Wide Variability in Catecholamine Levels From Adrenal Venous Sampling in Primary Aldosteronism.

INTRODUCTION: While adrenal venous sampling (AVS) differentiates between the unilateral and bilateral disease in patients with primary aldosteronism (PA), it is unknown if AVS can determine laterality of pheochromocytoma in patients with bilateral adrenal masses. This study analyzes adrenal vein (AV) epinephrine and norepinephrine levels in nonpheochromocytoma patients to determine the "normal" range. MATERIALS AND METHODS: We reviewed patients who underwent AVS for PA between 2009 and 2019 at a single institution; pheochromocytoma was excluded. Aldosterone, cortisol, epinephrine, and norepinephrine levels were obtained from the inferior vena cava (IVC), left adrenal vein (LAV), and right adrenal vein (RAV). Successful AV cannulation was defined by an AV/IVC cortisol ratio of ≥3:1 or an AV epinephrine level ≥364 pg/mL. Plasma measurements (pg/mL) are median values with interquartile ranges; normal ranges for epinephrine and norepinephrine are 10-200 pg/mL and 80-520 pg/mL, respectively. RESULTS: AVS was performed in 172 patients in 405 AVs (173 LAV and 232 RAV). Median epinephrine levels were IVC = 19 (14 and 34), LAV = 3811 (1870 and 6915), and RAV = 2897 (1500 and 5288). Median norepinephrine levels were IVC = 325 (186 and 479), LAV = 1450 (896 and 2050), and RAV = 786 (436 and 1582). There was a difference between LAV and RAV epinephrine levels (P = 0.024) and between LAV and RAV norepinephrine (P = 0.002) levels. CONCLUSIONS: This extensive experience with AVS demonstrated a wide range of "normal" AV catecholamine levels in patients without pheochromocytoma, which suggests that the utility of AVS to determine disease laterality in patients with pheochromocytoma and bilateral adrenal nodules is likely to be limited.

Utility of Epinephrine Levels in Determining Adrenal Vein Cannulation During Adrenal Venous Sampling for Primary Aldosteronism.

OBJECTIVE: In patients with primary aldosteronism, adrenal venous sampling (AVS) is performed to determine the presence of unilateral or bilateral adrenal disease. During AVS, verification of catheter positioning within the left adrenal vein (AV) and the right AV by comparison of AV and inferior vena cava (IVC) cortisol levels can be variable. The objective of this study was to determine the utility of AV epinephrine levels in assessing successful AV cannulation. METHODS: This was a single institution, retrospective review of patients who underwent AVS with cosyntropin stimulation for primary aldosteronism between 2009 and 2018. Successful cannulation of the AV was defined by an AV/IVC cortisol ratio selectivity index (SI) ≥3:1. Epinephrine thresholds to predict catheter placement in the AV were determined using logistic regression. The calculated epinephrine thresholds were compared with previously published thresholds. RESULTS: AVS was performed on 101 consecutive patients and, based on the SI, successful cannulation of the left AV and right AV occurred in 98 (97%) and 91(90%) patients, respectively. The calculated optimal epinephrine threshold to predict AV cannulation was 364 pg/mL (sensitivity, 92.1%; specificity, 94.6%) and the calculated optimal AV/IVC epinephrine ratio threshold was 27.4, (sensitivity, 92.1%; specificity, 91.3%). Among the 14 patients with failed AV cannulation, 3 patients would have been considered to have successful AVS using AV epinephrine levels >364 pg/mL and AV/IVC epinephrine ratio >27.4 thresholds. CONCLUSION: Obtaining 2 right AV samples routinely as well as AV and IVC epinephrine levels during AVS could prevent unnecessary repeat AVS in patients with failed AV cannulation based on cortisol-based SI <3:1.

Subtype Identification of Surgically Curable Primary Aldosteronism During Treatment With Mineralocorticoid Receptor Blockade.

