertension has greatly increased the diagnosis of PA (2). It is now widely accepted that this syndrome is the most common form of endocrine hypertension. PA is specifically treated by unilateral adrenalectomy (preferably by laparoscopic surgery) or pharmacologically with a mineralocorticoid receptor (MR) antagonist that competitively inhibits the binding of aldosterone to the MR (3).

Patients with PA have an increased risk of cardiovascular and cerebrovascular events and target organ damage (heart and kidney) relative to patients with essential hypertension and a matched cardiovascular risk profile (4, 5, 6, 7) or compared with the general population with hypertension (8). Patients with PA also display an increased prevalence of metabolic syndrome and diabetes (4, 9, 10, 11), osteoporotic fractures (12) and symptoms of depression with a reduced quality of life (13, 14). Some of these comorbidities may be associated with cortisol co-secretion (15). All available evidence indicates that an early diagnosis and appropriate clinical management (surgical or medical) is mandatory to minimize the increased risks associated with PA (5, 16, 17, 18).

The diagnostic management of PA comprises three phases: screening tests, case confirmation and differentiation of unilateral from bilateral forms of PA for therapeutic decision making and appropriate treatment (Fig. 1).

Figure 1
Figure 1

Flow chart for the diagnostic workup of primary aldosteronism. *Please refer to Table 1 for patients with hypertension to be screened for PA ADX, adrenalectomy; CT, computer-assisted tomography; MR, mineralocorticoid receptor; PA, primary aldosteronism.

Citation: European Journal of Endocrinology 179, 1; 10.1530/EJE-17-0990

Diagnosis: screening

Measurement of plasma aldosterone concentrations (PACs) and plasma renin activity (PRA) or the direct renin concentration (DRC) to assess the ARR is the most reliable currently available method of screening for PA. The Endocrine Society (ES) Clinical Practice Guideline recommends screening patients with an increased likelihood of PA (Table 1) (3). It has been suggested that all patients with hypertension should be screened for PA (19), based on the findings of the prospective PATO study (8), which reported a 5.9% prevalence of PA in 1672 unselected patients with hypertension in primary care (8). However, evidence that a systematic screening approach (compared with selective screening) results in a reduction of morbidity, mortality and cardiovascular disease of patients with hypertension to an extent that would justify the increased costs and burden on health systems is lacking.

Table 1

Screening for primary aldosteronism.

Risk groups recommended to be screened for primary aldosteronism according to ES guideline
 Patients with sustained blood pressure above 150/100 mmHg, grade 2 and grade 3 hypertension
 Patients with resistant hypertension (blood pressure not controlled by three conventional drugs including a diuretic) or controlled BP (<140/90 mmHg) on four or more antihypertensive drugs
 Patients with hypertension and spontaneous or diuretic induced hypokalemia
 Patients with hypertension and an adrenal incidentaloma
 Patients with hypertension and sleep apnea
 Patients with hypertension and a family history of early-onset hypertension or cerebrovascular accident at a young age (<40 years)
 All first-degree relatives of patients with PA

Includes data from Funder et al. (3) and Stowasser & Gordon (20).

To screen for PA by the ARR, it is recommended that medications interfering with the renin-angiotensin system, and specifically those that may stimulate renin secretion, should be withdrawn (this applies throughout the diagnostic workup for PA because other tests and procedures also rely on measurements of steroids under conditions of suppressed renin). Antihypertensive medication that interferes with the ARR includes diuretics (including spironolactone) and should be withdrawn for 4 weeks. Other drugs that should be withdrawn, but for a lesser period of 2 weeks prior to testing, are β-blockers, clonidine, methyldopa, non-steroidal anti-inflammatory drugs, ACE inhibitors, angiotensin receptor blockers and dihydropyridine calcium blockers (3, 20). However, in many instances, interpretation of the ARR is confidently possible without changing interfering medications. Non-dihydropyridine long-acting calcium channel blockers (verapamil or diltiazem), the vasodilator hydralazine and α1-adrenergic receptor blockers have limited or no effects on the ARR compared to the above and are suggested to control hypertension in those patients with elevated blood pressure requiring medical treatment (3, 20). As a caveat, severe deleterious side effects have been reported by adjustment of antihypertensive therapy in accordance with the ES guideline during screening for PA (21). In our center, more than 90% of patients receive adjusted medication according to the ES guideline during screening, and serious adverse events have been reduced to a minimum after appropriate exclusion of high-risk patients.

Before performing the ARR screening test, patients should avoid a low salt diet and have a minimum intake of 5 g NaCl/day. Hypokalemia, if present, should be corrected. To allow activation of the renin-angiotensin system, blood samples are withdrawn in the morning when patients have been out of bed for ≥2 h. The assay characteristics and the use of different available commercial assays for the measurement of PAC, PRA or DRC can highly influence the ARR (22). The method dependence of aldosterone and renin measurements has contributed to the lack of a standardized cut-off value for ARR screening and the wide variability in upper reference limits used across centers. The Japan ES Guidelines recommend a specific cut-off for the ARR (ARR > 200 with PAC in pg/mL and PRA in ng/mL/h and indicate that the risk of PA increases with PAC > 120–150 pg/mL) with a specific commercially available assay (23). Radioimmunoassays are widely employed for the measurement of plasma PAC, PRA or DRC but assays using chemiluminescence have been shown to be reliable alternatives (24, 25, 26) using simultaneous assays for PAC and DRC (24).

An elevated ARR can result if the PRA (or DRC) is very low even if the PAC is low-normal and inconsistent with PA. Some centers do not proceed with the diagnostic workup of PA of such patients and require a minimum PAC in addition to an elevated ARR for a positive screening test. At least, baseline PAC should be higher than the normal range of confirmatory tests, as discussed later (20).

Diagnosis: confirmatory testing

Confirmatory testing is considered mandatory by the ES guideline for a definitive diagnosis of PA. An exception is in evident cases of PA with spontaneous hypokalemia and a PAC > 20 ng/dL (550 pmol/L) with PRA (or DRC) below assay detection limits (3). Confirmation or exclusion of the diagnosis of PA is performed by ≥1 confirmatory tests as recommended by the ES guideline (3).

Confirmatory tests demonstrate the inappropriate production of aldosterone in response to exogenously administered agents that normally completely suppress or inhibit circulating angiotensin II levels (the endogenous positive regulator of aldosterone production). The test thereby confirms that aldosterone production is autonomous of the renin-angiotensin system.

Potassium is a key regulator of aldosterone production and hypokalemia (if present) should be corrected with slow-release KCl tablets prior to confirmatory testing because failure to do so may produce a false-negative result. Since sodium chloride infusion during confirmatory testing may further deteriorate plasma potassium levels we administer KCl tablets even in patients with low-normal potassium levels. Stress-induced increases of ACTH – indicated by an increase in plasma cortisol concentration – can interfere with aldosterone suppression and produce a false-positive test result. Consequently, cortisol levels should be monitored during confirmatory testing, and the aldosterone response interpreted with caution if increased cortisol levels indicate inappropriate stress at the end of the test.

The most commonly employed suppression tests use saline loading (either by intravenous infusion or orally), fludrocortisone (FST) or a captopril challenge (Table 2). Confirmatory testing based on saline loading are widely in use because they are straight forward and reliable and have low costs but saline loading by infusion (2 L i.v. infusion of 0.9% NaCl over 4 h) or oral sodium intake (6 g/day for 3 days, aldosterone measured in a 24 h urine collection over days 3–4) carry the risk of acute volume overload especially in those predisposed by left ventricular or renal dysfunction. The saline infusion test has a sensitivity of 83% using a cut-off of <6.8 ng/dL (188 pmol/L) (27) and 88% using a cut-off of <5.0 ng/dL (<139 pmol/L) (28). A recent study suggested that up to 29% of patients with PA with suppressed aldosterone below 5.0 ng/dL (139 pmol/L) were patients with unilateral aldosteronism and candidates for surgery (29). The authors suggest that patients with an elevated ARR and elevated basal aldosterone concentrations may directly undergo AVS without a suppression test, a strategy also proposed in the recently published guideline for patients with hypokalemia (3). The sensitivity of the saline infusion test is reportedly increased by performing the test in the seated position (29, 30, 31). The captopril challenge test (25–50 mg orally administered captopril after sitting or standing for >1 h) is likewise easily performed and circumvents potential fluid overload in patients who are at risk due to compromised renal or cardiac function. The FST requires the consumption of fludrocortisone with sodium and potassium supplementation and up to 5-day hospitalization to ensure control of blood pressure and plasma potassium concentrations that must be closely monitored throughout the test because of the risk of hypokalemia. Proponents of the FST highlight the safety of the test in expert hands with a superior sensitivity compared with other methods (a detailed protocol is described in Stowasser & Gordon (20)). The test is nonetheless unfeasible in most countries because of cost limitations imposed by the requirement for several days of hospitalization.

Table 2

Confirmatory testing for primary aldosteronism.

