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Background: It has been postulated that chronic kidney disease (CKD) is a state of relative 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) insufficiency, resulting in increased cortisol-mediated mineralocorticoid receptor (MR) activation. We hypothesized that relative 11βHSD2 insufficiency manifests across a wide spectrum of progressively declining kidney function, including within the normal range., Methods: Adult participants were recruited at two academic centers. A discovery cohort (n=500) enrolled individuals with estimated glomerular filtration rate (eGFR) ranging from normal to CKD stage 5, in whom serum cortisol-to-cortisone (F/E) was measured as a biomarker of 11βHSD2 activity. A validation cohort (n=101) enrolled only individuals with normal kidney function (eGFR ≥ 60 mL/min/1.73 m2) in whom 11βHSD2 activity was assessed via serum F/E and 11-hydroxy-to-11-keto androgen (11OH/K) ratios following multiple maneuvers: oral sodium suppression test (OSST), dexamethasone suppression test (DST), and ACTH-stimulation test (ACTHstim)., Results: In the discovery cohort, lower eGFR was associated with higher F/E (P-trend<0.001). Similarly, in the validation cohort, with normal eGFR, an inverse association between eGFR and both F/E and 11OH/K ratios was observed (P-trend<0.01), which persisted following DST (P-trend<0.001) and ACTHstim (P-trend< 0.05). The fractional excretion of potassium, a marker of renal MR activity, was higher with higher F/E (P-trend < 0.01) and with lower eGFR (P-trend<0.0001)., Conclusions: A continuum of declining 11βHSD2 activity was observed with progressively lower eGFR in individuals spanning a wide spectrum of kidney function, including those with apparently normal kidney function. These findings implicate cortisol-mediated MR activation in the pathophysiology of hypertension and cardiovascular disease in CKD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Importance: Mitotane (Lysodren, o,p'-DDD [1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane)] is currently the only United States Food and Drug Administration and European Medicines Agency-approved product for the treatment of adrenocortical carcinoma., Observations: Mitotane is challenging to administer; however, its toxicities (specifically adrenal insufficiency) are well known, and the management of adverse consequences has established approaches. While often viewed through the prism of a cytotoxic agent, it can also interfere with hormone production making it a valuable asset in managing functional ACC. A recently completed prospective trial has shed some light on its use in the adjuvant setting, but further clarity is needed. Many think mitotane has a role in the advanced or metastatic setting, although prospective data are lacking and retrospective analyses are often difficult to interpret., Conclusions and Relevance: When used carefully and thoughtfully, especially in patients with hormonal excess, mitotane is an important component of the treatment armamentarium for ACC., (Published by Oxford University Press 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Context: Primary aldosteronism is a form of low-renin hypertension characterized by dysregulated aldosterone production., Objective: To investigate the contributions of renin-independent aldosteronism and ACTH-mediated aldosteronism in individuals with a low-renin phenotype representing the entire continuum of blood pressure., Design/participants: Human physiology study of 348 participants with a low-renin phenotype with severe and/or resistant hypertension, hypertension with hypokalemia, elevated blood pressure and stage I/II hypertension, and normal blood pressure., Setting: 4 international centers., Interventions/main Outcome Measures: The saline suppression test (SST) to quantify the magnitude of renin-independent aldosteronism; dexamethasone suppression and ACTH-stimulation tests to quantify the magnitude of ACTH-mediated aldosteronism; adrenal venous sampling to determine lateralization., Results: There was a continuum of nonsuppressible and renin-independent aldosterone production following SST that paralleled the magnitude of the blood pressure continuum and transcended conventional diagnostic thresholds. In parallel, there was a full continuum of ACTH-mediated aldosteronism wherein post-SST aldosterone levels were strongly correlated with ACTH-stimulated aldosterone production (r = 0.75, P < .0001) and nonsuppressible aldosterone production postdexamethasone (r = 0.40, P < .0001). Beyond participants who met the criteria for primary aldosteronism (post-SST aldosterone of ≥10 ng/dL or ≥277 pmol/L), the continuum of nonsuppressible and renin-independent aldosterone production persisted below this diagnostic threshold, wherein 15% still had lateralizing aldosteronism amenable to surgical adrenalectomy and the remainder were treated with mineralocorticoid receptor antagonists., Conclusion: In the context of a low-renin phenotype, there is a continuum of primary aldosteronism and dysregulated aldosterone production that is prominently influenced by ACTH. A large proportion of individuals with low renin may benefit from aldosterone-directed therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Extracellular calcium critically regulates physiologic aldosterone production. Moreover, abnormal calcium flux and signaling are involved in the pathogenesis of the majority of primary aldosteronism cases., Methods: We investigated the influence of the saline suppression test (SST) on calcium homeostasis in prospectively recruited participants (n = 86)., Results: During SST, 100% of participants had decreases in serum calcium, with 48% developing frank hypocalcemia. Serum calcium declined from 2.30 ± 0.08 mmol/L to 2.13 ± 0.08 mmol/L (P < .001) with parallel increases in parathyroid hormone from 6.06 ± 2.39 pmol/L to 8.13 ± 2.42 pmol/L (P < .001). In contrast, serum potassium and bicarbonate did not change, whereas eGFR increased and serum glucose decreased (P < .001). Lower body surface area (translating to greater effective circulating volume expansion during SST) was associated with greater reductions in (β = .33, P = .001), and absolutely lower, serum calcium levels (β = .25, P = .001). When evaluating clinically-relevant diagnostic thresholds, participants with post-SST aldosterone levels <138 pmol/L had lower post-SST calcium and 25-hydroxyvitamin D levels (P < .05), and higher post-SST parathyroid hormone levels (P < .05) compared with those with post-SST aldosterone levels >277 pmol/L., Conclusion: SST uniformly decreases serum calcium, which is likely to be due to the combination of variable dilution, increased renal clearance, and vitamin D status. These acute reductions in bioavailable calcium are associated with lower post-SST aldosterone. Given the critical role of extracellular calcium in regulating aldosterone production, these findings warrant renewed inquiry into the validity of SST interpretations for excluding primary aldosteronism., Competing Interests: Conflict of interest: JMB reports consulting fees unrelated to the contents of this work from Bayer and Astra Zeneca. AV reports consulting fees unrelated to the contents of this work from Corcept Therapeutics, Mineralys, HRA Pharma., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Glucocorticoids are widely prescribed as anti-inflammatory and immunosuppressive agents. This results in at least 1% of the population using chronic glucocorticoid therapy, being at risk for glucocorticoid-induced adrenal insufficiency. This risk is dependent on the dose, duration and potency of the glucocorticoid, route of administration, and individual susceptibility. Once glucocorticoid-induced adrenal insufficiency develops or is suspected, it necessitates careful education and management of affected patients. Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency. In general, tapering of glucocorticoids can be more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing. The degree and persistence of HPA axis suppression after cessation of glucocorticoid therapy are dependent on overall exposure and recovery of adrenal function varies greatly amongst individuals. This first European Society of Endocrinology/Endocrine Society joint clinical practice guideline provides guidance on this clinically relevant condition to aid clinicians involved in the care of patients on chronic glucocorticoid therapy., (This article has been co-published with permission in The Journal of Clinical Endocrinology & Metabolism and European Journal of Endocrinology. © The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Primary aldosteronism (PA) is an endocrinopathy characterized by dysregulated aldosterone production that occurs despite suppression of renin and angiotensin II, and that is non-suppressible by volume and sodium loading. The effectiveness of surgical adrenalectomy for patients with lateralizing PA is characterized by the attenuation of excess aldosterone production leading to blood pressure reduction, correction of hypokalemia, and increases in renin-biomarkers that collectively indicate a reversal of PA pathophysiology and restoration of normal physiology. Even though the vast majority of patients with PA will ultimately be treated medically rather than surgically, there is a lack of guidance on how to optimize medical therapy and on key metrics of success. Herein, we review the evidence justifying approaches to medical management of PA and biomarkers that reflect endocrine principles of restoring normal physiology. We review the current arsenal of medical therapies, including dietary sodium restriction, steroidal and nonsteroidal mineralocorticoid receptor antagonists, epithelial sodium channel inhibitors, and aldosterone synthase inhibitors. It is crucial that clinicians recognize that multimodal medical treatment for PA can be highly effective at reducing the risk for adverse cardiovascular and kidney outcomes when titrated with intention. The key biomarkers reflective of optimized medical therapy are unsurprisingly similar to the physiologic expectations following surgical adrenalectomy: control of blood pressure with the fewest number of antihypertensive agents, normalization of serum potassium without supplementation, and a rise in renin. Pragmatic approaches to achieve these objectives while mitigating adverse effects are reviewed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Mineralocorticoid receptor antagonists (MRAs) are often empirically used for patients with low-renin hypertension (LRH) or probable primary aldosteronism (PA) who decline surgery. However, the optimal approach to MRA therapy is unknown. Studies have shown that a rise in renin is an effective biomarker of prevention of cardiovascular complications of PA. This study aimed to determine whether empiric MRA therapy in patients with LRH or probable PA targeting unsuppressed renin is associated with a decrease in blood pressure and/or proteinuria., Methods: Retrospective single-center cohort study from 2005 to 2021 included adults with LRH or probable PA (renin activity <1.0 ng/ml/h and detectable aldosterone levels). All patients were empirically treated with an MRA, targeting renin ≥1.0 ng/ml/h., Results: Out of 39 patients studied, 32 (82.1%) achieved unsuppressed renin. Systolic and diastolic blood pressure decreased from 148.0 and 81.2 to 125.8 and 71.6 mm Hg, respectively (P < 0.001 for both). Similar blood pressure reductions were seen whether patients had high (>10 ng/dl) or low (<10 ng/dl) aldosterone levels. The majority (24/39; 61.5%) of patients had at least one baseline anti-hypertensive medication stopped. Among the six patients who had detectable proteinuria and albumin-to-creatinine (ACR) measurements post-treatment, the mean ACR decreased from 179.0 to 36.1 mg/g (P = 0.03). None of the patients studied had to completely stop treatment due to adverse reactions., Conclusions: Empiric MRA therapy in patients with LRH or probable PA targeting unsuppressed renin can safely and effectively improve blood pressure control and reduce proteinuria., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)