BACKGROUND: Current guidelines and consensus documents recommend withdrawal of mineralocorticoid receptor antagonists (MRAs) before primary aldosteronism (PA) subtyping by adrenal vein sampling (AVS), but this practice can cause severe hypokalemia and uncontrolled high blood pressure. Our aim was to investigate if unilateral PA can be identified by AVS during MRA treatment. METHODS: We compared the rate of unilateral PA identification between patients with and without MRA treatment in large data sets of patients submitted to AVS while off renin-angiotensin system blockers and ß-blockers. In sensitivity analyses, the between-group differences of lateralization index values after propensity score matching and the rate of unilateral PA identification in subgroups with undetectable (≤2 mUI/L), suppressed (<8.2 mUI/L), and unsuppressed (≥8.2 mUI/L) direct renin concentration levels were also evaluated. RESULTS: Plasma aldosterone concentration, direct renin concentration, and blood pressure values were similar in non-MRA-treated (n=779) and MRA-treated (n=61) patients with PA, but the latter required more antihypertensive agents (P=0.001) and showed a higher rate of adrenal nodules (82% versus 67%; P=0.022) and adrenalectomy (72% versus 54%; P=0.01). However, they exhibited no significant differences in commonly used AVS indices and the area under the receiving operating characteristic curve of lateralization index, both under unstimulated conditions and postcosyntropin. Several sensitivity analyses confirmed these results in propensity score matching adjusted models and in patients with undetectable, or suppressed or unsuppressed renin levels. CONCLUSIONS: At doses that controlled blood pressure and potassium levels, MRAs did not preclude the identification of unilateral PA at AVS. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01234220.

Unilaterally Selective Adrenal Vein Sampling for Identification of Surgically Curable Primary Aldosteronism.

BACKGROUND: Adrenal venous sampling is recommended for the identification of unilateral surgically curable primary aldosteronism but is often clinically useless, owing to failed bilateral adrenal vein cannulation. OBJECTIVES: To investigate if only unilaterally selective adrenal vein sampling studies can allow the identification of the responsible adrenal. METHODS: Among 1625 patients consecutively submitted to adrenal vein sampling in tertiary referral centers, we selected those with selective adrenal vein sampling results in at least one side; we used surgically cured unilateral primary aldosteronism as gold reference. The accuracy of different values of the relative aldosterone secretion index (RASI), which estimates the amount of aldosterone produced in each adrenal gland corrected for catheterization selectivity, was examined. RESULTS: We found prominent differences in RASI values distribution between patients with and without unilateral primary aldosteronism. The diagnostic accuracy of RASI values estimated by the area under receiver operating characteristic curves was 0.714 and 0.855, respectively, in the responsible and the contralateral side; RASI values >2.55 and ≤0.96 on the former and the latter side furnished the highest accuracy for detection of surgically cured unilateral primary aldosteronism. Moreover, in the patients without unilateral primary aldosteronism, only 20% and 16% had RASI values ≤0.96 and >2.55. CONCLUSIONS: With the strength of a large real-life data set and use of the gold reference entailing an unambiguous diagnosis of unilateral primary aldosteronism, these results indicate the feasibility of identifying unilateral primary aldosteronism using unilaterally selective adrenal vein sampling results. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01234220.

Feasibility of Imaging-Guided Adrenalectomy in Young Patients With Primary Aldosteronism.

Many of the patients with primary aldosteronism (PA) are denied curative adrenalectomy because of limited availability or failure of adrenal vein sampling. It has been suggested that adrenal vein sampling can be omitted in young patients with a unilateral adrenal nodule, who show a florid biochemical PA phenotype. As this suggestion was based on a very low quality of evidence, we tested the applicability and accuracy of imaging, performed by computed tomography and/or magnetic resonance, for identification of unilateral PA, as determined by biochemical and/or clinical cure after unilateral adrenalectomy. Among 1625 patients with PA submitted to adrenal vein sampling in a multicenter multiethnic international study, 473 were ≤45 years of age; 231 of them had exhaustive imaging and follow-up data. Fifty-three percentage had a unilateral adrenal nodule, 43% had no nodules, and 4% bilateral nodules. Fifty-six percentage (n=131) received adrenalectomy and 128 were unambiguously diagnosed as unilateral PA. A unilateral adrenal nodule on imaging and hypokalemia were the strongest predictors of unilateral PA at regression analysis. Accordingly, imaging allowed correct identification of the responsible adrenal in 95% of the adrenalectomized patients with a unilateral nodule. The rate raised to 100% in the patients with hypokalemia, who comprised 29% of the total, but fell to 88% in those without hypokalemia. Therefore, a unilateral nodule and hypokalemia could be used to identify unilateral PA in patients ≤45 years of age if adrenal vein sampling is not easily available. However, adrenal vein sampling remains indispensable in 71% of the young patients, who showed no nodules/bilateral nodules at imaging and/or no hypokalemia. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01234220.