Confirmatory testDiagnostic cut-off values
Saline infusion test (SIT)PAC > 5–10 ng/dL (140–280 pmol/L)
Oral salt loading test (SLT)uAldo > 12 µg/24 h (33 nmol/day)* or >14 µg/24 h (39 nmol/24 h)
Fludrocortisone suppression test (FST)Upright PAC > 6 ng/dL (170 pmol/L) on day 4 at 10:00 h with PRA < 1 ng/mL/h and plasma cortisol less than the value at 07:00 h
Captopril challenge test (CCT)Decrease in PAC ≤ 30% (or ARR > 200 pg/mL/ng/mL/h)**

Protocols describing confirmatory testing in detail are described in Stowasser and Gordon (20). Includes data from Funder et al. (3).

*At the Mayo clinic; At the Cleveland clinic; To exclude any confounding effect of ACTH; **Decrease in PAC ≤ 30% as defined by the ES Guideline (3) and ARR > 200 pg/mL/ng/mL/h by the Japan ES Guidelines (23).

PAC, plasma aldosterone concentration; PRA, plasma renin activity; uAldo, urinary aldosterone.

Diagnosis: subtype differentiation

Subtype diagnosis begins with the exclusion of patients with a rare form of PA caused by an aldosterone-producing carcinoma using an imaging technique such as CT scanning or magnetic resonance imaging (MRI). The value of CT scanning and MRI have been questioned since they might not faithfully distinguish the source of aldosterone excess, and micro-APAs (≤10 mm in diameter) are often undetectable by current imaging methods (32, 33). In addition, the proportion of patients with adrenal incidentalomas increases with age leading to false-positive imaging findings and reduced specificity. Therefore, the ES guideline issued a strong recommendation to perform AVS in every patient who is a candidate for surgery to reliably differentiate unilateral from bilateral PA.

Blood samples are obtained for steroid measurements from the right and left adrenal veins to determine if the overproduction of aldosterone originates from a unilateral or bilateral source (Fig. 2). Some experts recommend AVS in all patients with confirmed PA (34), others consider predictors of unilateral disease and patient preference (35, 36). According to the ES guideline, young patients (<35 years) with imaging findings of a unilateral adenoma (>10 mm and a normal appearing contralateral adrenal) can bypass AVS if they display a marked phenotype (for example, PAC > 30 ng/dL (831 pmol/L) and spontaneous hypokalemia at baseline) (3). Although selecting patients to bypass AVS and proceed to surgery on the basis of young age, imaging results and PA phenotype has been reported to lack specificity (37), data from a multicentric study in Japan reported that factors based on young age and specific imaging and biochemical characteristics as recommended by the ES guideline could accurately predict unilateral disease (38).

Figure 2
Figure 2

Differentiation of unilateral from bilateral forms of primary aldosteronism by adrenal venous sampling. Adrenal venous sampling is performed according to a defined standardized protocol in patients with confirmed PA after withdrawal of interfering medication (see text for details). Adrenal veins are sequentially catheterized via the femoral veins and blood is sampled from the inferior vena cava and from the right and left adrenal veins. The success of catheterization of each adrenal vein is indicated by the selectivity index (Tables 3 and 4) that can be determined by a rapid-onset cortisol assay (41, 42, 43). Plasma aldosterone and cortisol concentrations are measured in all blood samples. Adrenal venous plasma aldosterone concentrations are corrected for any dilution by blood from the inferior phrenic vein (on the left side) or from the inferior vena cava (on the right side) by dividing by the respective plasma cortisol concentrations (aldosterone-to-cortisol ratios). The measurements of aldosterone and cortisol are used to derive the lateralization index and the contralateral ratio (Table 3).

Citation: European Journal of Endocrinology 179, 1; 10.1530/EJE-17-0990

In preparation for AVS, antihypertensive medication that interferes with the renin-angiotensin system, specifically by stimulating renin secretion, should be withdrawn. Loop and thiazide diuretics, amiloride and MR antagonists should be interrupted 4 weeks before AVS and substituted for antihypertensive medication with less (or minimal) effects on renin secretion such as α1-adrenergic receptor blockers and non-dihydropyridine long-acting calcium channel blockers (verapamil or diltiazem). If PRA or concentration is suppressed, AVS can be performed irrespective of the time of drug withdrawal (39) and, in exceptional cases, MR antagonist therapy can be continued during AVS if renin remains suppressed (40).

The success of AVS, determined by the correct cannulation of the adrenal veins, is measured by the selectivity index (SI), which is calculated as the ratio of cortisol in the adrenal vein and in a peripheral vein. The cannulation of the adrenal veins is particularly challenging on the right side because of anatomical differences between the right and left adrenal veins (Fig. 2). Success rates differ greatly but can be improved by a rapid cortisol assay to ascertain when resampling is necessary if the AVS was unsuccessful (41, 42). The use of such an assay has increased the proportion of successful AVS from 55% to 85% in the experience of one referral center largely due to an increased successful cannulation of the right adrenal vein (43). The lateralization of aldosterone production is usually calculated by the lateralization index (LI) although the LI is sometimes considered together with a requirement for contralateral suppression of aldosterone production to define lateralization (Tables 3 and 4). There is no standardized cut-off for the SI, or indeed for any of the indices used in AVS. Although there have been attempts to standardize AVS protocols (39, 44), the reference limits remain arbitrary to some extent and the interpretation of AVS results vary widely across centers (Table 4).

Table 3

Definition and interpretation of adrenal venous sampling criteria.

AVS indexDefinition and interpretation
Selectivity index (SI)(Cortisol)AV/(Cortisol)PVIndicates successful AVS with correct cannulation of adrenal veins
Lateralization index (LI)((Aldosterone)/(Cortisol))IpsilateralAV/((Aldosterone)/(Cortisol))ContralateralAVMeasures lateralization of aldosterone production
Contralateral ratio (CLR)((Aldosterone)/(Cortisol))ContralateralAV/((Aldosterone)/(Cortisol))PVInhibition of aldosterone production from the non-dominant adrenal gland (contralateral suppression, CLR ≤ 1)

ACTH, adrenocorticotropic hormone; AV, adrenal vein; AVS, adrenal venous sampling; PA, primary aldosteronism; PV, peripheral vein (often the inferior vena cava); the ipsilateral AV is the adrenal vein from the adrenal with excess aldosterone production and the contralateral AV is the adrenal vein from the adrenal on the opposite side.

Table 4

Different protocols and interpretation of adrenal venous sampling.

Referral centerUnstimulated or ACTH infusionSuccessful AVSDiagnosis of unilateral PA
Munich, ParisUnstimulatedSI ≥ 2LI ≥ 4
TorinoUnstimulated + continuous ACTH infusionSI ≥ 3LI ≥ 4 or LI ≥ 3 and CLR ≤ 1
BrisbaneUnstimulatedSI ≥ 3LI ≥ 2.5 and CLR ≤ 1
RochesterContinuous ACTH infusionSI ≥ 5LI ≥ 4
SendaiBolus ACTH infusionSI ≥ 5LI ≥ 2.6
Yokohama CityBolus + continuous ACTH infusion(Cortisol)AV >200 µg/dL*(PAC)ipsilateralAV >1400 ng/dL*

Includes data from Williams et al. (48).

*In accordance with the Japan ES Guidelines (23).

ACTH, adrenocorticotropic hormone; AVS, adrenal venous sampling; LI, lateralization index; PA, primary aldosteronism; PAC, plasma aldosterone concentration; SI, selectivity index.

AVS is performed in the morning when ACTH-stimulated aldosterone production is maximal following at least 1-h recumbency to avoid the effects of postural changes on the stimulation of the renin-angiotensin system. An AVS procedure with an exogenously administered synthetic derivative of ACTH (ACTH 1–24, called cosyntropin) is used by some for various reasons that include increasing technical success rates, stimulating the production of aldosterone from APAs and minimizing variations in cortisol and aldosterone production caused by stress-induced ACTH release during non-simultaneous AVS. Although some concerns have been raised on the possible stimulation of aldosterone production from the contralateral adrenal gland (non-dominant gland) in unilateral PA, AVS with ACTH infusion can improve the technical success rate of AVS (45, 46) and can perform as well as unstimulated protocols with ACTH administered as a bolus (usually 0.25 mg (10 IU)) or continuous infusion (initiated 30 min before the procedure (50 µg/h)) performing equally well (47). The effects of ACTH stimulation were illustrated by a study in which a bolus of 250 µg of ACTH increased bilateral selectivity from 67% in the basal state to 92% post stimulation. At the same time, discordance between basal and post-ACTH values was observed in 28% of patients, which were mostly lateralized cases under basal conditions that became bilateral post-ACTH. Therefore, ACTH stimulation may reduce the proportion of lateralized PA. We observed no significant differences in the post-surgical clinical outcomes of patients with unilateral PA diagnosed by AVS with an unstimulated protocol (n = 331) relative to patients diagnosed with an ACTH infusion protocol (n = 374) (48). In our center, we generally perform bilateral simultaneous AVS without ACTH stimulation. ACTH stimulation is restricted to specific situations: for example, if patients are at risk of an allergic reaction to the anesthetic, if AVS is performed in the afternoon and if patients receive chronic low-dose synthetic glucocorticoid treatment (i.e. 5 mg prednisolone/day).