Background: Hypertension plus obstructive sleep apnea (OSA) is recommended in some guidelines as an indication to screen for primary aldosteronism (PA), yet prior data has brought the validity of this recommendation into question. Given this context, it remains unknown whether this screening recommendation is being implemented into clinical practice., Methods: We conducted a population-based retrospective cohort study of all adult Ontario (Canada) residents with hypertension plus OSA from 2009 to 2020 with follow-up through 2021 utilizing provincial health administrative data. We measured the proportion of individuals who underwent PA screening via the aldosterone-to-renin ratio by year. We further examined screening rates among patients with hypertension plus OSA by the presence of concurrent hypokalemia and resistant hypertension. Clinical predictors associated with screening were assessed via Cox regression modeling., Results: The study cohort included 53,130 adults with both hypertension and OSA, of which only 634 (1.2%) underwent PA screening. Among patients with hypertension, OSA, and hypokalemia, the proportion of eligible patients screened increased to 2.8%. Among patients ≥65 years with hypertension, OSA, and prescription of ≥4 antihypertensive medications, the proportion of eligible patients screened was 1.8%. Older age was associated with a decreased likelihood of screening while hypokalemia and subspecialty care with internal medicine, cardiology, endocrinology, or nephrology were associated with an increased likelihood of screening. No associations with screening were identified with sex, rural residence, cardiovascular disease, diabetes, or respirology subspecialty care., Conclusions: The population-level uptake of the guideline recommendation to screen all patients with hypertension plus OSA for PA is exceedingly low., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We are witnessing a revolution in our understanding of primary aldosteronism (PA). In the past 2 decades, we have learned that PA is a highly prevalent syndrome that is largely attributable to pathogenic somatic mutations, that contributes to cardiovascular, metabolic, and kidney disease, and that when recognized, can be adequately treated with widely available mineralocorticoid receptor antagonists and/or surgical adrenalectomy. Unfortunately, PA is rarely diagnosed, or adequately treated, mainly because of a lack of awareness and education. Most clinicians still possess an outdated understanding of PA; from primary care physicians to hypertension specialists, there is an urgent need to redefine and reintroduce PA to clinicians with a modern and practical approach. In this state-of-the-art review, we provide readers with the most updated knowledge on the pathogenesis, prevalence, diagnosis, and treatment of PA. In particular, we underscore the public health importance of promptly recognizing and treating PA and provide pragmatic solutions to modify clinical practices to achieve this., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Randomized controlled trials have demonstrated the efficacy of mineralocorticoid receptor (MR) antagonism in delaying chronic kidney disease (CKD) progression in diabetes; however, they have not investigated the role of aldosterone or whether these beneficial effects could be achieved in individuals without diabetes., Methods and Results: The association between serum aldosterone concentrations and kidney disease progression was investigated among 3680 participants in the Chronic Renal Insufficiency Cohort. The primary outcome was CKD progression [defined as the composite of 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, whichever occurred first]. The associations between serum aldosterone and kidney disease outcomes were assessed using Cox proportional hazard models. At baseline, higher aldosterone concentrations were associated with a lower eGFR, lower serum potassium, greater urinary potassium, and protein excretion. Over a median follow-up of 9.6 years, 1412 participants developed CKD progression. In adjusted models, each doubling of serum aldosterone was associated with a 11% increased risk of CKD progression [hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.04-1.18]. Individuals with the highest quartile of serum aldosterone had a 45% increased risk of CKD progression (HR 1.45, 95% CI 1.22-1.73) compared with the lowest quartile. The risk for CKD progression was similar regardless of whether patients had concomitant diabetes (P-interaction = 0.10)., Conclusion: Higher serum aldosterone levels among individuals with CKD are independently associated with an increased risk for kidney disease progression, irrespective of concomitant diabetes. These findings provide mechanistic support for MR antagonists in delaying CKD progression and suggest that they may also have a role in those without diabetes., Competing Interests: Conflict of interest: An.V. reports consulting fees unrelated to the contents of this work from Corcept Therapeutics, Mineralys, HRA Pharma. S.S.W. reports consulting fees unrelated to the contents of this work from BioMarin, GSK, Bain Capital, and Metro Biotechnology. As.V. has no financial disclosure., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Urinary bladder paraganglioma (UBPGL) is rare., Objective: We aimed to characterize the presentation and outcomes of patients diagnosed with UBPGL., Methods: We conducted a multicenter study of consecutive patients with pathologically confirmed UBPGL evaluated between 1971 and 2021. Outcomes included repeat bladder surgery, metastases, and disease-specific mortality., Results: Patients (n=110 total; n=56 [51%] women) were diagnosed with UBPGL at a median age of 50 years (interquartile range [IQR], 36-61 years). Median tumor size was 2 cm (IQR, 1-4 cm). UBPGL was diagnosed prior to biopsy in only 37 (34%), and only 69 (63%) patients had evaluation for catecholamine excess. In addition to the initial bladder surgery, 26 (25%) required multiple therapies, including repeat surgery in 10 (9%). Synchronous metastases were present in 9 (8%) patients, and 24 (22%) other patients with UBPGL developed metachronous metastases at a median of 4 years (IQR, 2-10 years) after the initial diagnosis. Development of metachronous metastases was associated with younger age (hazard ratio [HR] 0.97; 95% CI, 0.94-0.99), UBPGL size (HR 1.69; 95% CI, 1.31-2.17), and a higher degree of catecholamine excess (HR 5.48; 95% CI, 1.40-21.39). Disease-specific mortality was higher in patients with synchronous metastases (HR 20.80; 95% CI, 1.30-332.91). Choice of initial surgery, genetic association, sex, or presence of muscular involvement on pathology were not associated with development of metastases or mortality., Conclusions: Only a minority of patients were diagnosed before biopsy/surgery, reflecting need for better diagnostic strategies. All patients with UBPGL should have lifelong monitoring for development of recurrence and metastases., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Normal-appearing adrenal glands on cross-sectional imaging may still be the source of aldosterone production in primary aldosteronism (PA)., Methods: We evaluated the prevalence of aldosterone production among morphologically normal-appearing adrenal glands and the impact of this phenomenon on interpretations of localization studies and treatment decisions. We performed a retrospective cohort study of PA patients with at least 1 normal adrenal gland and reanalyzed contemporary studies to assess interpretations of imaging and adrenal venous sampling (AVS) at the individual patient and adrenal levels., Results: Among 243 patients, 43 (18%) had bilateral normal-appearing adrenals and 200 (82%) had a unilateral normal-appearing adrenal, for a total of 286 normal-appearing adrenal glands. 38% of these normal-appearing adrenal glands were a source of aldosteronism on AVS, resulting in discordance between imaging and AVS findings in 31% of patients. Most patients with lateralizing PA underwent curative unilateral treatment (80%); however, curative treatment was pursued in 92% of patients who had concordant imaging-AVS results but in only 38% who had discordant results (P < 0.05). In young patients, imaging-AVS discordance was detected in 32% of those under 45 years and 21% of those under 35 years. Among 20 contemporary studies (including 4,904 patients and 6,934 normal-appearing adrenal glands), up to 64% of normal-appearing adrenals were a source of aldosteronism resulting in 31% of patients having discordant results., Conclusions: Morphologically normal-appearing adrenal glands are commonly the source of aldosterone production in PA, even among young patients. The lack of awareness of this issue may result in inappropriate treatment recommendations., (© American Journal of Hypertension, Ltd 2021. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Context: Current evidence on determinants of quality of life (QoL) in patients with adrenal insufficiency (AI) is limited., Objective: This work aimed to identify the determinants of QoL in different subtypes of AI., Methods: This multicenter cross-sectional survey study was conducted using a patient-centered questionnaire, the Short Form-36., Results: Of 529 participants, 223 (42.2%) had primary AI, 190 (35.9%) had secondary AI, and 116 (21.9%) had glucocorticoid-induced AI. Median age was 58 years (interquartile range: 43-68 years) and 342 (64.8%) were women. In multivariable analyses, patients were more likely to report worse physical scores if they were women (odds ratio [OR]: 3.3; 95% CI, 1.8-6.0), had secondary AI or glucocorticoid-induced AI (OR: 2.5; 95% CI, 1.4-4.3), had shorter duration of AI (OR: 2.0; 95% CI, 1.1-3.6), were treated with more than 25 mg hydrocortisone equivalent daily (OR: 2.3; 95% CI, 1.2-4.6), had more comorbidities related to glucocorticoid excess (OR: 2.3; 95% CI, 1.3-4.0), reported a higher financial burden from AI (OR: 2.1; 95% CI, 1.3-3.6), and reported difficulties with AI management (OR: 2.5; 95% CI, 1.2-5.2). Women (OR: 2.1; 95% CI, 1.08-4.0), shorter duration of AI (OR: 2.4; 95% CI, 1.4-4.3), higher financial burden (OR: 2.3; 95% CI, 1.3-4.0), difficulties with AI management (OR: 2.6; 95% CI, 1.4-4.9), and lack of family support (OR: 9.1; 95% CI, 2.3-33.3) were associated with worse mental component scores., Conclusion: In patients with AI, QoL could be improved by addressing certain determinants, such as avoiding GC overreplacement, providing in-depth education on self-management, offering more comprehensive insurance coverage, and ensuring better family support., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Incidentally discovered adrenal adenomas are common. Assessment for possible autonomous cortisol excess (ACS) is warranted for all adrenal adenomas, given the association with increased cardiometabolic disease., Objective: To evaluate the discriminatory capacity of 3-dimensional volumetry on computed tomography (CT) to identify ACS., Methods: Two radiologists, blinded to hormonal levels, prospectively analyzed CT images of 149 adult patients with unilateral, incidentally discovered, adrenal adenomas. Diameter and volumetry of the adenoma, volumetry of the contralateral adrenal gland, and the adenoma volume-to-contralateral gland volume (AV/CV) ratio were measured. ACS was defined as cortisol ≥ 1.8 mcg/dL after 1-mg dexamethasone suppression test (DST) and a morning ACTH ≤ 15. pg/mL., Results: We observed that ACS was diagnosed in 35 (23.4%) patients. Cortisol post-DST was positively correlated with adenoma diameter and volume, and inversely correlated with contralateral adrenal gland volume. Cortisol post-DST was positively correlated with the AV/CV ratio (r = 0.46, P < 0.001) and ACTH was inversely correlated (r = -0.28, P < 0.001). The AV/CV ratio displayed the highest odds ratio (1.40; 95% CI, 1.18-1.65) and area under curve (0.91; 95% CI, 0.86-0.96) for predicting ACS. An AV/CV ratio ≥ 1 (48% of the cohort) had a sensitivity of 97% and a specificity of 70% to identify ACS., Conclusion: CT volumetry of adrenal adenomas and contralateral adrenal glands has a high discriminatory capacity to identify ACS. The combination of this simple and low-cost radiological phenotyping can supplement biochemical testing to substantially improve the identification of ACS., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: The role of cytoreduction of adrenocortical carcinoma (ACC) remains poorly understood., Objective: To analyze the impact of cytoreductive surgery of the primary tumor in patients with metastatic ACC., Design and Setting: We performed a multicentric, retrospective paired cohort study comparing the overall survival (OS) in patients with metastatic ACC who were treated either with cytoreductive surgery (CR group) or without cytoreductive surgery (no-CR group) of the primary tumor. Data were retrieved from 9 referral centers in the American-Australian-Asian Adrenal Alliance collaborative research group., Patients: Patients aged ≥18 years with metastatic ACC at initial presentation who were treated between January 1, 1995, and May 31, 2019., Intervention: Performance (or not) of cytoreductive surgery of the primary tumor., Main Outcome and Measures: A propensity score match was done using age and the number of organs with metastasis (≤2 or >2). The main outcome was OS, determined from the date of diagnosis until death or until last follow-up for living patients., Results: Of 339 patients pooled, 239 were paired and included: 128 in the CR group and 111 in the no-CR group. The mean follow-up was 67 months. Patients in the no-CR group had greater risk of death than did patients in the CR group (hazard ratio [HR] = 3.18; 95% CI, 2.34-4.32). Independent predictors of survival included age (HR = 1.02; 95% CI, 1.00-1.03), hormone excess (HR = 2.56; 95% CI, 1.66-3.92), and local metastasis therapy (HR = 0.41; 95% CI, 0.47-0.65)., Conclusion: Cytoreductive surgery of the primary tumor in patients with metastatic ACC is associated with prolonged survival., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: The COVID-19 pandemic has impacted healthcare environment., Objective: To determine the impact of the pandemic on self-reported outcomes in patients with adrenal insufficiency (AI)., Design and Setting: Prospective longitudinal survey study at 2 tertiary centers., Participants: Patients with AI., Intervention: Patient-centered questionnaire., Main Outcome Measures: Depression Anxiety Stress Scales-21, Short Form-36, and AI self-management., Results: Of 342 patients, 157 (46%) had primary AI, 109 (32%) had secondary AI, and 76 (22%) had glucocorticoid-induced AI. When compared to prepandemic, daily glucocorticoid dose and number of adrenal crises did not change. However, patients reported a higher financial impact from AI (34% vs 23%, P = 0.006) and difficulty accessing medical care (31% vs 7%, P < 0.0001) during the pandemic. A third of patients reported difficulty managing AI during the pandemic. After adjusting for duration and subtypes of AI, younger patients [odds ratio (OR) 2.3, CI 95% 1.3-4.1], women (OR 3.7, CI 95% 1.9-7.1), poor healthcare access(OR 4.2, CI 95% 2.3-7.7), lack of good insurance support (OR 2.8, CI 95% 1.3-5.9), and those with a higher financial impact (OR 2.3, CI 95% 1.3-4.3) reported greater difficulties managing AI. Patients were more likely to report a higher anxiety score (≥8) if they found managing AI challenging during the pandemic (OR 3.0, CI 95% 1.3-6.9), and had lower Physical Component Summary (OR 4.9, CI 95% 2.2-11.0) and Mental Component Summary (OR 4.1, CI 95% 1.8-9.5) scores prior to the pandemic., Conclusions: A third of patients with AI reported difficulties with management of AI during the pandemic, particularly in younger patients, women, and those with poor healthcare access., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Current evidence on determinants of adverse health outcomes in patients with adrenal insufficiency (AI) is scarce, especially in regards to AI subtypes., Objective: To determine predictors of adverse outcomes in different subtypes of AI., Design and Setting: Cross-sectional survey study at 2 tertiary centers., Participants: A total of 696 patients with AI: primary AI (PAI, 42%), secondary AI (SAI, 32%), and glucocorticoid-induced AI (GIAI, 26%)., Intervention: Patient-centered questionnaire., Main Outcome Measures: Patients' knowledge, self-management of AI, self-perceived health, and adverse outcomes., Results: The incidence rate of adrenal crisis was 24/100 patient-years with 44% experiencing at least 1 adrenal crisis since diagnosis (59% in PAI vs 31% in SAI vs 37% in GIAI, P < .0001). All patients described high degrees of discomfort with self-management and receiving prompt treatment. Patients with PAI were most likely to develop adrenal crises (adjusted OR 2.8, 95% CI 1.9-4.0) despite reporting better self-perceived health (adjusted OR 3.3, 95% CI 2.1-5.3), understanding of their diagnosis (89% vs 74-81% in other subtypes, P = .002), higher comfort with self-management (62% vs 52-61% in other sub types, P = .005), and higher likelihood to receive prompt treatment for adrenal crises in the emergency department (42% vs 19-30% in other subtypes, P < .0001)., Conclusions: Patients with AI reported high degrees of discomfort with self-management and treatment delays when presenting with adrenal crises. Despite better self-perceived health and understanding of diagnosis, patients with PAI experienced the highest frequency of adrenal crises. A multidimensional educational effort is needed for patients and providers to improve the outcomes of all subtypes of AI., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Variability of aldosterone concentrations has been described in patients with primary aldosteronism., Methods: We performed a retrospective cohort study of 340 patients with primary aldosteronism who underwent adrenal venous sampling (AVS) at a tertiary referral center, 116 of whom also had a peripheral venous aldosterone measured hours before the procedure. AVS was performed by the same interventional radiologist using bilateral, simultaneous sampling, under unstimulated and then stimulated conditions, and each sample was obtained in triplicate. Main outcome measures were: (i) change in day of AVS venous aldosterone from pre-AVS to intra-AVS and (ii) variability of triplicate adrenal venous aldosterone concentrations during AVS., Results: Within an average duration of 131 minutes, 81% of patients had a decline in circulating aldosterone concentrations (relative decrease of 51% and median decrease of 7.0 ng/dl). More than a quarter (26%) of all patients had an inferior vena cava aldosterone of ≤5 ng/dl at AVS initiation. The mean coefficient of variation of triplicate adrenal aldosterone concentrations was 30% and 39%, in the left and right veins, respectively (corresponding to a percentage difference of 57% and 73%), resulting in lateralization discordance in up to 17% of patients if the lateralization index were calculated using only one unstimulated aldosterone-to-cortisol ratio rather than the average of triplicate measures., Conclusions: Circulating aldosterone levels can reach nadirs conventionally considered incompatible with the primary aldosteronism diagnosis, and adrenal venous aldosterone concentrations exhibit acute variability that can confound AVS interpretation. A single venous aldosterone measurement lacks precision and reproducibility in primary aldosteronism., (© American Journal of Hypertension, Ltd 2020. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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.

