Bilateral Primary Aldosteronism Research Articles

Primary Aldosteronism with Parathyroid Hormone Elevation: A Single-center Retrospective Study.

Objective Primary aldosteronism (PA) is a major cause of secondary hypertension. The association between PA and other hormone disorders is unclear. The present study aimed to evaluate whether the parathyroid hormone (PTH) value is associated with PA subtypes or specific treatments. Methods We enrolled 135 patients with PA who had their PTH value measured before undergoing a specific treatment. We evaluated whether PTH value is associated with PA subtypes or with specific treatments. The present study is a single-center retrospective study (2011-2018). Results Our study showed that, among the patients with PA, the proportion of those with PTH elevation was >30%. The PTH value was significantly correlated with both the basal plasma aldosterone concentration (PAC) and PAC after a captopril challenge test. However, the PTH value was not significantly different between the patients with unilateral and bilateral PA. We observed that the serum PTH value decreased after treatment of PA with unilateral adrenalectomy or mineralocorticoid receptor antagonists. Conclusion Our findings suggest that the PTH value in PA patients might be associated with the autonomous production of aldosterone. However, there was no correlation between the PTH value and PA subtypes in our study. Additionally, our study showed that targeted treatment for PA may lead to a decrease in the serum PTH levels. Hence, the PTH value could potentially be used as an index for measuring the suitability for PA treatment.

Recent Development toward the Next Clinical Practice of Primary Aldosteronism: A Literature Review.

For the last seven decades, primary aldosteronism (PA) has been gradually recognized as a leading cause of secondary hypertension harboring increased risks of cardiovascular incidents compared to essential hypertension. Clinically, PA consists of two major subtypes, surgically curable and uncurable phenotypes, determined as unilateral or bilateral PA by adrenal venous sampling. In order to further optimize the treatment, surgery or medications, diagnostic procedures from screening to subtype differentiation is indispensable, while in the general clinical practice, the work-up rate is extremely low even in the patients with refractory hypertension because of the time-consuming and labor-intensive nature of the procedures. Therefore, a novel tool to simplify the diagnostic flow has been recently in enormous demand. In this review, we focus on recent progress in the following clinically important topics of PA: prevalence of PA and its subtypes, newly revealed histopathological classification of aldosterone-producing lesions, novel diagnostic biomarkers and prediction scores. More effective strategy to diagnose PA based on better understanding of its epidemiology and pathology should lead to early detection of PA and could decrease the cardiovascular and renal complications of the patients.

Adrenal Venous Sampling in Young Patients with Primary Aldosteronism. Extravagance or Irreplaceable?

Current clinical guidelines suggest that adrenal venous sampling (AVS) may not be mandatory in young patients with primary aldosteronism (PA) and a solitary adrenal adenoma on imaging. The aim of this study was to further elucidate whether conventional imaging alone is sufficient to distinguish unilateral from bilateral PA among patients aged 40 years or younger. This was a retrospective study where data from 45 patients with PA, aged between 26 and 40 years, who underwent successful AVS between 2005 and 2019, were analyzed. Results concerning laterality on imaging studies and AVS were recorded. Outcome in surgically treated patients was assessed according to the Primary Aldosteronism Surgical Outcomes criteria. In 4 of 25 patients with unilateral aldosterone production according to AVS, computed tomography inaccurately suggested bilateral disease. Following unilateral adrenalectomy, all 4 patients showed complete clinical success. Five of 20 patients with bilateral aldosterone production according to AVS had a solitary adrenal nodule (8-19 mm) on imaging. Two of these 5 patients were treated with unilateral adrenalectomy, neither having complete biochemical and/or clinical success postoperatively. Two of 16 patients younger than 35 years had discordant results, 1 with unilateral and 1 with bilateral aldosterone production, according to AVS. Imaging studies inaccurately predicted laterality in a significant number of young patients with PA. In contrast to current clinical guidelines, our results support AVS for subtype evaluation in young adults with PA, including patients 35 years or younger.

Sex Differences in Renal Outcomes After Medical Treatment for Bilateral Primary Aldosteronism.