The recently published SPARTACUS trial studied in a randomized fashion whether CT imaging based subtype determination was equivalent to AVS-based decision making (49). The primary outcome of the study was the intensity of antihypertensive medication measured as defined daily drug dose (DDD) 1 year after initiation of specific treatment. Outcomes were essentially similar: the median DDDs of 92 patients receiving CT-based treatment (in 46 adrenalectomy and in 46 MRA treatment) was 3.0 vs 3.0 in those receiving AVS-based treatment (46 adrenalectomies and 46 treated by MRA, P = 0.53). In the surgical groups, target blood pressure was reached in 39 (42%) patients and 41 (45%) of the operated patients, respectively (P = 0.82). Additional secondary endpoints, such as health-related quality of life or biochemical remission (80% vs 89%, P = 0.25), were not different. Details of the study and perceived weaknesses in its design and methodology have been discussed in an unprecedented and ongoing flood of commentaries (50, 51, 52, 53) splitting the community into those who were for or against AVS. The emotions arising from the study are in part due to the trial highlighting that a sophisticated procedure such as AVS is not 100% accurate, having a failure rate of approximately 5% (48), and that CT-based management might be better than previously thought. As a consequence of this debate, centers that used AVS for therapeutic decision making will continue to do so but will likely exempt young patients with imaging-positive adenomas. Centers without access to AVS will base their decision making with increased confidence on CT imaging, acknowledging that this strategy might have a failure rate of up to 20% (49).

Treatment

The underlying cause of PA determines the appropriate treatment, surgical or medical management. For patients with unilateral PA, adrenalectomy offers the possibility of blood pressure remission or clinical improvement and the resolution of excess aldosterone production. In an international cohort study, unilateral adrenalectomy normalized blood pressure in 37% of 705 patients with PA and substantially improved the clinical outcome (blood pressure and antihypertensive medication response) in a further 47% (48). A successful biochemical outcome (correction of hypokalemia – if present pre-surgery – and normalization of the ARR) was achieved in 94% of 699 patients (48).

Patients with bilateral PA are most effectively treated medically with an MR antagonist, usually spironolactone (54). Other patients included in this category are those with unilateral PA who opt for medical rather than surgical management or those who are unfit for surgery. Cases of spontaneous complete biochemical remission have been reported in patients with bilateral PA after long-term treatment with MR antagonists in (2 of 37 patients treated with spironolactone (5.4%) at 10.8 and 12.9 years following diagnosis (55)) and in patients following long-term treatment with potassium canrenoate (56).

Spironolactone is a competitive inhibitor of aldosterone for its receptor, the MR. It is non-selective and displays both antagonist activity to the androgen receptor and agonist activity to the progesterone receptor. The non-selective action of spironolactone can cause the associated adverse effects including gynecomastia, erectile dysfunction and menstrual irregularities. The incidence of gynecomastia increases from <6.9% at a dose of <50 mg/day to 52% at >150 mg/day (57). Eplerenone is a selective MR antagonist that has no adverse effects but displays lower efficacy and high cost compared with spironolactone (58, 59). In Japan, eplerenone is approved for the treatment of hypertension, in the United States and in Europe, for the treatment of congestive heart failure after a myocardial infarction.

A longitudinal study that included 602 patients with PA (treated with a MR antagonist) compared with 41 853 age-matched patients with essential hypertension treated conventionally demonstrated a significantly higher rates of cardiovascular events independent of blood pressure control in the PA group (60). Patients with PA also had higher adjusted risks for incident mortality, diabetes and atrial fibrillation. The excess risk for cardiovascular events and mortality was limited to patients with PA whose renin activity remained suppressed (<1 μg/L per h) on MR antagonists. The study suggests that titrating the increase in PRA as a response to MR antagonist therapy instead of blood pressure control would be a more effective therapeutic approach to avoid the excess cardiovascular risk associated with PA (60). The PAPY study analyzed long-term cardiovascular outcomes and mortality in 1125 patients screened for PA and treated according to biochemical results: unilateral adrenalectomy (4.8%) in patients with APA, MR antagonist treatment (6.4%) in patients with BAH and standard medical treatment in the remaining 88.8% with essential hypertension. After a median of 11.2 years, overall survival was similar in patients treated for PA and for essential hypertension. MR antagonist treatment but not adrenalectomy was associated with a higher risk of atrial fibrillation (61). In summary, both studies raise the question of uptitrating the dose of MR antagonists to block the MR more effectively and reduce long-term complications.

Genetic forms of PA

A number of somatic mutations have been identified in ion channels and transporters that drive the aldosterone excess in patients with APAs (62, 63). No clinical application has been firmly established although a potential future use may lie in steroid profiling to circumvent AVS in patients with bilateral disease by selection of those patients with a high probability of having an APA (64) or by selecting patients with an APA carrying KCNJS mutations using macrolide antibiotics as selective inhibitors (65).

Germline variants have also been identified that cause rare familial forms of PA (62, 63). The invasive procedure of AVS is unnecessary in patients with familial hyperaldosteronism types I and III (FH type I and FH type III) (66, 67) because the former is effectively treated with glucocorticoids (such as dexamethasone) and the latter is treated by bilateral adrenalectomy or with MR antagonists. Therefore, in accordance with the ES Society Guideline (3), genetic testing is recommended in patients with a diagnosis of early-onset PA (<20 years old) or with a family history of PA or stroke at a young age (<40 years) for the presence of the hybrid CYP11B1/CYP11B2 gene that causes FH type I (66) and in very young patients with a diagnosis of PA (for example, <20 years) for germline mutations in the KCNJ5 gene that cause FH type III (68). Genetic testing of patients in these target groups offers the possibility of an early diagnosis of asymptomatic relatives and provides timely treatment when appropriate. AVS should be performed in patients with familial hyperaldosteronism types II and IV (69, 70, 71) because these patients have been treated successfully by unilateral adrenalectomy as well as with MR antagonists (62).

Germline heterozygous mutations in the voltage-gated chloride channel CIC-2, encoded by the CLCN2 gene, have been identified in families with FH-II and in patients with sporadic childhood-onset PA (72, 73). CIC-2 is expressed in adrenal glomerulosa cells, and the mutated channels show gain of function with increased chloride conductance at resting potentials resulting in increased expression of aldosterone synthase and aldosterone secretion. These findings establish CLCN2 mutations as a cause of early-onset PA.

Conclusions

Since the publication of the ES guideline on PA in 2016, several high-quality reports have advanced our knowledge of the genetics, diagnosis, subtype differentiation and treatment of PA. In general, these data confirm the diagnostic and therapeutic algorithm of the guideline. An exception is the SPARTACUS study but an independent trial which takes into account the criticisms of the many commentaries will resolve the issue of the validity of the results. In addition, novel functional imaging methods of PA, such as CXCR4 PET-CT imaging (74), could offer an alternative to ease the subtyping of PA. In summary, accumulating evidence highlights the importance of an early diagnosis and indicates that specific treatments can minimize or reverse the adverse effects of aldosterone excess. However, simplified procedures are required to enable timely, cost-effective and patient-friendly screening and diagnosis for PA.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No (694913) to M R) and by the Deutsche Forschungsgemeinschaft (DFG) (within the CRC/Transregio 205/1 ‘The Adrenal: Central Relay in Health and Disease’ to M R and T A W; and grant RE 752/20-1 to M R) and the Else Kröner-Fresenius Stiftung in support of the German Conns Registry-Else-Kröner Hyperaldosteronism Registry (2013_A182 and 2015_A171 to M R).

Acknowledgements

The excellent artwork of Francesca Williams is gratefully acknowledged.

References

  • 1

    Conn JW & Part I. Painting background. Part II. Primary aldosteronism, a new clinical syndrome. Journal of Laboratory and Clinical Medicine 1955 45 317.

    • Search Google Scholar
    • Export Citation
  • 2

    Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, Gomez-Sanchez CE, Veglio F, Young WF Jr. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. Journal of Clinical Endocrinology and Metabolism 2004 89 10451050. (https://doi.org/10.1210/jc.2003-031337)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M & Young WF Jr. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism 2016 101 18891916. (https://doi.org/10.1210/jc.2015-4061)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Monticone S, D’Ascenzo F, Moretti C, Williams TA, Veglio F, Gaita F & Mulatero P. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis. Lancet Diabetes and Endocrinology 2018 6 4150. (https://doi.org/10.1016/S2213-8587(17)30319-4)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Sechi LA, Novello M, Lapenna R, Baroselli S, Nadalini E, Colussi GL & Catena C. Long-term renal outcomes in patients with primary aldosteronism. Journal of the American Medical Association 2006 295 26382645.