Context: New approaches are needed to address the evolution of the primary aldosteronism syndrome and to increase its recognition. Herein, we review evidence indicating that primary aldosteronism is a prevalent syndrome that is mostly unrecognized, and present a pragmatic and pathophysiology-based approach to improve diagnosis and treatment., Methods: Evidence was gathered from published guidelines and studies identified from PubMed by searching for primary aldosteronism, aldosterone, renin, and hypertension. This evidence was supplemented by the authors' personal knowledge, research experience, and clinical encounters in primary aldosteronism., Interpretation of Evidence: Renin-independent aldosterone production is a prevalent phenotype that is diagnosed as primary aldosteronism when severe in magnitude, but is largely unrecognized when milder in severity. Renin-independent aldosterone production can be detected in normotensive and hypertensive individuals, and the magnitude of this biochemical phenotype parallels the magnitude of blood pressure elevation, the risk for incident hypertension and cardiovascular disease, and the likelihood and magnitude of blood pressure reduction with mineralocorticoid receptor antagonist therapy. Expansion of the indications to screen for primary aldosteronism, combined with the use of a pathophysiology-based approach that emphasizes inappropriate aldosterone production in the context of renin suppression, will substantially increase the diagnostic and therapeutic yields for primary aldosteronism., Conclusions: The landscape of primary aldosteronism has evolved to recognize that it is a prevalent syndrome of renin-independent aldosterone production that contributes to the pathogenesis of hypertension and cardiovascular disease. Expanding screening indications and simplifying the diagnostic approach will enable implementation of targeted treatment for primary aldosteronism., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Complex relationships between aldosterone and calcium homeostasis have been proposed., Objective: To disentangle the influence of aldosterone and intravascular volume on calcium physiology., Design: Patient-oriented and epidemiology studies., Setting: Clinical research center and nationwide cohorts., Participants/interventions: Patient-oriented study (n = 18): Participants were evaluated after completing a sodium-restricted (RES) diet to contract intravascular volume and after a liberalized-sodium (LIB) diet to expand intravascular volume. Cross-sectional studies (n = 3755): the association between 24h urinary sodium and calcium excretion and risk for kidney stones was assessed., Results: Patient-oriented study: compared to a RES-diet, a LIB-diet suppressed renin activity (LIB: 0.3 [0.1, 0.4] vs. RES: 3.1 [1.7, 5.3] ng/mL/h; P < 0.001) and plasma aldosterone (LIB: 2.0 [2.0, 2.7] vs. RES: 20.0 [16.1, 31.0] vs. ng/dL; P < 0.001), but increased calciuria (LIB: 238.4 ± 112.3 vs. RES: 112.9 ± 60.8 mg/24hr; P < 0.0001) and decreased serum calcium (LIB: 8.9 ± 0.3 vs. RES: 9.8 ± 0.4 mg/dL; P < 0.0001). Epidemiology study: mean urinary calcium excretion was higher with greater urinary sodium excretion. Compared to a urinary sodium excretion of < 120 mEq/day, a urinary sodium excretion of ≥220 mEq/day was associated with a higher risk for having kidney stones in women (risk ratio = 1.79 [95% confidence interval 1.05, 3.04]) and men (risk ratio = 2.06 [95% confidence interval 1.27, 3.32])., Conclusions: High dietary sodium intake suppresses aldosterone, decreases serum calcium, and increases calciuria and the risk for developing kidney stones. Our findings help disentangle the influences of volume from aldosterone on calcium homeostasis and provide support for the recommendation to restrict dietary sodium for kidney stone prevention., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Classical epidemiology has focused on the control of confounding, but it is only recently that epidemiologists have started to focus on the bias produced by colliders. A collider for a certain pair of variables (e.g. an outcome Y and an exposure A) is a third variable (C) that is caused by both. In a directed acyclic graph (DAG), a collider is the variable in the middle of an inverted fork (i.e. the variable C in A → C ← Y). Controlling for, or conditioning an analysis on a collider (i.e. through stratification or regression) can introduce a spurious association between its causes. This potentially explains many paradoxical findings in the medical literature, where established risk factors for a particular outcome appear protective. We use an example from non-communicable disease epidemiology to contextualize and explain the effect of conditioning on a collider. We generate a dataset with 1000 observations, and run Monte-Carlo simulations to estimate the effect of 24-h dietary sodium intake on systolic blood pressure, controlling for age, which acts as a confounder, and 24-h urinary protein excretion, which acts as a collider. We illustrate how adding a collider to a regression model introduces bias. Thus, to prevent paradoxical associations, epidemiologists estimating causal effects should be wary of conditioning on colliders. We provide R code in easy-to-read boxes throughout the manuscript, and a GitHub repository [https://github.com/migariane/ColliderApp] for the reader to reproduce our example. We also provide an educational web application allowing real-time interaction to visualize the paradoxical effect of conditioning on a collider [http://watzilei.com/shiny/collider/]., (© The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Context: Classical apparent mineralocorticoid excess (AME) is a rare recessive disorder, caused by severe 11β-hydroxysteroid dehydrogenase type 2 enzyme (11β-HSD2) deficiency. AME manifests as low-renin pediatric hypertension, hypokalemia and high cortisol/cortisone (F/E) ratio., Objective: To evaluate nonclassic AME (NC-AME) due to partial 11β-HSD2 insufficiency and its association with hypertension, mineralocorticoid receptor (MR) activation, and inflammatory parameters., Design: Cross-sectional study., Setting: Primary care cohort., Participants: We recruited 127 adolescents and adults. Subjects with secondary hypertension were excluded. We measured clinical, biochemical, renal, vascular, and inflammatory variables. Sequencing of HSD11B2 gene was performed in all subjects., Main Outcome Measure: NC-AME., Results: Serum F/E ratio was positively associated with systolic blood pressure (BP), microalbuminuria, and high-sensitivity C-reactive protein (hs-CRP). Serum cortisone correlated with MR activation parameters even when adjusted for age, body mass index, and sex: lower cortisone with higher potassium excretion (partial r = -0.29, P = 0.002) and with lower plasma renin activity (PRA) (partial r = 0.29, P = 0.001). Consistently, we identified 9 in 127 subjects (7.1%) with high F/E ratios (first quartile) and low cortisone (last quartile), suggestive of NC-AME. These subjects had higher systolic BP, 141.4 ± 25.7 mm Hg vs 127.3 ± 18.1 mm Hg, P = 0.03; lower PRA, 0.36 ± 0.19 ng/L*s vs 0.64 ± 0.47 ng/L*s, P < 0.0001; and greater potassium excretion, microalbuminuria, hs-CRP, and plasminogen activator inhibitor. We only found in 2 out of 9 subjects with NC-AME heterozygous mutations in the HSD11B2 gene., Conclusions: These findings suggest a spectrum of partial 11β-HSD2 insufficiency in a primary care cohort without the classic phenotype and genotype of AME. NC-AME may represent a phenotype of MR activation and cardiovascular risk, suggesting that these subjects could be treated with MR antagonists.