A higher incidence of bilateral primary aldosteronism in women is reported. Treatment of bilateral primary aldosteronism usually involves mineralocorticoid receptor antagonists. However, the impact of sex on renal outcomes is unknown. We compared renal outcomes between the sexes after mineralocorticoid receptor antagonist initiation by analyzing data obtained from 415 female and 313 male patients with bilateral primary aldosteronism who were treated with spironolactone or eplerenone in the JPAS (Japan Primary Aldosteronism Study). Over the course of 5 years, the temporal reduction in the estimated glomerular filtration rate was greater in women than in men (P<0.001). Systolic blood pressure levels were equal between the sexes, despite higher doses of antihypertensive drugs in men. The mean of the annual decline in estimated glomerular filtration rate during what we termed the late phase, or 6 to 60 months after mineralocorticoid receptor antagonist initiation, was larger in women than in men after adjusting for patient characteristics (-1.33 mL/min per 1.73 m2 per year versus -1.04 mL/min per 1.73 m2 per year, P<0.01). Female sex was a significant predictor of greater annual decline during the late phase in patients taking spironolactone but not in those taking eplerenone. Spironolactone use and diabetes were independent predictors of a greater annual decline in estimated glomerular filtration rate during the late phase in women. These findings suggest that female sex is associated with poorer renal outcomes in patients receiving mineralocorticoid receptor antagonist for bilateral primary aldosteronism.

Update: Selective adrenal venous sampling (AVS) - Indication, technique, and significance.

Primary aldosteronism (PA) is the most common detectable cause of secondary hypertension. The majority of patients have either an adrenal aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia (BAH) demanding different therapeutic approaches. Screening tests and imaging cannot reliably distinguish between a unilateral or bilateral PA. This review article gives an overview concerning etiology, diagnostics, and therapeutic options of PA, and reviews the indication, the technique, and relevance of selective adrenal venous sampling (AVS) in the context of the current literature and the authors' experience. AVS can verify or exclude a unilaterally dominated secretion with a high success rate. Patients with PA and a unilateral APA can be treated curatively by adrenalectomy. AVS is an established diagnostic examination for differentiation of unilateral from bilateral adrenal disease in patients with PA. · Selective adrenal venous sampling (AVS) is a safe, reliable, and minimally invasive method to detect a unilateral or bilateral adrenal adrenal gland disease.. · Verification of lateralization by AVS has direct therapeutic relevance for patients with primary aldosteronism (PA).. · AVS can be performed with low radiation exposure, without contrast medium, and with a high success rate when performed by an experienced interventional radiologist.. · Loberg C, Antoch G, Stegbauer J et al. Update: Selective adrenal venous sampling (AVS) - Indication, technique, and significance. Fortschr Röntgenstr 2021; 193: 658 - 666.

Functional imaging with 11C-metomidate PET for subtype diagnosis in primary aldosteronism.

Endocrine Society guidelines recommend adrenal venous sampling (AVS) in primary aldosteronism (PA) if adrenalectomy is considered. We tested whether functional imaging of adrenal cortex with 11C-metomidate (11C-MTO) could offer a noninvasive alternative to AVS in the subtype classification of PA. We prospectively recruited 58 patients with confirmed PA who were eligible for adrenal surgery. Subjects underwent AVS and 11C-MTO-PET without dexamethasone pretreatment in random order. The lateralization of 11C-MTO-PET and adrenal CT were compared with AVS in all subjects and in a prespecified adrenalectomy subgroup in which the diagnosis was confirmed with immunohistochemical staining for CYP11B2. In the whole study population, the concordance of AVS and 11C-MTO-PET was 51% and did not differ from that of AVS and adrenal CT (53%). The concordance of AVS and 11C-MTO-PET was 55% in unilateral and 44% in bilateral PA. In receiver operating characteristics analysis, the maximum standardized uptake value ratio of 1.16 in 11C-MTO-PET had an AUC of 0.507 (P = n.s.) to predict allocation to adrenalectomy or medical therapy with sensitivity of 55% and specificity of 44%. In the prespecified adrenalectomy subgroup, AVS and 11C-MTO-PET were concordant in 10 of 19 subjects with CYP11B2-positive adenoma and in 6 of 10 with CYP11B2-positivity without an adenoma. The concordance of 11C-MTO-PET with AVS was clinically suboptimal, and did not outperform adrenal CT. In a subgroup with CYP11B2-positive adenoma, 11C-MTO-PET identified 53% of cases. 11C-MTO-PET appeared to be inferior to AVS for subtype classification of PA.