    • Search Google Scholar
    • Export Citation
  • 6

    Mulatero P, Monticone S, Bertello C, Viola A, Tizzani D, Iannaccone A, Crudo V, Burrello J, Milan A & Rabbia F et al. Long-term cardio- and cerebrovascular events in patients with primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 2013 98 48264833. (https://doi.org/10.1210/jc.2013-2805)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Savard S, Amar L, Plouin PF & Steichen O. Cardiovascular complications associated with primary aldosteronism: a controlled cross-sectional study. Hypertension 2013 62 331336. (https://doi.org/10.1161/HYPERTENSIONAHA.113.01060)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Monticone S, Burrello J, Tizzani D, Bertello C, Viola A, Buffolo F, Gabetti L, Mengozzi G, Williams TA & Rabbia F et al. Prevalence and clinical manifestations of primary aldosteronism encountered in primarycarepractice. Journal of the American College of Cardiology 2017 69 18111820. (https://doi.org/10.1016/j.jacc.2017.01.052)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Fallo F, Veglio F, Bertello C, Sonino N, Della Mea P, Ermani M, Rabbia F, Federspil G & Mulatero P. Prevalence and characteristics of the metabolic syndrome in primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 2006 91 454459. (https://doi.org/10.1210/jc.2005-1733)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Fischer E, Adolf C, Pallauf A, Then C, Bidlingmaier M, Beuschlein F, Seissler J & Reincke M. Aldosterone excess impairs first phase insulin secretion in primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 2013 98 25132520. (https://doi.org/10.1210/jc.2012-3934)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Hanslik G, Wallaschofski H, Dietz A, Riester A, Reincke M, Allolio B, Lang K, Quack I, Rump LC & Willenberg HS et al. Increased prevalence of diabetes mellitus and the metabolic syndrome in patients with primary aldosteronism of the German Conn’s Registry. European Journal of Endocrinology 2015 173 665675. (https://doi.org/10.1530/EJE-15-0450)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Salcuni AS, Carnevale V, Battista C, Palmieri S, Eller-Vainicher C, Guarnieri V, Pugliese F, Guglielmi G, Desina G & Minisola S et al. Primary aldosteronism as a cause of secondary osteoporosis. European Journal of Endocrinology 2017 177 431437. (https://doi.org/10.1530/EJE-17-0417)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Apostolopoulou K, Künzel HE, Gerum S, Merkle K, Schulz S, Fischer E, Pallauf A, Brand V, Bidlingmaier M, Endres S et al. Gender differences in anxiety and depressive symptoms in patients with primary hyperaldosteronism: a cross-sectional study. World Journal of Biological Psychiatry 2014 15 2635. (https://doi.org/10.3109/15622975.2012.665480)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Ahmed AH, Gordon RD, Sukor N, Pimenta E & Stowasser M. Quality of life in patients with bilateral primary aldosteronism before and during treatment with spironolactone and/or amiloride, including a comparison with our previously published results in those with unilateral disease treated surgically. Journal of Clinical Endocrinology and Metabolism 2011 96 29042911. (https://doi.org/10.1210/jc.2011-0138)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Arlt W, Lang K, Sitch AJ, Dietz AS, Rhayem Y, Bancos I, Feuchtinger A, Chortis V, Gilligan LC & Ludwig P et al. Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism. JCI Insight 2017 2 93136. (https://doi.org/10.1172/jci.insight.93136)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Catena C, Colussi G, Lapenna R, Nadalini E, Chiuch A, Gianfagna P & Sechi LA. Long-term cardiac effects of adrenalectomy or mineralocorticoid antagonists in patients with primary aldosteronism. Hypertension 2007 50 911918. (https://doi.org/10.1161/HYPERTENSIONAHA.107.095448)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Rossi GP, Cesari M, Cuspidi C, Maiolino G, Cicala MV, Bisogni V, Mantero F & Pessina AC. Long-term control of arterial hypertension and regression of left ventricular hypertrophy with treatment of primary aldosteronism. Hypertension 2013 62 6269. (https://doi.org/10.1161/HYPERTENSIONAHA.113.01316)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Marzano L, Colussi G, Sechi LA & Catena C. Adrenalectomy is comparable with medical treatment for reduction of left ventricular mass in primary aldosteronism: meta-analysis of long-term studies. American Journal of Hypertension 2015 28 312318. (https://doi.org/10.1093/ajh/hpu154)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Maiolino G, Calò LA & Rossi GP. The time has come for systematic screening for primary aldosteronism in all hypertensives. Journal of the American College of Cardiology 2017 69 18211823. (https://doi.org/10.1016/j.jacc.2017.02.041)

    • Search Google Scholar
    • Export Citation
  • 20

    Stowasser M & Gordon RD. Primary aldosteronism: changing definitions and new concepts of physiology and pathophysiology both inside and outside the kidney. Physiological Reviews 2016 96 13271384. (https://doi.org/10.1152/physrev.00026.2015)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Fischer E, Beuschlein F, Bidlingmaier M & Reincke M. Commentary on the Endocrine Society Practice Guidelines: consequences of adjustment of antihypertensive medication in screening of primary aldosteronism. Reviews in Endocrine and Metabolic Disorders 2011 12 4348. (https://doi.org/10.1007/s11154-011-9163-7)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Fischer E, Reuschl S, Quinkler M, Rump LC, Hahner S, Bidlingmaier M, Reincke M & Participants of the German Conn’s Registry – Else Kröner-Fresenius-Hyperaldosteronism Registry. Assay characteristics influence the aldosterone to renin ratio as a screening tool for primary aldosteronism: results of the German Conn’s registry. Hormone Metabolic Research 2013 45 526531. (https://doi.org/10.1055/s-0033-1343448)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Nishikawa T, Omura M, Satoh F, Shibata H, Takahashi K, Tamura N, Tanabe A & Task Force Committee on Primary Aldosteronism, The Japan Endocrine Society. Guidelines for the diagnosis and treatment of primary aldosteronism – the Japan Endocrine Society 2009. Endocrine Journal 2011 58 711721. (https://doi.org/10.1507/endocrj.EJ11-0133)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Manolopoulou J, Fischer E, Dietz A, Diederich S, Holmes D, Junnila R, Grimminger P, Reincke M, Morganti A & Bidlingmaier M. Clinical validation for the aldosterone-to-renin ratio and aldosterone suppression testing using simultaneous fully automated chemiluminescence immunoassays. Journal of Hypertension 2015 33 25002511. (https://doi.org/10.1097/HJH.0000000000000727)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Burrello J, Monticone S, Buffolo F, Lucchiari M, Tetti M, Rabbia F, Mengozzi G, Williams TA, Veglio F & Mulatero P. Diagnostic accuracy of aldosterone and renin measurement by chemiluminescent immunoassay and radioimmunoassay in primary aldosteronism. Journal of Hypertension 2016 34 920927. (https://doi.org/10.1097/HJH.0000000000000880)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Rossi GP, Ceolotto G, Rossitto G, Seccia TM, Maiolino G, Berton C, Basso D & Plebani M. Prospective validation of an automated chemiluminescence-based assay of renin and aldosterone for the work-up of arterial hypertension. Clinical Chemistry and Laboratory Medicine 2016 54 14411450. (https://doi.org/10.1515/cclm-2015-1094)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Rossi GP, Belfiore A & Bernini G, Desideri G, Fabris B, Ferri C, Giacchetti G, Letizia C, Maccario M, Mallamaci F et al. Prospective evaluation of the saline infusion test for excluding primary aldosteronism due to aldosterone-producing adenoma. Journal of Hypertension 2007 25 14331442. (https://doi.org/10.1097/HJH.0b013e328126856e)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Mulatero P, Milan A, Fallo F, Regolisti G, Pizzolo F, Fardella C, Mosso L, Marafetti L, Veglio F & Maccario M. Comparison of confirmatory tests for the diagnosis of primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 2006 91 26182623. (https://doi.org/10.1210/jc.2006-0078)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Cornu E, Steichen O, Nogueira-Silva L, Küpers E, Pagny JY, Grataloup C, Baron S, Zinzindohoue F, Plouin PF & Amar L. Suppression of aldosterone secretion after recumbent saline infusion does not exclude lateralized primary aldosteronism. Hypertension 2016 68 989994. (https://doi.org/10.1161/HYPERTENSIONAHA.116.07214)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Ahmed AH, Cowley D, Wolley M, Gordon RD, Xu S, Taylor PJ & Stowasser M. Seated saline suppression testing for the diagnosis of primary aldosteronism: a preliminary study. Journal of Clinical Endocrinology and Metabolism 2014 99 27452753. (https://doi.org/10.1210/jc.2014-1153)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31