Identification of Surgically Curable Primary Aldosteronism by Imaging in a Large, Multiethnic International Study.

CONTEXT: Adrenal gland imaging is recommended by the current guidelines for the workup of primary aldosteronism (PA). However, its diagnostic performance has not been established in large, multiethnic cohorts of patients who undergo adrenal vein sampling (AVS) and adrenalectomy. OBJECTIVE: This work aims to assess the diagnostic accuracy of cross-sectional adrenal imaging. METHODS: This international multicenter study took place in tertiary referral centers. A total of 1625 PA patients seeking surgical cure were enrolled in an international study involving 19 centers in North America, Europe, Asia, and Australia. Of these, 1311 (81%) had imaging data available and 369 (23%), who received a final diagnosis of surgically cured unilateral PA, were examined. Patients underwent AVS and imaging by computed tomography and/or magnetic resonance imaging. The accuracy of detection of unilateral PA at imaging was estimated by the area under the receiver operator characteristics curve using cure (biochemical and/or full clinical success) as the reference at follow-up after unilateral adrenalectomy. RESULTS: In the cohort of 1311 patients with imaging data available, 34% and 7% of cases showed no detectable or bilateral nodules, respectively. Imaging did not detect the culprit adrenal in 28% of the surgically cured unilateral PA patients. Moreover, the clinical outcome did not differ significantly between the imaging-positive and imaging-negative patients. CONCLUSION: Cross-sectional imaging did not identify a lateralized cause of disease in around 40% of PA patients and failed to identify the culprit adrenal in more than one-fourth of patients with unilateral PA.

Subtyping of Primary Aldosteronism in the AVIS-2 Study: Assessment of Selectivity and Lateralization.

CONTEXT: Adrenal venous sampling (AVS) is the key test for subtyping primary aldosteronism (PA), but its interpretation varies widely across referral centers and this can adversely affect the management of PA patients. OBJECTIVES: To investigate in a real-life study the rate of bilateral success and identification of unilateral aldosteronism and their impact on blood pressure outcomes in PA subtyped by AVS. DESIGN AND SETTINGS: In a retrospective analysis of the largest international registry of individual AVS data (AVIS-2 study), we investigated how different cut-off values of the selectivity index (SI) and lateralization index (LI) affected rate of bilateral success, identification of unilateral aldosteronism, and blood pressure outcomes. RESULTS: AVIS-2 recruited 1625 individual AVS studies performed between 2000 and 2015 in 19 tertiary referral centers. Under unstimulated conditions, the rate of biochemically confirmed bilateral AVS success progressively decreased with increasing SI cut-offs; furthermore, with currently used LI cut-offs, the rate of identified unilateral PA leading to adrenalectomy was as low as <25%. A within-patient pairwise comparison of 402 AVS performed both under unstimulated and cosyntropin-stimulated conditions showed that cosyntropin increased the confirmed rate of bilateral selectivity for SI cut-offs ≥ 2.0, but reduced lateralization rates (P < 0.001). Post-adrenalectomy outcomes were not improved by use of cosyntropin or more restrictive diagnostic criteria. CONCLUSION: Commonly used SI and LI cut-offs are associated with disappointingly low rates of biochemically defined AVS success and identified unilateral PA. Evidence-based protocols entailing less restrictive interpretative cut-offs might optimize the clinical use of this costly and invasive test. (J Clin Endocrinol Metab XX: 0-0, 2020).

VANISHING PAPILLARY THYROID CARCINOMA: MORPHOLOGICAL CHANGES AFTER FINE-NEEDLE ASPIRATION.