Background: Higher fibroblast growth factor-23 (FGF23) concentrations have been found to be associated with incident heart failure (HF). Experimental data suggest FGF23 directly stimulates myocardial hypertrophy. FGF23 may also enhance renin-angiotensin-aldosterone system activity. Whether FGF23 is associated with increased HF risk in populations with hypertension and whether this association is weaker in the presence of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy is unknown., Methods: We studied 2,858 adults with hypertension free of cardiovascular disease at baseline (65.6 ± 9.5 years, 46.2% male) participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We investigated the association of baseline serum intact FGF23 with incident HF over a 14-year median follow-up and whether ACEI/ARB therapy modified this risk. We also investigated the relationship of FGF23 with aldosterone and plasma renin activity in a random subgroup of the entire MESA cohort with available assays (N = 1,642)., Results: In adjusted Cox regression models, higher FGF23 was associated with a 63% greater hazard of incident HF (hazard ratio: 1.63, 95% confidence interval: [1.13-2.36] per 1-unit increase in log-transformed FGF23), which persisted after exclusion of participants with chronic kidney disease (hazard ratio: 1.94 [1.10-3.43]). There was no heterogeneity by ACEI/ARB use (Pinteraction = 0.438). FGF23 improved model fit over covariables (likelihood ratio χ2 = 6.67, P = 0.010). In multivariable linear regression models, there was no association between FGF23 and aldosterone or plasma renin activity., Conclusions: Higher FGF23 concentrations are associated with a significantly increased risk of HF in hypertension but this risk did not differ by ACEI/ARB treatment status. FGF23 may be a useful biomarker for HF risk in hypertensive populations.