    Stowasser M. Is it the beginning of the end for the recumbent saline infusion test? Hypertension 2016 68 857858. (https://doi.org/10.1161/HYPERTENSIONAHA.116.07337)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Rossi GP, Chiesura-Corona M, Tregnaghi A, Zanin L, Perale R, Soattin S, Pelizzo MR, Feltrin GP & Pessina AC. Imaging of aldosterone-secreting adenomas: a prospective comparison of computed tomography and magnetic resonance imaging in 27 patients with suspected primary aldosteronism. Journal of Human Hypertension 1993 7 357363.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Kempers MJ, Lenders JW, van Outheusden L, van der Wilt GJ, Schultze Kool LJ, Hermus AR & Deinum J. Systematic review: diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism. Annals of Internal Medicine 2009 151 329337. (https://doi.org/10.7326/0003-4819-151-5-200909010-00007)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Gordon RD, Stowasser M & Rutherford JC. Primary aldosteronism: are we diagnosing and operating on too few patients? World Journal of Surgery 2001 25 941947. (https://doi.org/10.1007/s00268-001-0033-4)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR & van Heerden JA. Role for adrenal venous sampling in primary aldosteronism. Surgery 2004 136 12271235. (https://doi.org/10.1016/j.surg.2004.06.051)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Young WF. Primary aldosteronism: renaissance of a syndrome. Clinical Endocrinology 2007 66 607618. (https://doi.org/10.1111/j.1365-2265.2007.02775.x)

  • 37

    Riester A, Fischer E, Degenhart C, Reiser MF, Bidlingmaier M, Beuschlein F, Reincke M & Quinkler M. Age below 40 or a recently proposed clinical prediction score cannot bypass adrenal venous sampling in primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 2014 99 E1035E1039. (https://doi.org/10.1210/jc.2013-3789)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38

    Umakoshi H, Ogasawara T, Takeda Y, Kurihara I, Itoh H, Katabami T, Ichijo T, Wada N, Shibayama Y & Yoshimoto T et al. Accuracy of adrenal computed tomography in predicting the unilateral subtype in young patients with hypokalaemia and elevation of aldosterone in primary aldosteronism. Clinical Endocrinology 2018 88 645651. (https://doi.org/10.1111/cen.13582)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Monticone S, Viola A, Rossato D, Veglio F, Reincke M, Gomez-Sanchez C & Mulatero P. Adrenal vein sampling in primary aldosteronism: towards a standardised protocol. Lancet Diabetes and Endocrinology 2015 3 296303. (https://doi.org/10.1016/S2213-8587(14)70069-5)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40

    Haase M, Riester A, Kröpil P, Hahner S, Degenhart C, Willenberg HS & Reincke M. Outcome of adrenal vein sampling performed during concurrent mineralocorticoid receptor antagonist therapy. Journal of Clinical Endocrinology and Metabolism 2014 99 43974402. (https://doi.org/10.1210/jc.2014-2788)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41

    Mengozzi G, Rossato D, Bertello C, Garrone C, Milan A, Pagni R, Veglio F & Mulatero P. Rapid cortisol assay during adrenal vein sampling in patients with primary aldosteronism. Clinical Chemistry 2007 53 19681971. (https://doi.org/10.1373/clinchem.2007.092080)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Auchus RJ, Michaelis C, Wians FH Jr, Dolmatch BL, Josephs SC, Trimmer CK, Anderson ME & Nwariaku FE. Rapid cortisol assays improve the success rate of adrenal vein sampling for primary aldosteronism. Annals of Surgery 2009 249 318321. (https://doi.org/10.1097/SLA.0b013e3181961d77)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Betz MJ, Degenhart C, Fischer E, Pallauf A, Brand V, Linsenmaier U, Beuschlein F, Bidlingmaier M & Reincke M. Adrenal vein sampling using rapid cortisol assays in primary aldosteronism is useful in centers with low success rates. European Journal of Endocrinology 2011 165 301306. (https://doi.org/10.1530/EJE-11-0287)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Rossi GP, Auchus RJ, Brown M, Lenders JW, Naruse M, Plouin PF, Satoh F, Young WF Jr. An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism. Hypertension 2014 63 151160. (https://doi.org/10.1161/HYPERTENSIONAHA.113.02097)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Wolley MJ, Ahmed AH, Gordon RD & Stowasser M. Does ACTH improve the diagnostic performance of adrenal vein sampling for subtyping primary aldosteronism? Clinical Endocrinology 2016 85 703709. (https://doi.org/10.1111/cen.13110)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    El Ghorayeb N, Mazzuco TL, Bourdeau I, Mailhot JP, Zhu PS, Thérasse E & Lacroix A. Basal and post-ACTH aldosterone and its ratios are useful during adrenal vein sampling in primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 2016 101 18261835. (https://doi.org/10.1210/jc.2015-3915)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47

    Monticone S, Satoh F, Giacchetti G, Viola A, Morimoto R, Kudo M, Iwakura Y, Ono Y, Turchi F & Paci E et al. Effect of adrenocorticotropic hormone stimulation during adrenal vein sampling in primary aldosteronism. Hypertension 2012 59 840846. (https://doi.org/10.1161/HYPERTENSIONAHA.111.189548)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Williams TA, Lenders JWM, Mulatero P, Burrello J, Rottenkolber M, Adolf C, Satoh F, Amar L, Quinkler M & Deinum J et al. Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. Lancet Diabetes and Endocrinology 2017 5 689699. (https://doi.org/10.1016/S2213-8587(17)30135-3)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49

    Dekkers T, Prejbisz A, Kool LJS, Groenewoud HJMM, Velema M, Spiering W, Kołodziejczyk-Kruk S, Arntz M & Kądziela J, Langenhuijsen JF et al. Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial. Lancet Diabetes and Endocrinology 2016 4 739746. (https://doi.org/10.1016/S2213-8587(16)30100-0)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 50

    Funder JW & Rossi GP. Adrenal vein sampling versus CT scanning in primary aldosteronism. Lancet Diabetes and Endocrinology 2016 4 886. (https://doi.org/10.1016/S2213-8587(16)30240-6)

    • Search Google Scholar
    • Export Citation
  • 51

    Beuschlein F, Mulatero P, Asbach E, Monticone S, Catena C, Sechi LA & Stowasser M. The SPARTACUS trial: controversies and unresolved issues. Hormone Metabolic Research 2017 49 936942. (https://doi.org/10.1055/s-0043-120524)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 52

    Rossi GP & Funder JW. Adrenal vein sampling is the preferred method to select patients with primary aldosteronism for adrenalectomy: pro side of the argument. Hypertension 2018 71 59. (https://doi.org/10.1161/HYPERTENSIONAHA.117.09295)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53

    Deinum J, Prejbisz A, Lenders JWM & van der Wilt GJ Adrenal vein sampling is the preferred method to select patients with primary aldosteronism for adrenalectomy: con side of the argument. Hypertension 2018 71 1014. (https://doi.org/10.1161/HYPERTENSIONAHA.117.09294)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54

    Young WF Jr & Klee GG. Primary aldosteronism. Diagnostic evaluation. Endocrinology Metabolism Clinics of North America 1988 17 367395.

  • 55

    Fischer E, Beuschlein F, Degenhart C, Jung P, Bidlingmaier M & Reincke M. Spontaneous remission of idiopathic aldosteronism after long-term treatment with spironolactone: results from the German Conn’s Registry. Clinical Endocrinology 2012 76 473477. (https://doi.org/10.1111/j.1365-2265.2011.04243.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56

    Armanini D, Fiore C & Pellati D. Spontaneous resolution of idiopathic aldosteronism after long-term treatment with potassium canrenoate. Hypertension 2007 50 e69e70. (https://doi.org/10.1161/HYPERTENSIONAHA.107.096925)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 57

    Jeunemaitre X, Chatellier G, Kreft-Jais C, Charru A, DeVries C, Plouin PF, Corvol P & Menard J. Efficacy and tolerance of spironolactone in essential hypertension. American Journal of Cardiology 1987 60 820825. (https://doi.org/10.1016/0002-9149(87)91030-7)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 58

    Weinberger MH, Roniker B, Krause SL & Weiss RJ. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. American Journal of Hypertension 2002 15 709716. (https://doi.org/10.1016/S0895-7061(02)02957-6)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59

    Roush GC, Ernst ME, Kostis JB, Yeasmin S & Sica DA. Dose doubling, relative potency, and dose equivalence of potassium-sparing diuretics affecting blood pressure and serum potassium: systematic review and meta-analyses. Journal of Hypertension 2016 34 1119. (https://doi.org/10.1097/HJH.0000000000000762)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60

    Hundemer GL, Curhan GC, Yozamp N, Wang M & Vaidya A. Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study. Lancet Diabetes and Endocrinology 2018 6 5159. (https://doi.org/10.1016/S2213-8587(17)30367-4)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 61

    Rossi GP, Maiolino G, Flego A, Belfiore A, Bernini G, Fabris B, Ferri C, Giacchetti G, Letizia C & Maccario M et al. Adrenalectomy lowers incident atrial fibrillation in primary aldosteronism patients at long term. Hypertension 2018 71 585591. (https://doi.org/10.1161/HYPERTENSIONAHA.117.10596

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62

    Prada ETA, Burrello J, Reincke M & Williams TA. Old and new concepts in the molecular pathogenesis of primary aldosteronism Hypertension 2017 70 875881. (https://doi.org/10.1161/HYPERTENSIONAHA.117.10111)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63