MANAGEMENT OF ENDOCRINE DISEASE: The role of surgical adrenalectomy in primary aldosteronism.

Primary aldosteronism is common and contributes to adverse cardiovascular, kidney, and metabolic outcomes. When instituted early and effectively, targeted therapies can mitigate these adverse outcomes. Surgical adrenalectomy is among the most effective treatments because it has the potential to cure, or attenuate the severity of, pathologic aldosterone excess, resulting in a host of biochemical and clinical changes that improve health outcomes. Herein, we review the role of surgical adrenalectomy in primary aldosteronism while emphasizing the physiologic ramifications of surgical intervention, and compare these to other targeted medical therapies for primary aldosteronism. We specifically review the role of curative adrenalectomy for unilateral primary aldosteronism, the role of non-curative adrenalectomy for bilateral primary aldosteronism, and how these interventions influence biochemical and clinical outcomes in relation to medical therapies for primary aldosteronism.

Higher prevalence of metabolic disorders in patients with bilateral primary aldosteronism than unilateral primary aldosteronism.

Metabolic syndrome (MetS) is a frequent clinical condition in hypertension patients and is more frequently reported in primary aldosteronism (PA). This study is aimed at investigating the prevalence of MetS and its components in the two major types of patients with adrenal venous sampling (AVS)-confirmed unilateral PA and bilateral PA. This was a retrospective cross-section study. We analysed metabolic parameters from 169 PA patients subtyped by AVS, including 85 unilateral PA patients and 84 bilateral PA patients, and we also included 169 non-PA patients matched for age and sex. Patients with unilateral PA had higher concentrations of aldosterone and lower serum potassium than patients with bilateral PA. However, patients with bilateral PA had higher prevalence of MetS (79.8% vs 64.7%, P=.029), obesity (40.5% vs 24.7%, P=.029), dyslipidemia (72.6% vs 55.3%, P=.019) and hyperglycaemia (29.8% vs 16.5%, P=.040) than those with unilateral PA. Meanwhile, bilateral PA had higher BMI (27.55±4.58 vs 25.57±3.28kg/m2 , P=.001), waist circumference (98.54±11.44 vs 93.32±10.64cm, P=.003) and fasting plasma glucose (4.98±1.16 vs 4.64±0.93mmol/L, P=.034). The logistic regression analysis also showed that bilateral PA was associated with the presence of MetS after adjustment for age, sex and duration of hypertension. Patients with bilateral PA have a higher prevalence of MetS than those with unilateral PA, despite unilateral PA patients exhibiting higher concentrations of aldosterone and lower serum potassium, suggesting that unilateral PA and bilateral PA may have differing mechanisms of MetS.

Performance of the unilateral AV/IVC index in primary hyperaldosteronism subtype prediction: A validation study in a single tertiary centre.

Failure of cannulation of the right adrenal vein is frequent during AVS for investigation of primary aldosteronism (PA). The aldosterone:cortisol ratio of either adrenal vein compared with the inferior vena cava (AV/IVC index) has been proposed to differentiate between unilateral and bilateral disease, and aid in lateralization of unilateral disease. Sixty-two patients with unilateral or bilateral PA identified by either successful bilateral (45 patients) or unilateral (17 patients) adrenal vein cannulation, and with biochemical remission following surgery were enrolled into the analysis. The diagnostic performances of the previously identified AV/IVC index cut-offs of ≥5.5 to predict ipsilateral disease and ≤0.5 to predict contralateral disease were validated using data from the entire cohort. Fifty-three patients had unilateral PA and 9 patients bilateral PA. The area under ROC curve (AUROC) of the AV/IVC cut-off ≤0.5 for identifying unilateral aldosterone secretion from the contralateral adrenal was 0.95 (95% CI; 0.88-0.99), whereas the AUROC of the AV/IVC cut-off ≥5.5 for identifying unilateral aldosterone secretion from ipsilateral adrenal was 0.96 (95% CI; 0.92-0.99). The AV/IVC index cut-off value of 0.5 had 93% sensitivity and 91% specificity, and the AV/IVC index cut-off value of 5.5 had 21% sensitivity and 100% specificity. The optimal AV/IVC cut-offs to achieve 100% specificity for our cohort were >2.4 and <0.1 to predict ipsilateral and contralateral disease. Our data confirm that the AV/IVC index is a potential tool for subtype classification and lateralization in patients with PA in the setting of failed bilateral, but successful unilateral, adrenal vein cannulation during AVS.