Primary aldosteronism is characterized by aldosterone secretion that is independent of renin and angiotensin II and sodium status. The deleterious effects of primary aldosteronism are mediated by excessive activation of the mineralocorticoid receptor that results in the well-known consequences of volume expansion, hypertension, hypokalemia, and metabolic alkalosis, but it also increases the risk for cardiovascular and kidney disease, as well as death. For decades, the approaches to defining, diagnosing, and treating primary aldosteronism have been relatively constant and generally focused on detecting and treating the more severe presentations of the disease. However, emerging evidence suggests that the prevalence of primary aldosteronism is much greater than previously recognized, and that milder and nonclassical forms of renin-independent aldosterone secretion that impart heightened cardiovascular risk may be common. Public health efforts to prevent aldosterone-mediated end-organ disease will require improved capabilities to diagnose all forms of primary aldosteronism while optimizing the treatment approaches such that the excess risk for cardiovascular and kidney disease is adequately mitigated. In this review, we present a physiologic approach to considering the diagnosis, pathogenesis, and treatment of primary aldosteronism. We review evidence suggesting that primary aldosteronism manifests across a wide spectrum of severity, ranging from mild to overt, that correlates with cardiovascular risk. Furthermore, we review emerging evidence from genetic studies that begin to provide a theoretical explanation for the pathogenesis of primary aldosteronism and a link to its phenotypic severity spectrum and prevalence. Finally, we review human studies that provide insights into the optimal approach toward the treatment of primary aldosteronism.

Objective: Germline loss-of-function mutations in succinate dehydrogenase ( SDHx ) genes results in rare tumor syndromes that include pheochromocytoma, paraganglioma, and others. Here we report a case series of patients with adrenocortical carcinoma (ACC) that harbor SDHx mutations., Patients and Results: We report four unrelated patients with ACC and SDHx mutations. All cases presented with Cushing syndrome and large adrenal masses that were confirmed to be ACC on pathology. All four ACC specimens were found to have truncating mutations in either SDHC or SDHA , while cases 1, 2 and 3 also had the mutations confirmed in the germline: Case 1: SDHC c.397C > T, pR133X; Case 2: SDHC c.43C > T, p.R15X; Case 3: SDHA c.91C > T, p.R31X; Case 4: SDHA c.1258C > T, p.Q420X. Notably, Case 1 had a father and daughter who both harbored the same SDHC germline mutation, and the father had a paraganglioma and renal cell carcinoma. A combination of next generation sequencing, and/or immunohistochemistry, and/or mass spectroscopy was used to determine whether there was loss of heterozygosity and/or loss of SDH protein expression or function within the ACC. Potential evidence of loss of heterozygosity was observed only in Case 2., Conclusions: We observed truncating mutations in SDHA or SDHC in the ACC and/or germline of four unrelated patients. Given how statistically improbable the concurrence of ACC and pathogenic germline SDHx mutations is expected to be, these observations raise the question whether ACC may be a rare manifestation of SDHx mutation syndromes. Further studies are needed to investigate the possible role of SDH deficiency in ACC pathogenesis., (© 2017 European Society of Endocrinology.)

Context: Whether primary aldosteronism (PA) is the consequence of a monoclonal or multiclonal process is unclear., Case Description: A 48-year-old man with severe bilateral PA refractory to medical therapy underwent unilateral adrenalectomy of the dominant adrenal. Although computed tomography showed three left-sided cortical nodules, postsurgical histopathology and genetic analysis revealed five different adrenocortical adenomas. Two zona fasciculata (ZF)-like aldosterone-producing adenomas (APAs) each harbored distinct known somatic KCNJ5 mutations (L168R and T158A). A zona glomerulosa-like APA harbored a known CACNA1D G403R somatic mutation, whereas a zona reticularis-like adenoma, which was grossly black in pigmentation with histologic characteristics more associated with cortisol-producing adenomas, expressed CYP11B2, CYP17, and DHEA-ST by immunohistochemistry (IHC) and harbored no known somatic mutations. The fifth adenoma was ZF-type, negative for CYP11B2 and CYP17 IHC, and harbored no known somatic mutations., Conclusions: This case highlights complex intertumor heterogeneity in histology, steroidogenesis, and somatic mutations in multiple adrenocortical adenomas arising in a single patient with PA. These findings suggest that the syndrome of PA can involve heterogeneous and multiclonal functional adrenal adenomas., (Copyright © 2017 Endocrine Society)