OBJECTIVE: Fine-needle aspiration (FNA) of a thyroid nodule is typically considered a benign procedure. Uncommonly, morphological changes can occur in the nodule or tissue after the procedure. These changes have been noted in tissues like thyroid, breast, lymph node, and prostate. The objective of this case report is to report the rare occurrence of thyroid cancer diagnosed on FNA, appearing as a necrotic mass after near total thyroidectomy and to emphasize the need for confirmation of diagnosis with histopathology. METHODS: A 69-year-old man was seen for a self-discovered neck mass. Thyroid ultrasound demonstrated a thyroid nodule with suspicious features. Ultrasound-guided FNA of the nodule was performed with a 22-gauge needle without immediate complications. RESULTS: The cytology was read as consistent with papillary thyroid cancer with a preoperative thyroglobulin level of 15,288 ng/mL (normal range is 1.6-55 ng/mL). After a near total thyroidectomy, histopathology revealed complete infarction of the tumor with no evidence of cancerous tissue remaining. Based on the pathology report, he was considered cured of the cancer and did not receive radioactive iodine therapy. CONCLUSION: The occurrence of tissue infarction following FNA of a thyroid nodule is rare, reportedly <2%. We conclude a review of the original cytology material and a thorough examination of remaining viable tissue be made. Complete evaluation for invasion of the capsule or surrounding tissue must be ascertained to decrease diagnostic errors.

Clinical Outcomes of 1625 Patients With Primary Aldosteronism Subtyped With Adrenal Vein Sampling.

We sought to measure the clinical benefits of adrenal venous sampling (AVS), a test recommended by guidelines for primary aldosteronism (PA) patients seeking surgical cure, in a large registry of PA patients submitted to AVS. Data of 1625 consecutive patients submitted to AVS in 19 tertiary referral centers located in Asia, Australia, Europe, and North America were collected in a large multicenter international registry. The primary end points were the rate of bilateral success, ascertained lateralization of PA, adrenalectomy, and of cured arterial hypertension among AVS-guided and non AVS-guided adrenalectomy patients. AVS was successful in 80.1% of all cases but allowed identification of unilateral PA in only 45.5% by the criteria in use at each center. Adrenalectomy was performed in 41.8% of all patients and cured arterial hypertension in 19.6% of the patients, 2-fold more frequently in women than men (P<0.001). When AVS-guided, surgery provided a higher rate of cure of hypertension than when non-AVS-guided (40.0% versus 30.5%; P=0.027). Compared with surgical cases, patients treated medically needed more antihypertensive medications (P<0.001) and exhibited a higher rate of persistent hypokalemia requiring potassium supplementation (4.9% versus 2.3%; P<0.01). The low rate of adrenalectomy and cure of hypertension in PA patients seeking surgical cure indicates suboptimal AVS use, possibly related to issues in patient selection, technical success, and AVS data interpretation. Given the better outcomes of AVS-guided adrenalectomy, these results call for actions to improve the diagnostic use of this test that is necessary for detection of surgical PA candidates. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01234220.

Mechanisms for the increased fatigability of the lower limb in people with type 2 diabetes.

Fatiguing exercise is the basis of exercise training and a cornerstone of management of type 2 diabetes mellitus (T2D); however, little is known about the fatigability of limb muscles and the involved mechanisms in people with T2D. The purpose of this study was to compare fatigability of knee extensor muscles between people with T2D and controls without diabetes and determine the neural and muscular mechanisms for a dynamic fatiguing task. Seventeen people with T2D [ten men and seven women: 59.6 (9.0) yr] and twenty-one age-, body mass index-, and physical activity-matched controls [eleven men and ten women: 59.5 (9.6) yr] performed one hundred twenty high-velocity concentric contractions (one contraction/3 s) with a load equivalent to 20% maximal voluntary isometric contraction (MVIC) torque with the knee extensors. Transcranial magnetic stimulation (TMS) and electrical stimulation of the quadriceps were used to assess voluntary activation and contractile properties. People with T2D had larger reductions than controls in power during the fatiguing task [42.8 (24.2) vs. 26.4 (15.0)%; P < 0.001] and MVIC torque after the fatiguing task [37.6 (18.2) vs. 26.4 (12.1)%; P = 0.04]. People with T2D had greater reductions than controls in the electrically evoked twitch amplitude after the fatiguing task [44.0 (20.4) vs. 35.4 (12.1)%, respectively; P = 0.01]. However, the decrease in voluntary activation was similar between groups when assessed with electrical stimulation [12.1 (2.6) vs. 12.4 (4.4)% decrease; P = 0.84] and TMS ( P = 0.995). A greater decline in MVIC torque was associated with larger reductions of twitch amplitude ( r2 = 0.364, P = 0.002). Although neural mechanisms contributed to fatigability, contractile mechanisms were responsible for the greater knee extensor fatigability in men and women with T2D compared with healthy controls. NEW & NOTEWORTHY Transcranial magnetic stimulation and percutaneous muscle stimulation were used to determine the contributions of neural and contractile mechanisms of fatigability of the knee extensor muscles after a dynamic fatiguing task in men and women with type 2 diabetes (T2D) and healthy age-, body mass index-, and physical activity-matched controls. Although neural and contractile mechanisms contributed to greater fatigability of people with T2D, fatigability was primarily associated with impaired contractile mechanisms and glycemic control.