Management of primary aldosteronism and mineralocorticoid receptor-associated hypertension.

Resistant hypertension is associated with a poor prognosis due to organ damage caused by prolonged suboptimal blood pressure control. The concomitant use of mineralocorticoid receptor (MR) antagonists with other antihypertensives has been shown to improve blood pressure control in some patients with resistant hypertension, and such patients are considered to have MR-associated hypertension. MR-associated hypertension is classified into two subtypes: one with a high plasma aldosterone level, which includes primary aldosteronism (PA), and the other with a normal aldosterone level. In patients with unilateral PA, adrenalectomy may be the first-choice procedure, while in patients with bilateral PA, MR antagonists are selected. In addition, in patients with other types of MR-associated hypertension with high aldosterone levels, MR antagonists may be selected as a first-line therapy. In patients with normal aldosterone levels, ARBs or ACE inhibitors are used as a first-line therapy, and MR antagonists may be used as an add-on agent. Since MR antagonist therapy may have efficacy as a first-line or add-on agent in these patients, it is important to recognize this type of hypertension. Further studies are needed to elucidate the pathogenesis and management of MR-associated hypertension in more detail to improve the clinical outcomes of patients with MR-associated hypertension.

The Impact of Glucocorticoid Co-Secretion in Primary Aldosteronism on Thyroid Autoantibody Titers During the Course of Disease.

Excess aldosterone is associated with the increased risk of cardio-/cerebrovascular events as well as metabolic comorbidities not only due to its hypertensive effect but also due to its proinflammatory action. Autonomous cortisol secretion (ACS) in the setting of primary aldosteronism (PA) is known to worsen cardiovascular outcome and potentially exhibit immunosuppressive effects. The aim of this study was to determine the impact of ACS status in patients with PA on kinetics of thyroid autoantibodies (anti-TPO, anti-TG) pre and post therapy initiation. Ninety-seven PA patients (43 unilateral, 54 with bilateral PA) from the database of the German Conn’s Registry were included. Anti-TPO and anti-TG levels were measured pre and 6–12 months post therapeutic intervention. Patients were assessed for ACS according to their 24- hour urinary cortisol excretion, late night salivary cortisol and low-dose dexamethasone suppression test. Abnormal test results in line with ACS were identified in 74.2% of patients with PA. Following adrenalectomy, significant increases in anti-TPO levels were observed in patients with at least one abnormal test (p = 0.049), adrenalectomized patients with at least two pathological ACS tests (p = 0.015) and adrenalectomized patients with pathologic dexamethasone suppression tests (p = 0.018). No antibody increases were observed in unilateral PA patients without ACS and in patients with bilateral PA receiving mineralocorticoid antagonist therapy (MRA). Our data are in line with an immunosuppressive effect of mild glucocorticoid excess in PA on thyroid autoantibody titers. This effect is uncovered by adrenalectomy, but not by MRA treatment.

SUN-378 Unilateral Primary Aldosteronism as an Independent Risk Factor for Vertebral Fracture

Context: Primary aldosteronism (PA) is known to increase vertebral fracture (VF), although the detailed mechanism remains to be elucidated. PA consists of two subtypes: the unilateral and bilateral subtype. Patients with unilateral PA, who usually have a higher plasma aldosterone concentration than those with bilateral PA, exhibit a more severe clinical phenotype. We hypothesized that PA subtype affects the prevalence of VF. Objective: To evaluate whether unilateral PA is associated with the prevalence of VF. Design: Cross-sectional study in a single referral center. Patients: We identified 210 hypertensive patients whose clinical data were available for case-detection results. One hundred and fifty-two patients were diagnosed with PA using captopril challenge tests. Measurements: The prevalence of VF according to PA subtype. Results: We included 113 patients with PA who were subtype classified according to adrenal vein sampling, of whom 37 patients had unilateral PA and 76 patients had bilateral PA, whereas 58 patients had non-PA. We excluded 39 patients with PA who were not subtype classified. Patients with PA had a higher prevalence of VF (28% [32/113]) than those with non-PA (12% [7/58]; p = 0.020). Moreover, unilateral PA had a higher prevalence of VF (46% [17/37]) than bilateral PA (20% [15/76]; p = 0.021). There was no significant difference between bilateral PA and non-PA. Unilateral PA was an independent risk factor for VF after adjusting for age and sex (odds ratio, 3.16; 95% confidence interval, 1.12-8.92; p = 0.017). Among patients with unilateral PA, serum cortisol concentrations after 1 mg dexamethasone suppression test were higher in those with VF (1.32 ± 0.67 g/dl) than those without (0.96 ± 0.33 g/dl; p = 0.048). Conclusions: Unilateral PA is an independent risk factor for VF, which is associated with autonomous cortisol secretion. Thus, careful management is required to prevent the development of VF in patients with unilateral PA.