Context: Mild cases of autonomous aldosterone secretion may go unrecognized using current diagnostic criteria for primary aldosteronism (PA)., Objective: To investigate whether the inability to stimulate renin serves as a biomarker for unrecognized autonomous aldosterone secretion and mineralocorticoid receptor (MR) activation., Participants: Six hundred sixty-three normotensive and mildly hypertensive participants, who were confirmed to not have PA using current guideline criteria and were on no antihypertensive medications., Design: Participants had their maximally stimulated plasma renin activity (PRA) measured while standing upright after sodium restriction. Tertiles of maximally stimulated PRA were hypothesized to reflect the degree of MR activation: lowest PRA tertile = "Inappropriate/Excess MR Activity;" middle PRA tertile = "Intermediate MR Activity;"; and highest PRA tertile = "Physiologic MR Activity." All participants underwent detailed biochemical and vascular characterizations under conditions of liberalized sodium intake, and associations with stimulated PRA phenotypes were performed., Results: Participants with lower stimulated PRA had greater autonomous aldosterone secretion [higher aldosterone-to-renin ratio (P = 0.002), higher urine aldosterone excretion rate (P = 0.003), higher systolic blood pressure (P = 0.004), and lower renal plasma flow (P = 0.04)] and a nonsignificant trend toward lower serum potassium and higher urine potassium excretion, which became significant after stratification by hypertension status., Conclusions: In participants without clinical PA, the inability to stimulate renin was associated with greater autonomous aldosterone secretion, impaired vascular function, and suggestive trends in potassium handling that indicate an extensive spectrum of unrecognized MR activation., (Copyright © 2017 Endocrine Society)

Context: Obesity is associated with poor bone mineralization and quality. Fibroblast growth factor 23 (FGF23) plays an important role in skeletal physiology., Objective: To test hypothesis that greater adiposity results in higher FGF23 levels among individuals with normal estimated glomerular filtration rate (eGFR)., Design, Setting, Participants: Cross-sectional analyses among participants with eGFR ≥60 mL/min/1.73m2. We assessed the association between crude [body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR); n = 5610] and refined (abdominal adipose tissue area by computed tomography; n = 1313) measures of adiposity and FGF23 using multivariable linear regression., Main Outcome Measure: Serum FGF23., Results: FGF23 was higher across BMI categories (BMI <25: 37.7; BMI 25 to 29.99: 38.7; BMI 30 to 39.99: 39.8; BMI ≥40: 40.9 pg/mL, unadjusted P trend < 0.0001). The association between BMI and FGF23 was independent of known confounders of FGF23 (adjusted β = +7.2% higher FGF23 per 10 kg/m2; P < 0.0001). Similar results were observed using WC and WHR. Abdominal adipose tissue area was also independently associated with higher FGF23 (P < 0.01). Notably, the positive associations between FGF23 and adiposity were observed despite the fact that eGFR did not decline and serum phosphate levels did not increase with adiposity., Conclusion: In a large cohort with normal kidney function, adiposity was associated with higher FGF23 levels independent of known confounders, including eGFR and phosphate. Further studies are needed to evaluate the causes of higher FGF23 in settings of greater adiposity and the potential impact on skeletal health., (Copyright © 2017 by the Endocrine Society)

Context: The aldosterone to renin ratio (ARR) is recommended to screen for primary aldosteronism (PA)., Objective: To evaluate whether dietary sodium restriction results in misinterpretation of PA screening., Participants: Untreated hypertensives with ARR more than 20 on a high dietary sodium intake (HS) were also evaluated on a low dietary sodium intake (LS) (n = 241). Positive screening for PA was defined as: plasma renin activity (PRA) less than or equal to 1.0 ng/mL · h with serum aldosterone more than or equal to 6 ng/dL. PA was confirmed by a 24-hour urinary aldosterone excretion more than or equal to 12 mcg with urinary sodium more than 200 mmol., Results: Only 33% (79/241) of participants with an ARR more than 20 had a positive PA screen on HS. On LS, 56% (44/79) of these participants no longer met criteria for positive PA screening. When compared with participants with positive PA screening on both diets, participants with a positive screen on HS but negative on LS exhibited a significantly higher PRA on both diets. Remarkably, of the 48/79 participants who had PA confirmed, 52% had negative PA screening on LS. The distinguishing feature of these participants with "discordant" screening results was a larger rise in PRA on LS resulting in normalization of the ARR and higher Caucasian race prevalence., Conclusions: Sodium restriction is recommended in hypertension; however, it can significantly raise PRA, normalize the ARR, and result in false interpretation of PA screening. Milder phenotypes of PA, where PRA is not as suppressed, are most susceptible to dietary sodium influences on renin and ARR. Optimal screening for PA should occur under conditions of HS.

Context: Primary hyperparathyroidism (P-HPTH) is relatively common and predominantly affects women. Prior studies have shown that physical activity (PA) can lower PTH levels., Objective: Our objective was to evaluate the hypothesis that lower PA is a risk factor for developing P-HPTH., Design, Setting, and Participants: This prospective cohort study included 69 621 female participants in the Nurses' Health Study I followed for 22 years., Exposures: PA and other dietary and demographic exposures were quantified via detailed, and validated, biennial questionnaires., Outcomes: Incident P-HPTH was confirmed by medical record review after initial assessment by questionnaire. Adjusted Cox proportional hazards models were used to evaluate whether PA was an independent risk factor for developing P-HPTH. We also evaluated the risk of developing P-HPTH when combining low PA (<16 metabolic equivalent hours/week) with a previously identified independent risk factor for developing P-HPTH: low calcium intake (<800 mg/day). The relation between PA and PTH levels was evaluated in 625 participants., Results: We confirmed 302 incident cases of P-HPTH during 1 474 993 person-years of follow-up. Participants in the highest quintile (Q) of PA had a 50% lower risk of developing P-HPTH: age-adjusted relative risks and 95% confidence intervals for incident P-HPTH by lowest to highest of PA were Q1 = 1.0 (reference); Q2 = 0.83 (0.60–1.15); Q3 = 0.84 (0.61–1.15); Q4 = 0.50 (0.34–0.74); Q5 = 0.50 (0.35–0.73); P for trend <.001. Extensive multivariable adjustments did not materially change these findings. The adjusted relative risk for developing P-HPTH among participants with the combination lower PA and lower calcium intake was 2.37-fold (1.60–3.51) higher than in participants with higher PA and higher calcium intake. PA was inversely correlated with serum PTH (ρ = −0.09, P = .03); the mean adjusted serum PTH in Q 2–5 of PA was lower than in Q 1 (36.3 vs 39.1 pg/mL, P = .02)., Conclusion: Low physical activity may be a modifiable risk factor for developing P-HPTH in women.

Context: Hypertension is associated with higher PTH levels, and specific antihypertensive medications may modulate PTH. Whether hypertension or the use of specific antihypertensive medications influences the risk of developing incident primary hyperparathyroidism (P-HPTH) is not known., Objective: The purpose of this study was to investigate whether a history of hypertension and the use of specific antihypertensive medications determine the risk for developing P-HPTH in a large prospective study., Design/participants: A longitudinal prospective cohort of female nurses in the Nurses' Health Study I (n = 75 600), who did not have P-HPTH at baseline and completed a questionnaire assessment of lifetime history of P-HPTH were followed from 1986 to 2008. Most participants were white and postmenopausal., Setting: The study was a nationwide cohort study., Main Outcome Measure: Incident P-HPTH was assessed initially via questionnaire and then was confirmed by medical record review. Cox proportional hazards models were used to adjust for potential confounders., Results: We documented 347 incident cases of P-HPTH during 1 719 416 person-years of follow-up. The age-adjusted relative risk (RR) for incident P-HPTH associated with hypertension was 1.80 (95% confidence interval [CI], 1.43-2.26), and the multivariate-adjusted RR was 1.45 (95% CI, 1.10-1.91). Among participants with a history of hypertension, the use of furosemide, when compared with the use of other antihypertensive medications, was associated with increased risk for developing P-HPTH; age-adjusted RR for incident P-HPTH was 1.79 (95% CI, 1.15-2.79) and multivariate-adjusted RR was 1.71 (95% CI, 1.08-2.71)., Conclusions: In a large longitudinal prospective cohort study of mostly older white women, a history of hypertension and use of furosemide were associated with a significantly higher risk of developing P-HPTH.