    Zennaro MC, Boulkroun S & Fernandes-Rosa F. Genetic causes of functional adrenocortical adenomas. Endocrine Reviews 2017 38 516537. (https://doi.org/10.1210/er.2017-00189)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64

    Williams TA, Peitzsch M, Dietz AS, Dekkers T, Bidlingmaier M, Riester A, Treitl M, Rhayem Y, Beuschlein F & Lenders JW et al. Genotype-specific steroid profiles associated with aldosterone-producing adenomas. Hypertension 2016 67 139145. (https://doi.org/10.1161/HYPERTENSIONAHA.115.06186)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65

    Scholl UI, Abriola L, Zhang C, Reimer EN, Plummer M, Kazmierczak BI, Zhang J, Hoyer D, Merkel JS & Wang W et al. Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma. Journal of Clinical Investigation 2017 127 27392750. (https://doi.org/10.1172/JCI91733)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 66

    Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S & Lalouel JM. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992 355 262265. (https://doi.org/10.1038/355262a0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67

    Geller DS, Zhang J, Wisgerhof MV, Shackleton C, Kashgarian M & Lifton RP. A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. Journal of Clinical Endocrinology and Metabolism 2008 93 31173123. (https://doi.org/10.1210/jc.2008-0594)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 68

    Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A & Men CJ et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 2011 331 768772. (https://doi.org/10.1126/science.1198785)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69

    Stowasser M, Gordon RD, Tunny TJ, Klemm SA, Finn WL & Krek AL. Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism. Clinical and Experimental Pharmacology and Physiology 1992 19 319322. (https://doi.org/10.1111/j.1440-1681.1992.tb00462.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 70

    Scholl UI, Stölting G, Nelson-Williams C, Vichot AA, Choi M, Loring E, Prasad ML, Goh G, Carling T & Juhlin CC et al. Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. Elife 2015 4 e06315. (https://doi.org/10.7554/eLife.06315)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71

    Daniil G, Fernandes-Rosa FL, Chemin J, Blesneac I, Beltrand J, Polak M, Jeunemaitre X, Boulkroun S, Amar L & Strom TM et al. CACNA1H mutations are associated with different forms of primary aldosteronism. EBioMedicine 2016 13 225236. (https://doi.org/10.1016/j.ebiom.2016.10.002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72

    Scholl UI, Stölting G, Schewe J, Thiel A, Tan H, Nelson-Williams C, Vichot AA, Jin SC, Loring E & Untiet V et al. CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nature Genetics 2018 50 349354. (https://doi.org/10.1038/s41588-018-0048-5)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 73

    Fernandes-Rosa FL, Daniil G, Orozco IJ, Göppner C, El Zein R, Jain V, Boulkroun S, Jeunemaitre X, Amar L & Lefebvre H et al. A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. Nature Genetics 2018 50 355361. (https://doi.org/10.1038/s41588-018-0053-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 74

    Heinze B, Fuss CT, Mulatero P, Beuschlein F, Reincke M, Mustafa M, Schirbel A, Deutschbein T, Williams TA & Rhayem Y et al. Targeting CXCR4 (CXC Chemokine Receptor Type 4) for molecular imaging of aldosterone-producing adenoma. Hypertension 2018 71 317325. (https://doi.org/10.1161/HYPERTENSIONAHA.117.09975)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 7717 3205 270
PDF Downloads 8272 5328 434
  • View in gallery

    Flow chart for the diagnostic workup of primary aldosteronism. *Please refer to Table 1 for patients with hypertension to be screened for PA ADX, adrenalectomy; CT, computer-assisted tomography; MR, mineralocorticoid receptor; PA, primary aldosteronism.

  • View in gallery

    Differentiation of unilateral from bilateral forms of primary aldosteronism by adrenal venous sampling. Adrenal venous sampling is performed according to a defined standardized protocol in patients with confirmed PA after withdrawal of interfering medication (see text for details). Adrenal veins are sequentially catheterized via the femoral veins and blood is sampled from the inferior vena cava and from the right and left adrenal veins. The success of catheterization of each adrenal vein is indicated by the selectivity index (Tables 3 and 4) that can be determined by a rapid-onset cortisol assay (41, 42, 43). Plasma aldosterone and cortisol concentrations are measured in all blood samples. Adrenal venous plasma aldosterone concentrations are corrected for any dilution by blood from the inferior phrenic vein (on the left side) or from the inferior vena cava (on the right side) by dividing by the respective plasma cortisol concentrations (aldosterone-to-cortisol ratios). The measurements of aldosterone and cortisol are used to derive the lateralization index and the contralateral ratio (Table 3).

  • 1

    Conn JW & Part I. Painting background. Part II. Primary aldosteronism, a new clinical syndrome. Journal of Laboratory and Clinical Medicine 1955 45 317.

    • Search Google Scholar
    • Export Citation
  • 2

    Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, Gomez-Sanchez CE, Veglio F, Young WF Jr. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. Journal of Clinical Endocrinology and Metabolism 2004 89 10451050. (https://doi.org/10.1210/jc.2003-031337)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M & Young WF Jr. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism 2016 101 18891916. (https://doi.org/10.1210/jc.2015-4061)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Monticone S, D’Ascenzo F, Moretti C, Williams TA, Veglio F, Gaita F & Mulatero P. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis. Lancet Diabetes and Endocrinology 2018 6 4150. (https://doi.org/10.1016/S2213-8587(17)30319-4)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Sechi LA, Novello M, Lapenna R, Baroselli S, Nadalini E, Colussi GL & Catena C. Long-term renal outcomes in patients with primary aldosteronism. Journal of the American Medical Association 2006 295 26382645.

    • Search Google Scholar
    • Export Citation
  • 6

    Mulatero P, Monticone S, Bertello C, Viola A, Tizzani D, Iannaccone A, Crudo V, Burrello J, Milan A & Rabbia F et al. Long-term cardio- and cerebrovascular events in patients with primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 2013 98 48264833. (https://doi.org/10.1210/jc.2013-2805)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Savard S, Amar L, Plouin PF & Steichen O. Cardiovascular complications associated with primary aldosteronism: a controlled cross-sectional study. Hypertension 2013 62 331336. (https://doi.org/10.1161/HYPERTENSIONAHA.113.01060)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Monticone S, Burrello J, Tizzani D, Bertello C, Viola A, Buffolo F, Gabetti L, Mengozzi G, Williams TA & Rabbia F et al. Prevalence and clinical manifestations of primary aldosteronism encountered in primarycarepractice. Journal of the American College of Cardiology 2017 69 18111820. (https://doi.org/10.1016/j.jacc.2017.01.052)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Fallo F, Veglio F, Bertello C, Sonino N, Della Mea P, Ermani M, Rabbia F, Federspil G & Mulatero P. Prevalence and characteristics of the metabolic syndrome in primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 2006 91 454459. (https://doi.org/10.1210/jc.2005-1733)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Fischer E, Adolf C, Pallauf A, Then C, Bidlingmaier M, Beuschlein F, Seissler J & Reincke M. Aldosterone excess impairs first phase insulin secretion in primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 2013 98 25132520. (https://doi.org/10.1210/jc.2012-3934)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Hanslik G, Wallaschofski H, Dietz A, Riester A, Reincke M, Allolio B, Lang K, Quack I, Rump LC & Willenberg HS et al. Increased prevalence of diabetes mellitus and the metabolic syndrome in patients with primary aldosteronism of the German Conn’s Registry. European Journal of Endocrinology 2015 173 665675. (https://doi.org/10.1530/EJE-15-0450)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Salcuni AS, Carnevale V, Battista C, Palmieri S, Eller-Vainicher C, Guarnieri V, Pugliese F, Guglielmi G, Desina G & Minisola S et al. Primary aldosteronism as a cause of secondary osteoporosis. European Journal of Endocrinology 2017 177 431437. (https://doi.org/10.1530/EJE-17-0417)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Apostolopoulou K, Künzel HE, Gerum S, Merkle K, Schulz S, Fischer E, Pallauf A, Brand V, Bidlingmaier M, Endres S et al. Gender differences in anxiety and depressive symptoms in patients with primary hyperaldosteronism: a cross-sectional study. World Journal of Biological Psychiatry 2014 15 2635. (https://doi.org/10.3109/15622975.2012.665480)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Ahmed AH, Gordon RD, Sukor N, Pimenta E & Stowasser M. Quality of life in patients with bilateral primary aldosteronism before and during treatment with spironolactone and/or amiloride, including a comparison with our previously published results in those with unilateral disease treated surgically. Journal of Clinical Endocrinology and Metabolism 2011 96 29042911. (https://doi.org/10.1210/jc.2011-0138)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Arlt W, Lang K, Sitch AJ, Dietz AS, Rhayem Y, Bancos I, Feuchtinger A, Chortis V, Gilligan LC & Ludwig P et al. Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism. JCI Insight 2017 2 93136. (https://doi.org/10.1172/jci.insight.93136)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Catena C, Colussi G, Lapenna R, Nadalini E, Chiuch A, Gianfagna P & Sechi LA. Long-term cardiac effects of adrenalectomy or mineralocorticoid antagonists in patients with primary aldosteronism. Hypertension 2007 50 911918. (https://doi.org/10.1161/HYPERTENSIONAHA.107.095448)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Rossi GP, Cesari M, Cuspidi C, Maiolino G, Cicala MV, Bisogni V, Mantero F & Pessina AC. Long-term control of arterial hypertension and regression of left ventricular hypertrophy with treatment of primary aldosteronism. Hypertension 2013 62 6269. (https://doi.org/10.1161/HYPERTENSIONAHA.113.01316)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Marzano L, Colussi G, Sechi LA & Catena C. Adrenalectomy is comparable with medical treatment for reduction of left ventricular mass in primary aldosteronism: meta-analysis of long-term studies. American Journal of Hypertension 2015 28 312318. (https://doi.org/10.1093/ajh/hpu154)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Maiolino G, Calò LA & Rossi GP. The time has come for systematic screening for primary aldosteronism in all hypertensives. Journal of the American College of Cardiology 2017 69 18211823. (https://doi.org/10.1016/j.jacc.2017.02.041)