OR34-01 11C Metomidate PET-CT Identifies More Unilateral Primary Aldosteronism Than Adrenal Vein Sampling

Introduction. Adrenal vein sampling (AVS) is the current reference test to identify unilateral, surgically-curable primary aldosteronism (PA). However, AVS is invasive and technically difficult. Even in AVS-proven unilateral PA, up to 6% of patients with fail to have biochemical cure after surgery using the PASO criteria. 11C-Metomidate PET-CT offers a non-invasive alternative. We compared the accuracy of both PET-CT and AVS using post-surgery cure (PASO criteria) as the reference. Methods. This multi-centre prospective trial recruited 25 patients with confirmed PA, and all underwent CT, AVS, and PET-CT tests. Sequential AVS under ACTH-stimulation was done by an experienced interventionalist, and cortisol gradient of >5 was taken to be successful cannulation. Lateralization ratio >4 was consistent with unilateral PA. All results were reviewed at a multidisciplinary meeting to decide on the diagnosis (unilateral or bilateral PA) and management (secondary outcome). Primary outcome was biochemical cure using PASO criteria at 6 months post-surgery (ClinicalTrials.gov: NCTxxxxxxxx). Results. Recruitment for the study has been complete with 25 patients, 49.2 ± 9.5 yr, 14 females (56.0%). All 25 patients had successful AVS. 22 of 25 patients (88.0%) had unilateral PA, and 3 patients (12.0%) had bilateral PA. PET-CT identified unilateral PA in 18 of 22 patients (sensitivity 81.8%), while AVS identified unilateral PA in 15 of 22 patients (sensitivity 68.2%). In one patient, repeat AVS done simultaneously without ACTH-stimulation aided to identify unilateral PA, when initial AVS failed to do so. Other cases where AVS failed to identify unilateral PA were due to venous anomalies, and limitation of the lateralization cut-off of 4. 18 of 22 patients have undergone surgery, with 3 patients awaiting surgery, and 1 opting for medical treatment. Post-surgery, all patients had complete normalization of aldosterone-renin ratio, and hypokalemia (if present). 2 patients had bilateral PA on both PET-CT and AVS. 1 patient had discordant AVS and PET-CT results, with AVS lateralizing to right, and PET-CT to left. This patient was classified as bilateral PA and treated medically. Conclusion. This is the first study to demonstrate that 11C-Metomidate PET-CT may identify cases of unilateral PA not detected with AVS, using the stringent PASO criteria for post-operative biochemical cure.

SAT-547 Aldosterone-Potassium Ratio Predicts Primary Aldosteronism Subtype

Objective Prediction models have been developed to predict either unilateral or bilateral primary aldosteronism, and these have not been validated externally. We aimed to develop a simplified score to predict both subtypes and validate this externally. Methods Our development cohort was taken from 165 patients who underwent adrenal vein sampling (AVS) in two Asian tertiary centres. Unilateral disease was determined using both AVS and post-operative outcome. Multivariable analysis was used to construct prediction models. We validated our tool in a European cohort of 97 patients enrolled in a clinical trial. Previously published prediction models were also tested in our cohorts. Results Backward stepwise logistic regression analysis yielded a final tool using baseline-aldosterone-to-lowest-potassium ratio (APR, ng/dL/mmol/L), with an area under receiver operating characteristic curve of 0.80 (95% CI: 0.70 - 0.89). In the Asian development cohort, probability of bilateral disease was 90.0% (with APR <5) and probability of unilateral disease was 91.4% (with APR >15). Similar results were seen in the European validation cohort. Combining both cohorts, probability of bilateral disease was 76.7% (with APR <5), and probability for unilateral was 91.7% (with APR >15). Other models had similar predictive ability but required more variables, and were less sensitive for identifying bilateral PA. Conclusion The novel aldosterone-potassium ratio (APR) is a convenient score to guide clinicians and patients of various ethnicities on the probability of PA subtype. Using APR to identify patients more likely to benefit from AVS may be a cost-effective strategy to manage this common condition.