It is well established that the organ damage that complicates human diabetes is caused by prolonged hyperglycemia, but the cellular and molecular mechanisms by which high levels of glucose cause tissue damage in humans are still not fully understood. The prevalent hypothesis explaining the mechanisms that may underlie the pathogenesis of diabetes complications includes overproduction of reactive oxygen species, increased flux through the polyol pathway, overactivity of the hexosamine pathway causing intracellular formation of advanced glycation end products, and activation of protein kinase C isoforms. In addition, experimental and clinical evidence reported in past decades supports a strong link between the complement system, complement regulatory proteins, and the pathogenesis of diabetes complications. In this article, we summarize the body of evidence that supports a role for the complement system and complement regulatory proteins in the pathogenesis of diabetic vascular complications, with specific emphasis on the role of the membrane attack complex (MAC) and of CD59, an extracellular cell membrane-anchored inhibitor of MAC formation that is inactivated by nonenzymatic glycation. We discuss a pathogenic model of human diabetic complications in which a combination of CD59 inactivation by glycation and hyperglycemia-induced complement activation increases MAC deposition, activates pathways of intracellular signaling, and induces the release of proinflammatory, prothrombotic cytokines and growth factors. Combined, complement-dependent and complement-independent mechanisms induced by high glucose promote inflammation, proliferation, and thrombosis as characteristically seen in the target organs of diabetes complications.

Background: To investigate the association between resting heart rate and the risk of developing impaired fasting glucose (IFG), diabetes and conversion from IFG to diabetes., Methods: The prospective analysis included 73,357 participants of the Kailuan cohort (57,719 men and 15,638 women). Resting heart rate was measured via electrocardiogram in 2006. Incident diabetes was defined as either the fasting blood glucose (FBG) ≥ 7.0 mmol/l or new active use of diabetes medications during the 4-year follow-up period. IFG was defined as a FBG between 5.6 and 6.9 mmol/l. A meta-analysis including seven published prospective studies focused on heart rate and diabetes risk, and our current study was then conducted using random-effects models., Results: During 4 years of follow-up, 17,463 incident IFG cases and 4,649 incident diabetes cases were identified. The corresponding adjusted hazard ratios (HRs) for each 10 beats/min increase in heart rate were 1.23 [95% confidence interval (CI): 1.19, 1.27] for incident diabetes, 1.11 (95% CI: 1.09, 1.13) for incident IFG and 1.13 (95% CI: 1.08, 1.17) for IFG to diabetes conversion. The risks of incident IFG and diabetes were significantly higher among participants aged < 50 years than those aged ≥ 50 years (P-interaction < 0.02 for both). A meta-analysis confirmed the positive association between resting heart rate and diabetes risk (pooled HR for the highest vs lowest heart rate quintile = 1.59, 95% CI:1.27, 2.00; n = 8)., Conclusion: Faster resting heart rate is associated with higher risk of developing IFG and diabetes, suggesting that heart rate could be used to identify individuals with a higher future risk of diabetes., (© The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Context: Aberrant cellular oxygen sensing is a leading theory for development of pheochromocytoma (PHEO) and paraganglioma (PGL)., Objective: The objective of the study was to test the hypothesis that chronic hypoxia in patients with cyanotic congenital heart disease (CCHD) increases the risk for PHEO-PGL., Design/setting/participants: We investigated the association between CCHD and PHEO-PGL with two complementary studies: study 1) an international consortium was established to identify congenital heart disease (CHD) patients with a PHEO-PGL diagnosis confirmed by pathology or biochemistry and imaging; study 2) the 2000-2009 Nationwide Inpatient Survey, a nationally representative discharge database, was used to determine population-based cross-sectional PHEO-PGL frequency in hospitalized CCHD patients compared with noncyanotic CHD and those without CHD using multivariable logistic regression adjusted for age, sex, and genetic PHEO-PGL syndromes., Results: In study 1, we identified 20 PHEO-PGL cases, of which 18 had CCHD. Most presented with cardiovascular or psychiatric symptoms. Median cyanosis duration for the CCHD PHEO-PGL cases was 20 years (range 1-57 y). Cases were young at diagnosis (median 31.5 y, range 15-57 y) and 7 of 18 had multiple tumors (two bilateral PHEO; six multifocal or recurrent PGL), whereas 11 had single tumors (seven PHEO; four PGL). PGLs were abdominal (13 of 17) or head/neck (4 of 17). Cases displayed a noradrenergic biochemical phenotype similar to reported hypoxia-related PHEO-PGL genetic syndromes but without clinical signs of such syndromes. In study 2, hospitalized CCHD patients had an increased likelihood of PHEO-PGL (adjusted odds ratio 6.0, 95% confidence interval 2.6-13.7, P < .0001) compared with those without CHD; patients with noncyanotic CHD had no increased risk (odds ratio 0.9, P = .48)., Conclusions: There is a strong link between CCHD and PHEO-PGL. Whether these rare diseases coassociate due to hypoxic stress, common genetic or developmental factors, or some combination requires further investigation.

Context: Aldosterone and PTH are implicated in the pathogenesis of cardiovascular and skeletal diseases. An expanding body of evidence supports a bidirectional and positive physiologic relationship between aldosterone and PTH. Large population-based studies confirming this relationship, and whether it may be targeted as a potential method to mitigate the clinical consequences associated with excess aldosterone and PTH, are needed., Objective: We hypothesized that higher aldosterone levels would associate with higher PTH, and that the use of renin-angiotensin-aldosterone system (RAAS) inhibitors would predict lower PTH in a large, multi-ethnic, community-based cohort., Design, Setting, Participants: We conducted cross-sectional analyses of participants in the Multi-Ethnic Study of Atherosclerosis without apparent primary hyperparathyroidism or chronic kidney disease (n = 5668). We evaluated associations of RAAS inhibitor use with PTH concentration among 1888 treated hypertensive participants. We also tested associations of serum aldosterone concentration with PTH concentration among 1547 participants with these measurements., Outcome: Serum PTH concentration., Results: Higher aldosterone associated with higher PTH (β = 0.19 pg/ml per 1 ng/dl of aldosterone, P < .0001), and this finding was most pronounced among those with a primary hyperaldosteronism-like phenotype. There was a stepwise increment in PTH when comparing untreated normotensives, hypertensives using RAAS inhibitors, untreated hypertensives, and treated hypertensives using non-RAAS inhibitors (40.8, 45.0, 46.2, 47.1 pg/ml, respectively). The use of any RAAS inhibitor independently associated with lower PTH (β = -2.327 pg/ml per use of RAAS inhibitor, P = .006), when compared with the use of any non-RAAS inhibitor medication., Conclusions: Higher serum aldosterone concentration is associated with higher serum PTH concentration, and the use of RAAS inhibitors is associated with lower PTH concentration. These results extend prior evidence from observational and intervention studies suggesting a potentially important and modifiable relationship between the RAAS and PTH in humans.

Context: Human CD59, an inhibitor of the membrane attack complex of complement, is inactivated by glycation. Glycation inactivation of CD59 enhances complement-mediated injury in target organs of diabetes complications., Objective: We hypothesized that circulating soluble glycated CD59 (GCD59) represents a novel biomarker of blood glucose handling and aimed to conduct human study protocols to test this hypothesis. DESIGN, SETTING, PARTICIPANTS, AND OUTCOME MEASURES: Using a newly developed ELISA, we measured circulating soluble GCD59 in samples from 3 separate human studies evaluating acute and chronic glucose handling and glucose responses to insulin therapy. Study 1 (normal vs diabetic subjects) evaluated the cross-sectional association between GCD59 and glycated hemoglobin (HbA1c) in 400 subjects with and without type 2 diabetes. Study 2 (oral glucose tolerance test [OGTT] in nondiabetics) evaluated whether fasting GCD59 independently predicted the 2-hour glucose response to an OGTT in 109 subjects without a diagnosis of diabetes. Study 3 (intensified insulin treatment) evaluated the effect of intensification of glycemic control with insulin on GCD59 in 21 poorly controlled individuals with diabetes., Results: In study 1 (normal vs diabetic subjects), GCD59 was independently and positively associated with HbA1c in individuals with and without diabetes (β = 1.1, P < .0001 and β = 1.1 P < .001, respectively). In study 2 (OGTT in nondiabetics), a single GCD59 measurement independently predicted the results of the 2-hour OGTT (β = 19.8, P < .05) after multivariate modeling. In study 3 (intensified insulin treatment), intensification of glucose control with insulin resulted in a concomitant and parallel reduction of average weekly glucose and GCD59 within 2 weeks., Conclusions: We observed robust relationships between a single measurement of blood levels of GCD59 and both acute (2-hour OGTT) and chronic (HbA1c) measures of glucose handling. Lowering of GCD59 levels closely reflected lowering of average weekly glucose within 2 weeks. The role of GCD59 in the diagnosis, management, and vascular risk stratification in diabetes warrants further investigation.