'Euglycemic' Ketoacidosis in a Patient With Type 2 Diabetes Being Treated With Canagliflozin.

OBJECTIVE: Canagliflozin is a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, one of a class of novel antiglycemic agents that are gaining in popularity in the treatment of diabetes. METHODS: We describe a case in which a patient experienced difficult-to-treat metabolic ketoacidosis in the setting of canagliflozin use. RESULTS: A 52-year-old man with type 2 diabetes mellitus developed profound ketoacidosis without overt hyperglycemia while taking canagliflozin. Despite initiation of an insulin infusion, the metabolic acidosis persisted for 3 days. CONCLUSION: Treatment with canagliflozin was associated with development of euglycemic ketoacidosis.

Pathophysiology, diagnosis, and treatment of mineralocorticoid disorders.

The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure control, fluid, and electrolyte balance in humans. Chronic activation of mineralocorticoid production leads to dysregulation of the cardiovascular system and to hypertension. The key mineralocorticoid is aldosterone. Hyperaldosteronism causes sodium and fluid retention in the kidney. Combined with the actions of angiotensin II, chronic elevation in aldosterone leads to detrimental effects in the vasculature, heart, and brain. The adverse effects of excess aldosterone are heavily dependent on increased dietary salt intake as has been demonstrated in animal models and in humans. Hypertension develops due to complex genetic influences combined with environmental factors. In the last two decades, primary aldosteronism has been found to occur in 5% to 13% of subjects with hypertension. In addition, patients with hyperaldosteronism have more end organ manifestations such as left ventricular hypertrophy and have significant cardiovascular complications including higher rates of heart failure and atrial fibrillation compared to similarly matched patients with essential hypertension. The pathophysiology, diagnosis, and treatment of primary aldosteronism will be extensively reviewed. There are many pitfalls in the diagnosis and confirmation of the disorder that will be discussed. Other rare forms of hyper- and hypo-aldosteronism and unusual disorders of hypertension will also be reviewed in this article.

Evolution of a pheochromocytoma.

OBJECTIVE: To present a case that demonstrates the evolution of a pheochromocytoma over a several-year period and to emphasize the importance of a thorough work-up for pheochromocytoma in patients with neurofibromatosis type 1 (NF1) and hypertension. METHODS: We review the long-term clinical, biochemical, and imaging findings in a man with a complex medical history of hypertension, NF1, and cardiomyopathy. RESULTS: A 44-year-old man, with a well-documented history of headaches, hypertension, and NF1, was referred for evaluation of a right adrenal enlargement. He had developed cardiomyopathy and undergone an evaluation for cardiac transplantation. Initial computed tomography revealed subtle asymmetry in the upper right adrenal gland. Biochemical studies for pheochromocytoma yielded equivocal findings, with a 1.5-fold elevation in the urinary norepinephrine and near-normal urinary metanephrine level. Because 131I-metaiodobenzylguanidine imaging showed no tracer uptake in the area of the right adrenal gland, the patient was thought not to have a pheochromocytoma. The patient eventually underwent cardiac transplantation and did well. On reassessment 3 1/2 years later, he was found to have a larger right adrenal mass. The second endocrine evaluation demonstrated substantial elevation in the urinary metanephrine level, and the patient underwent laparoscopic right adrenalectomy to remove the tumor (3.5 by 3.0 by 2.5 cm), which proved to be a pheochromocytoma. CONCLUSION: This case shows that a pheochromocytoma can be difficult to diagnose and can evolve to become a large, biochemically active tumor. It is imperative that patients with an adrenal tumor undergo periodic reevaluation to ensure that the tumor remains stable in size. If the tumor enlarges, further biochemical testing is warranted.