SAT-LB76 Impact of Glucocorticoid Cosecretion in Primary Aldosteronism on Thyroid Autoantibody Titers During the Course of Disease

Context: Excess aldosterone is associated with the increased risk of cardio- and cerebrovascular events as well as metabolic comorbidities not only due to its hypertensive effect but also due to its proinflammatory action. Autonomous cortisol secretion (ACS) in the setting of primary aldosteronism (PA) is known to worsen cardiovascular outcome and potentially exhibit immunosuppressive effects.The aim of this study was to determine the impact of ACS status in patients with PA on kinetics of thyroid autoantibodies (anti-TPO, anti-TG) pre and post therapy initiation.Patients and Methods: 97 PA patients (43 with unilateral, 54 with bilateral PA) from the database of the German Conn’s Registry were included. Anti-TPO and anti-TG levels were measured pre and 6 to 12 months post therapeutic intervention. Patients were assessed for ACS according to their 24h urinary cortisol excretion, late night salivary cortisol and low-dose dexamethason suppression test.Results: Abnormal test results in line with ACS were identified in 74.2% of patients. Significant increases in anti-TPO levels were observed in adrenalectomized patients with at least one abnormal test (p = 0.049), adrenalectomized patients with at least two pathological ACS tests (p = 0.015) and adrenalectomized patients with pathologic dexamethasone suppression tests (p = 0.018). No antibody increases were observed in unilateral PA patients without ACS and in patients with bilateral PA receiving mineralocorticoid antagonist therapy.Conclusion: ACS appears to be a relevant factor in PA affecting thyroid autoimmune disease. The biochemical and clinical course maybe be exacerbated after resolution of hypercortisolism by adrenalectomy in PA.

SAT-558 A Dedicated Endocrine Hypertension Service Increases the Timely Diagnosis of Primary Aldosteronism

Background: Primary aldosteronism (PA) accounts for 3.2-12.7% of hypertension in primary care but is often diagnosed late, if at all. A delayed or missed diagnosis leads to poor blood pressure control and greater cardiovascular risk that could be averted with targeted treatment. An Endocrine Hypertension Service (EHS), encompassing an education program, streamlined diagnostic tests and dedicated PA clinic, was developed to address this issue. Aims: To analyse the impact of Victoria’s first dedicated EHS on the pattern of PA diagnoses. Methods: Socio-demographic and clinical data from all patients who attended the EHS since July 2016 (N=267) was collected prospectively. Patients were divided into Year 1 (Y1), Year 2 (Y2), and Year 3 (Y3), based on their first visit. Results: The proportion of referrals from primary care increased (20% in Y1 to 52% in Y3) with more referrals being made for treatment-naive hypertension (3% in Y1 to 19% in Y3). Patients with a hypertension diagnosis of 5 years or less at the time of referral to EHS increased from 34% in Y1 to 45% in Y3 whilst the percentage of patients with a hypertension diagnosis of more than 10 years decreased from 50% in Y1 to 35% in Y3. Consistent with an earlier presentation, the proportion of patients with end-organ damage at the time of referral decreased from 44% in Y1 to 29% in Y3. Almost a third of the PA patients had unilateral disease; all of those who underwent adrenalectomy had biochemical cure. Patients with bilateral PA were treated with spironolactone. Their systolic/diastolic blood pressure decreased by 15/12 mmHg in Y1, 17/13 mmHg in Y2 and 23/11 mmHg in Y3; while the mean number of antihypertensive medications decreased from 2.9 to 1.8 in Y1, 2.7 to 2.0 in Y2 and 2.2 to 1.6 in Y3 Conclusion: The EHS has facilitated an increase in referrals for PA screening from primary care, resulting in the earlier diagnosis of PA, when less complications are present, and optimised patient outcomes. A broader uptake of such a clinical service, integrated with education outreach, will bridge the gap between the reported high prevalence of PA and the actual low diagnostic rates.