Context: It is assumed that in individuals with type 2 diabetes mellitus (T2DM), blood pressure sensitivity to salt intake and the frequency of a low renin state are both increased compared with the nondiabetic population. However, studies supporting these assumptions may have been confounded by participant inclusion criteria, and study results may reflect target organ damage., Objective: The objective of this study was to examine in a cohort of T2DM 1) the frequency of salt sensitivity of blood pressure and 2) whether alterations of the renin-angiotensin-aldosterone system (RAAS) contribute to salt sensitivity in this population., Design, Patients, and Methods: Within participants of the HyperPATH cohort, four groups were analyzed: 1) T2DM with hypertension (HTN), n=51; 2) T2DM without HTN, n=30; 3) HTN only, n=451; and 4) normotensive, n=209. Phenotype studies were conducted after participants completed two dietary phases: liberal sodium (200 mmol/d) and low sodium (10 mmol/d) for 7 d each. Participants were admitted overnight to a clinical research center after each diet, and supine measurements of the RAAS before and after a 60-min angiotensin II infusion (3 ng/kg·min) were obtained., Results: Multivariate regression analysis demonstrated that T2DM status (all individuals with T2DM vs. individuals without T2DM) was not associated with the change in mean arterial pressure between the low and liberal sodium diets after accounting for age, gender, body mass index, race, and baseline blood pressure (T2DM status, P=0.5). Furthermore, two intermediate phenotypes of altered RAAS, low renin, and nonmodulation (NMOD), were associated with salt-sensitive blood pressure but occurred at different frequencies in the T2DM-HTN and HTN groups (low renin, 12% T2DM-HTN vs. 29% HTN; NMOD, 41% T2DM-HTN vs. 27% HTN; P=0.01)., Conclusion: The frequency of NMOD in participants with T2DM was significantly higher compared with HTN, suggesting that the salt sensitivity often seen in T2DM is driven by NMOD.

Context: Vitamin D deficiency and obesity are associated with increased tissue renin-angiotensin system (RAS) activity., Objective: The objective of the study was to evaluate whether vitamin D(3) therapy in obesity reduces tissue-RAS activity, as indicated by an increase in tissue sensitivity to angiotensin II (AngII)., Participants: Participants included obese subjects with hypertension and 25-hydroxyvitamin D less than 25 ng/ml., Design: Subjects were studied before and after 1 month of vitamin D(3) 15,000 IU/d, while in dietary sodium balance, and off all interfering medications. Fourteen subjects successfully completed all study procedures., Setting: The study was conducted at a clinical research center., Outcome Measures: At each study visit, tissue sensitivity to AngII was assessed by measuring renal plasma flow (RPF), mean arterial pressure (MAP), and adrenal secretion of aldosterone during an infusion of AngII. Subjects were then given captopril, and a second AngII infusion to evaluate the effect of captopril on tissue-RAS activity., Results: Vitamin D(3) therapy increased 25-hydroxyvitamin D (18 to 52 ng/ml) and basal RPF (+5%) and lowered supine MAP (-3%) (all P < 0.01). There was a greater decline in RPF and higher stimulation of aldosterone with AngII infusion after vitamin D(3) therapy (both P < 0.05). As anticipated, captopril increased the renal-vascular, MAP, and adrenal sensitivity to AngII, but this effect was much smaller after vitamin D(3) therapy, indicating that vitamin D(3) therapy corrected the tissue sensitivity to AngII akin to captopril., Conclusions: Vitamin D(3) therapy in obese hypertensives modified RPF, MAP, and tissue sensitivity to AngII similar to converting enzyme inhibition. Whether chronic vitamin D(3) therapy abrogates the development of diseases associated with excess RAS activity warrants investigation.

Objective: Previous studies have suggested that circulating adiponectin concentrations are associated positively with vitamin D and negatively with body mass index (BMI) but have not accounted for the influence of the renin-angiotensin-aldosterone system (RAAS) in this relationship. This is particularly relevant because increased RAAS activity is associated with obesity and is known to lower adiponectin levels. We evaluated the association between adiponectin and 25-hydroxyvitamin D (25(OH)D) after controlling RAAS activity with dietary sodium equilibration and also evaluated whether this relationship was influenced by BMI., Design: Cross-sectional study of 115 hypertensive Caucasian men from the Hypertensive Pathotype Consortium., Methods: To manipulate RAAS activity, all subjects underwent 1 week of high dietary sodium (HS) diet to suppress RAAS and 1 week of low dietary sodium (LS) diet to stimulate RAAS. Linear regression was used to evaluate the association between adiponectin and 25(OH)D, and the effect of BMI on this relationship, in each dietary condition., Results: Adiponectin was higher on HS, where circulating RAAS activity was low, when compared with LS (HS=2.9 versus LS=2.4 μg/ml, P<0.0001). 25(OH)D levels were positively associated with adiponectin, and BMI was a statistically significant effect modifier of the relationship between 25(OH)D and adiponectin on both diets (P interaction <0.01 between BMI and 25(OH)D)., Conclusions: Higher 25(OH)D concentrations were independently associated with higher adiponectin levels, particularly when BMI was high. Dietary sodium balance and circulating RAAS activity did not appear to affect this relationship. Future studies should explore whether vitamin D supplementation increases adiponectin levels in obesity.

Objective: Ipilimumab is a fully human MAB against cytotoxic T-lymphocyte antigen 4 (CTLA4). CTLA4 negatively regulates immune cell activation. In patients with metastatic melanoma, ipilimumab increases survival time and induces complete remission in some patients. However, immune-related adverse events including endocrinopathies have been reported. Bevacizumab, an angiogenesis inhibitor, has been used in combination with ipilimumab in patients with advanced melanoma., Patients and Methods: In this study, we report three patients who received ipilimumab alone or combined with bevacizumab therapy and developed thyroiditis, and the first report of euthyroid Graves' ophthalmopathy., Results: Case 1 is a 51-year-old female who presented with severe eye pain, proptosis, and periorbital edema. Laboratory results revealed normal TSH, elevated thyroid antibodies but low titer of anti-TSH receptor antibody. Imaging was consistent with Graves' ophthalmopathy. Cases 2 and 3 were referred for hyperthyroidism, and workup revealed thyroiditis. These three cases suggest that patients with advanced melanoma treated with ipilimumab +/- bevacizumab may be susceptible to a variety of thyroid disorders., Conclusions: Anti-CTLA4 therapy has shown promising results in treating advanced malignancy such as melanoma and renal carcinoma. A number of endocrinopathies, including thyroid disorders, may develop during ipilimumab therapy. The association of bevacizumab with endocrinopathies is not clear, although a few reports suggest a link to hypothyroidism. All patients on ipilimumab and/or bevacizumab therapy should be monitored for signs or symptoms of thyroiditis.

Background: Determination of left ventricular hypertrophy (LVH) via electrocardiogram (ECG) is a known independent risk factor for cardiovascular morbidity and mortality in hypertension (HTN). Dietary sodium and HTN are both associated with unfavorable alterations in left ventricular mass, however, to what extent their interplay affects ECG screening for LVH is unclear., Methods: The effects of controlled dietary sodium manipulation on ECG determinants of LVH in hypertensive subjects were evaluated using well-established voltage criteria for LVH. ECGs from 80 hypertensive subjects were evaluated following random sequence assignment to 7 days of high sodium (HS) intake (200 mEq/24 h), and then 7 days of low sodium (LS) intake (10 mEq/24 h)., Results: Sodium restriction over 7 days resulted in significant decreases in overall, and LVH-specific, ECG voltages. Most subjects exhibited decrements in overall ECG voltage with sodium restriction (72%); however, a smaller subset displayed higher voltages when on LS intake (28%). The prevalence of ECG-determined LVH was significantly lowered with LS diet (HS diet 22/80 (28%) vs. LS diet 8/80 (10%), P < 0.05). Subjects exhibiting reversal of LVH status with sodium restriction were younger, demonstrated salt sensitivity of blood pressure, and lower LVH-specific ECG voltage., Conclusions: Short-term dietary sodium fluctuations can significantly alter overall ECG voltage and the prevalence of ECG-determined LVH in hypertensive individuals. Inclusion of dietary sodium assessment when screening hypertensive subjects for LVH by ECG may improve the consistency of cardiac risk assessment.