    • Search Google Scholar
    • Export Citation
  • 20

    Stowasser M & Gordon RD. Primary aldosteronism: changing definitions and new concepts of physiology and pathophysiology both inside and outside the kidney. Physiological Reviews 2016 96 13271384. (https://doi.org/10.1152/physrev.00026.2015)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Fischer E, Beuschlein F, Bidlingmaier M & Reincke M. Commentary on the Endocrine Society Practice Guidelines: consequences of adjustment of antihypertensive medication in screening of primary aldosteronism. Reviews in Endocrine and Metabolic Disorders 2011 12 4348. (https://doi.org/10.1007/s11154-011-9163-7)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Fischer E, Reuschl S, Quinkler M, Rump LC, Hahner S, Bidlingmaier M, Reincke M & Participants of the German Conn’s Registry – Else Kröner-Fresenius-Hyperaldosteronism Registry. Assay characteristics influence the aldosterone to renin ratio as a screening tool for primary aldosteronism: results of the German Conn’s registry. Hormone Metabolic Research 2013 45 526531. (https://doi.org/10.1055/s-0033-1343448)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    Nishikawa T, Omura M, Satoh F, Shibata H, Takahashi K, Tamura N, Tanabe A & Task Force Committee on Primary Aldosteronism, The Japan Endocrine Society. Guidelines for the diagnosis and treatment of primary aldosteronism – the Japan Endocrine Society 2009. Endocrine Journal 2011 58 711721. (https://doi.org/10.1507/endocrj.EJ11-0133)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Manolopoulou J, Fischer E, Dietz A, Diederich S, Holmes D, Junnila R, Grimminger P, Reincke M, Morganti A & Bidlingmaier M. Clinical validation for the aldosterone-to-renin ratio and aldosterone suppression testing using simultaneous fully automated chemiluminescence immunoassays. Journal of Hypertension 2015 33 25002511. (https://doi.org/10.1097/HJH.0000000000000727)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Burrello J, Monticone S, Buffolo F, Lucchiari M, Tetti M, Rabbia F, Mengozzi G, Williams TA, Veglio F & Mulatero P. Diagnostic accuracy of aldosterone and renin measurement by chemiluminescent immunoassay and radioimmunoassay in primary aldosteronism. Journal of Hypertension 2016 34 920927. (https://doi.org/10.1097/HJH.0000000000000880)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Rossi GP, Ceolotto G, Rossitto G, Seccia TM, Maiolino G, Berton C, Basso D & Plebani M. Prospective validation of an automated chemiluminescence-based assay of renin and aldosterone for the work-up of arterial hypertension. Clinical Chemistry and Laboratory Medicine 2016 54 14411450. (https://doi.org/10.1515/cclm-2015-1094)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Rossi GP, Belfiore A & Bernini G, Desideri G, Fabris B, Ferri C, Giacchetti G, Letizia C, Maccario M, Mallamaci F et al. Prospective evaluation of the saline infusion test for excluding primary aldosteronism due to aldosterone-producing adenoma. Journal of Hypertension 2007 25 14331442. (https://doi.org/10.1097/HJH.0b013e328126856e)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Mulatero P, Milan A, Fallo F, Regolisti G, Pizzolo F, Fardella C, Mosso L, Marafetti L, Veglio F & Maccario M. Comparison of confirmatory tests for the diagnosis of primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 2006 91 26182623. (https://doi.org/10.1210/jc.2006-0078)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Cornu E, Steichen O, Nogueira-Silva L, Küpers E, Pagny JY, Grataloup C, Baron S, Zinzindohoue F, Plouin PF & Amar L. Suppression of aldosterone secretion after recumbent saline infusion does not exclude lateralized primary aldosteronism. Hypertension 2016 68 989994. (https://doi.org/10.1161/HYPERTENSIONAHA.116.07214)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Ahmed AH, Cowley D, Wolley M, Gordon RD, Xu S, Taylor PJ & Stowasser M. Seated saline suppression testing for the diagnosis of primary aldosteronism: a preliminary study. Journal of Clinical Endocrinology and Metabolism 2014 99 27452753. (https://doi.org/10.1210/jc.2014-1153)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31

    Stowasser M. Is it the beginning of the end for the recumbent saline infusion test? Hypertension 2016 68 857858. (https://doi.org/10.1161/HYPERTENSIONAHA.116.07337)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Rossi GP, Chiesura-Corona M, Tregnaghi A, Zanin L, Perale R, Soattin S, Pelizzo MR, Feltrin GP & Pessina AC. Imaging of aldosterone-secreting adenomas: a prospective comparison of computed tomography and magnetic resonance imaging in 27 patients with suspected primary aldosteronism. Journal of Human Hypertension 1993 7 357363.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Kempers MJ, Lenders JW, van Outheusden L, van der Wilt GJ, Schultze Kool LJ, Hermus AR & Deinum J. Systematic review: diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism. Annals of Internal Medicine 2009 151 329337. (https://doi.org/10.7326/0003-4819-151-5-200909010-00007)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Gordon RD, Stowasser M & Rutherford JC. Primary aldosteronism: are we diagnosing and operating on too few patients? World Journal of Surgery 2001 25 941947. (https://doi.org/10.1007/s00268-001-0033-4)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR & van Heerden JA. Role for adrenal venous sampling in primary aldosteronism. Surgery 2004 136 12271235. (https://doi.org/10.1016/j.surg.2004.06.051)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Young WF. Primary aldosteronism: renaissance of a syndrome. Clinical Endocrinology 2007 66 607618. (https://doi.org/10.1111/j.1365-2265.2007.02775.x)

  • 37

    Riester A, Fischer E, Degenhart C, Reiser MF, Bidlingmaier M, Beuschlein F, Reincke M & Quinkler M. Age below 40 or a recently proposed clinical prediction score cannot bypass adrenal venous sampling in primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 2014 99 E1035E1039. (https://doi.org/10.1210/jc.2013-3789)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38

    Umakoshi H, Ogasawara T, Takeda Y, Kurihara I, Itoh H, Katabami T, Ichijo T, Wada N, Shibayama Y & Yoshimoto T et al. Accuracy of adrenal computed tomography in predicting the unilateral subtype in young patients with hypokalaemia and elevation of aldosterone in primary aldosteronism. Clinical Endocrinology 2018 88 645651. (https://doi.org/10.1111/cen.13582)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Monticone S, Viola A, Rossato D, Veglio F, Reincke M, Gomez-Sanchez C & Mulatero P. Adrenal vein sampling in primary aldosteronism: towards a standardised protocol. Lancet Diabetes and Endocrinology 2015 3 296303. (https://doi.org/10.1016/S2213-8587(14)70069-5)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40

    Haase M, Riester A, Kröpil P, Hahner S, Degenhart C, Willenberg HS & Reincke M. Outcome of adrenal vein sampling performed during concurrent mineralocorticoid receptor antagonist therapy. Journal of Clinical Endocrinology and Metabolism 2014 99 43974402. (https://doi.org/10.1210/jc.2014-2788)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41

    Mengozzi G, Rossato D, Bertello C, Garrone C, Milan A, Pagni R, Veglio F & Mulatero P. Rapid cortisol assay during adrenal vein sampling in patients with primary aldosteronism. Clinical Chemistry 2007 53 19681971. (https://doi.org/10.1373/clinchem.2007.092080)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Auchus RJ, Michaelis C, Wians FH Jr, Dolmatch BL, Josephs SC, Trimmer CK, Anderson ME & Nwariaku FE. Rapid cortisol assays improve the success rate of adrenal vein sampling for primary aldosteronism. Annals of Surgery 2009 249 318321. (https://doi.org/10.1097/SLA.0b013e3181961d77)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Betz MJ, Degenhart C, Fischer E, Pallauf A, Brand V, Linsenmaier U, Beuschlein F, Bidlingmaier M & Reincke M. Adrenal vein sampling using rapid cortisol assays in primary aldosteronism is useful in centers with low success rates. European Journal of Endocrinology 2011 165 301306. (https://doi.org/10.1530/EJE-11-0287)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44