SUN-161 Primary Aldosteronism and Klinefelter’s Syndrome: Two Cases

Background: Primary aldosteronism (PA) is more common than expected. Aberrant adrenal expression of LH receptor in patients with PA has been reported, however, its physiological role on the development of PA is still unknown. Herein, we report two unique cases of PA in patients with untreated Klinefelter’s syndrome, characterized as increased serum LH, suggesting a possible contribution of the syndrome to PA development. Clinical Cases: Case 1 was a 39-year-old man with obesity and hypertension since his 20s. His plasma aldosterone concentration (PAC) and renin activity (PRA) were 220 pg/mL and 0.4 ng/mL/h, respectively. He was diagnosed as having bilateral PA by confirmatory tests and adrenal venous sampling (AVS). Klinefelter’s syndrome was suspected as he showed gynecomastia and small testes, and it was confirmed on the basis of a low serum total testosterone level (57.3 ng/dL), high serum LH level (50.9 mIU/mL), and chromosome analysis. Case 2 was a 28-year-old man who had untreated Klinefelter’s syndrome diagnosed in his childhood and a two-year history of hypertension and hypokalemia. PAC and PRA were 247 pg/mL and 0.3 ng/mL/h, respectively. He was diagnosed as having a 10 mm-sized aldosterone-producing adenoma (APA) by AVS. In the APA, immunohistochemical analysis showed co-expression of LH receptor and CYP11B2. Conclusion: Our cases of untreated Klinefelter’s syndrome complicated with PA suggest that increased serum LH levels and adipose tissues, caused by primary hypogonadism, could contribute to PA development. The possible complication of PA in hypertensive patients with Klinefelter’s syndrome should be carefully considered.

OR34-03 Variable and Pulsatile Circulating Aldosterone Levels in Primary Aldosteronism: Implications for Diagnosis and Sub-Type Differentiation

Introduction: Considerable intra-individual variability in circulating aldosterone levels has been observed in patients with primary aldosteronism (PA). The magnitude and implications of this phenomenon are not well characterized. Objective: To evaluate the acute variability in aldosterone in patients with confirmed PA. Methods: 373 patients with confirmed PA underwent adrenal venous sampling (AVS) after appropriate catheterization of bilateral adrenal veins. Peripheral venous aldosterone levels were measured 2 hours prior to AVS while in supine posture. After anesthesia induction with fentanyl and midazolam, AVS was performed while in the same supine posture, and aldosterone levels were drawn from the inferior vena cava (IVC) and in triplicate from the bilateral adrenal veins over 10 minutes. Differences between the pre-AVS and intra-AVS IVC aldosterone levels were analyzed, and regression models used to identify independent predictors of change. Coefficients of variation (COV) between triplicate aldosterone levels in each adrenal vein were calculated. Results: 81% of patients demonstrated a decrease in aldosterone concentration from pre-AVS to the intra-AVS IVC measurement. The mean decrease in aldosterone was 10.5 ng/dL (95% CI: 7.6–13.3) and the mean relative decrease in aldosterone was 39% (95% CI: 27–51%, P<0.0001). The absolute decrease in aldosterone was striking, with 48% of patients who had a decrease in aldosterone exhibiting an IVC aldosterone of less than or equal to 5 ng/dL. The absolute decrease in aldosterone was significantly associated with a higher aldosterone level (p<0.001) and lower systolic blood pressure at diagnosis (p=0.02). A wide variation in triplicate aldosterone values was seen in the span of 10-minute sampling, ranging from 1–300%, with COV of 21.0% in the left adrenal vein and 25.0% in the right adrenal vein. If the lowest of three aldosterone-to-cortisol (A/C) ratios on the dominant side and highest of three A/C ratios on the contralateral side were used instead of the average of the three values, the interpretation of the AVS would have changed from unilateral PA to bilateral PA in 15.9% of cases. Conclusions: These findings underscore the pulsatile and variable nature of circulating aldosterone levels in patients with bona fide PA. Aldosterone levels substantially declined in 81% of patients within a period of 2 hours while maintaining a fixed and supine posture. In half of these patients, aldosterone levels declined to 5 ng/dL or below, a threshold typically considered incompatible with PA. Further, adrenal venous aldosterone levels exhibited large variations on repeated sampling within a 10-minute span that could have influenced the interpretation of sub-type differentiation in nearly 16% of cases. Single circulating aldosterone values lack precision and reproducibility and may result in incorrect diagnosis and sub-type differentiation.

OR34-04 Efficiency of Adrenal Venous Sampling in the Treatment Choice of Primary Aldosteronism (AVSTAT Study)

BACKGROUND: Adrenal venous sampling (AVS) is strongly recommended for a subtype diagnosis of primary aldosteronism (PA) if adrenalectomy (ADX) is desired by the patient. Given various issues related to AVS such as technical demand, invasive nature, expensive cost and radiation exposure, AVS is expected to lead efficiently to the subtype diagnosis and ADX. Aim: Primary objective was to assess the performance of AVS to determine treatment of PA by investigating the ratio of unilateral disease and rate of ADX following AVS in patients with unilateral disease. Methods: Sixteen major referral centers in ENS@T (n=10) and Japan (n=6) participated in the study. Study period was from 2006 to 2018. Data on total number of PA patients, AVS (total number and number of successful procedures), number of patients with unilateral diseases, and number of patients that underwent ADX were collected by a questionnaire-based survey. In addition, reasons for not proceeding to ADX in patients with a unilateral diagnosis were investigated. The diagnosis of PA was based on the positive case detection and at least one positive result in confirmatory testing. Results: Total number of confirmed PA patients and conducted AVS showed a dramatic increase during the past decade (PA: 1061 pts/ 2006–2011 to 3718 pts/ 2012–2018; AVS: 720/ 2006–2011 to 2448/ 2012–2018). Success rate of AVS was improved from 79.0% (2006–2011) to 92.5% (2012–2018). Both rate of unilateral PA and ADX of successful procedures decreased from 42.7% (2006–2011) to 37.3% (2012–2018) and from 40.8% (2006–2011) to 34.9% (2012–2018), respectively. Of the patients with successful AVS, bilateral disease was diagnosed in 63.5% (1812/2854 pts). Of the unilateral PA patients, 11.9% (125/ 1054 pts) were not subjected to ADX. The rate of the patients not subjected to ADX was significantly higher in Japan than in ENS@T centers both in patients with successful AVS (75.8% vs. 53.4%) and with unilateral disease (19.9% vs. 8.6%). Clinical decision against ADX in unilateral disease was made by the physicians in 33.3%, the patients in 33.3%, and both in 33.3%. Medical factors for Dr.’s decision against ADX in unilateral disease included good blood pressure control, normokalemia, comorbidities (e.g. DM, CKD), non-lateralized CT findings (e.g. no tumor, contralateral tumor), and discordant results among different criteria of AVS.Conclusions: High prevalence of bilateral disease and change of treatment policy after implementation affected the efficiency of AVS as an essential diagnostic procedure prior to ADX. Development of non-invasive procedures to exclude bilateral PA and more strict indication of AVS are warranted.

The Potential Role of Aldosterone-Producing Cell Clusters in Adrenal Disease.

Primary aldosteronism (PA) is the most common cause of secondary hypertension. The hallmark of PA is adrenal production of aldosterone under suppressed renin conditions. PA subtypes include adrenal unilateral and bilateral hyperaldosteronism. Considerable progress has been made in defining the role for somatic gene mutations in aldosterone-producing adenomas (APA) as the primary cause of unilateral PA. This includes the use of next-generation sequencing (NGS) to define recurrent somatic mutations in APA that disrupt calcium signaling, increase aldosterone synthase (CYP11B2) expression, and aldosterone production. The use of CYP11B2 immunohistochemistry on adrenal glands from normal subjects, patients with unilateral and bilateral PA has allowed the identification of CYP11B2-positive cell foci, termed aldosterone-producing cell clusters (APCC). APCC lie beneath the adrenal capsule and like APA, many APCC harbor somatic gene mutations known to increase aldosterone production. These findings suggest that APCC may play a role in pathologic progression of PA. Herein, we provide an update on recent research directed at characterizing APCC and also discuss the unanswered questions related to the role of APCC in PA.