    Rossi GP, Auchus RJ, Brown M, Lenders JW, Naruse M, Plouin PF, Satoh F, Young WF Jr. An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism. Hypertension 2014 63 151160. (https://doi.org/10.1161/HYPERTENSIONAHA.113.02097)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Wolley MJ, Ahmed AH, Gordon RD & Stowasser M. Does ACTH improve the diagnostic performance of adrenal vein sampling for subtyping primary aldosteronism? Clinical Endocrinology 2016 85 703709. (https://doi.org/10.1111/cen.13110)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46

    El Ghorayeb N, Mazzuco TL, Bourdeau I, Mailhot JP, Zhu PS, Thérasse E & Lacroix A. Basal and post-ACTH aldosterone and its ratios are useful during adrenal vein sampling in primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 2016 101 18261835. (https://doi.org/10.1210/jc.2015-3915)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47

    Monticone S, Satoh F, Giacchetti G, Viola A, Morimoto R, Kudo M, Iwakura Y, Ono Y, Turchi F & Paci E et al. Effect of adrenocorticotropic hormone stimulation during adrenal vein sampling in primary aldosteronism. Hypertension 2012 59 840846. (https://doi.org/10.1161/HYPERTENSIONAHA.111.189548)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48

    Williams TA, Lenders JWM, Mulatero P, Burrello J, Rottenkolber M, Adolf C, Satoh F, Amar L, Quinkler M & Deinum J et al. Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. Lancet Diabetes and Endocrinology 2017 5 689699. (https://doi.org/10.1016/S2213-8587(17)30135-3)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49

    Dekkers T, Prejbisz A, Kool LJS, Groenewoud HJMM, Velema M, Spiering W, Kołodziejczyk-Kruk S, Arntz M & Kądziela J, Langenhuijsen JF et al. Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial. Lancet Diabetes and Endocrinology 2016 4 739746. (https://doi.org/10.1016/S2213-8587(16)30100-0)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 50

    Funder JW & Rossi GP. Adrenal vein sampling versus CT scanning in primary aldosteronism. Lancet Diabetes and Endocrinology 2016 4 886. (https://doi.org/10.1016/S2213-8587(16)30240-6)

    • Search Google Scholar
    • Export Citation
  • 51

    Beuschlein F, Mulatero P, Asbach E, Monticone S, Catena C, Sechi LA & Stowasser M. The SPARTACUS trial: controversies and unresolved issues. Hormone Metabolic Research 2017 49 936942. (https://doi.org/10.1055/s-0043-120524)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 52

    Rossi GP & Funder JW. Adrenal vein sampling is the preferred method to select patients with primary aldosteronism for adrenalectomy: pro side of the argument. Hypertension 2018 71 59. (https://doi.org/10.1161/HYPERTENSIONAHA.117.09295)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53

    Deinum J, Prejbisz A, Lenders JWM & van der Wilt GJ Adrenal vein sampling is the preferred method to select patients with primary aldosteronism for adrenalectomy: con side of the argument. Hypertension 2018 71 1014. (https://doi.org/10.1161/HYPERTENSIONAHA.117.09294)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54

    Young WF Jr & Klee GG. Primary aldosteronism. Diagnostic evaluation. Endocrinology Metabolism Clinics of North America 1988 17 367395.

  • 55

    Fischer E, Beuschlein F, Degenhart C, Jung P, Bidlingmaier M & Reincke M. Spontaneous remission of idiopathic aldosteronism after long-term treatment with spironolactone: results from the German Conn’s Registry. Clinical Endocrinology 2012 76 473477. (https://doi.org/10.1111/j.1365-2265.2011.04243.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56

    Armanini D, Fiore C & Pellati D. Spontaneous resolution of idiopathic aldosteronism after long-term treatment with potassium canrenoate. Hypertension 2007 50 e69e70. (https://doi.org/10.1161/HYPERTENSIONAHA.107.096925)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 57

    Jeunemaitre X, Chatellier G, Kreft-Jais C, Charru A, DeVries C, Plouin PF, Corvol P & Menard J. Efficacy and tolerance of spironolactone in essential hypertension. American Journal of Cardiology 1987 60 820825. (https://doi.org/10.1016/0002-9149(87)91030-7)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 58

    Weinberger MH, Roniker B, Krause SL & Weiss RJ. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. American Journal of Hypertension 2002 15 709716. (https://doi.org/10.1016/S0895-7061(02)02957-6)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59

    Roush GC, Ernst ME, Kostis JB, Yeasmin S & Sica DA. Dose doubling, relative potency, and dose equivalence of potassium-sparing diuretics affecting blood pressure and serum potassium: systematic review and meta-analyses. Journal of Hypertension 2016 34 1119. (https://doi.org/10.1097/HJH.0000000000000762)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60

    Hundemer GL, Curhan GC, Yozamp N, Wang M & Vaidya A. Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study. Lancet Diabetes and Endocrinology 2018 6 5159. (https://doi.org/10.1016/S2213-8587(17)30367-4)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 61

    Rossi GP, Maiolino G, Flego A, Belfiore A, Bernini G, Fabris B, Ferri C, Giacchetti G, Letizia C & Maccario M et al. Adrenalectomy lowers incident atrial fibrillation in primary aldosteronism patients at long term. Hypertension 2018 71 585591. (https://doi.org/10.1161/HYPERTENSIONAHA.117.10596

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62

    Prada ETA, Burrello J, Reincke M & Williams TA. Old and new concepts in the molecular pathogenesis of primary aldosteronism Hypertension 2017 70 875881. (https://doi.org/10.1161/HYPERTENSIONAHA.117.10111)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63

    Zennaro MC, Boulkroun S & Fernandes-Rosa F. Genetic causes of functional adrenocortical adenomas. Endocrine Reviews 2017 38 516537. (https://doi.org/10.1210/er.2017-00189)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64

    Williams TA, Peitzsch M, Dietz AS, Dekkers T, Bidlingmaier M, Riester A, Treitl M, Rhayem Y, Beuschlein F & Lenders JW et al. Genotype-specific steroid profiles associated with aldosterone-producing adenomas. Hypertension 2016 67 139145. (https://doi.org/10.1161/HYPERTENSIONAHA.115.06186)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65

    Scholl UI, Abriola L, Zhang C, Reimer EN, Plummer M, Kazmierczak BI, Zhang J, Hoyer D, Merkel JS & Wang W et al. Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma. Journal of Clinical Investigation 2017 127 27392750. (https://doi.org/10.1172/JCI91733)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 66

    Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S & Lalouel JM. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992 355 262265. (https://doi.org/10.1038/355262a0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67

    Geller DS, Zhang J, Wisgerhof MV, Shackleton C, Kashgarian M & Lifton RP. A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. Journal of Clinical Endocrinology and Metabolism 2008 93 31173123. (https://doi.org/10.1210/jc.2008-0594)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 68

    Choi M, Scholl UI, Yue P, Björklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A & Men CJ et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 2011 331 768772. (https://doi.org/10.1126/science.1198785)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69

    Stowasser M, Gordon RD, Tunny TJ, Klemm SA, Finn WL & Krek AL. Familial hyperaldosteronism type II: five families with a new variety of primary aldosteronism. Clinical and Experimental Pharmacology and Physiology 1992 19 319322. (https://doi.org/10.1111/j.1440-1681.1992.tb00462.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 70

    Scholl UI, Stölting G, Nelson-Williams C, Vichot AA, Choi M, Loring E, Prasad ML, Goh G, Carling T & Juhlin CC et al. Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. Elife 2015 4 e06315. (https://doi.org/10.7554/eLife.06315)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71

    Daniil G, Fernandes-Rosa FL, Chemin J, Blesneac I, Beltrand J, Polak M, Jeunemaitre X, Boulkroun S, Amar L & Strom TM et al. CACNA1H mutations are associated with different forms of primary aldosteronism. EBioMedicine 2016 13 225236. (https://doi.org/10.1016/j.ebiom.2016.10.002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72

    Scholl UI, Stölting G, Schewe J, Thiel A, Tan H, Nelson-Williams C, Vichot AA, Jin SC, Loring E & Untiet V et al. CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nature Genetics 2018 50 349354. (https://doi.org/10.1038/s41588-018-0048-5)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 73

    Fernandes-Rosa FL, Daniil G, Orozco IJ, Göppner C, El Zein R, Jain V, Boulkroun S, Jeunemaitre X, Amar L & Lefebvre H et al. A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. Nature Genetics 2018 50 355361. (https://doi.org/10.1038/s41588-018-0053-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 74

    Heinze B, Fuss CT, Mulatero P, Beuschlein F, Reincke M, Mustafa M, Schirbel A, Deutschbein T, Williams TA & Rhayem Y et al. Targeting CXCR4 (CXC Chemokine Receptor Type 4) for molecular imaging of aldosterone-producing adenoma. Hypertension 2018 71 317325. (https://doi.org/10.1161/HYPERTENSIONAHA.117.09975)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation