A picture of hyperparathyroidism secondary to increased urinary calcium excretion was found in 116 patients with primary aldosteronism (PA), compared with 110 essential hypertensives. After medical or surgical treatment in 40 PA patients, parathyroid hormone (PTH) levels were significantly reduced and bone mineral density (BMD) significantly increased at the lumbar spine, femoral neck, and total hip.

INTRODUCTION:

Recent studies have shown that aldosterone induces urinary calcium excretion leading to a reduction of calcemia with consequent secondary hyperparathyroidism and BMD loss. In patients with PA, this picture of hyperparathyroidism is significantly improved by treatment with adrenal surgery or with mineralocorticoid receptor antagonists. On these premises, the aim of the present study was to evaluate calcium and phosphate metabolism parameters in PA patients, compared with patients with essential hypertension (EH) and the effect of treatment of aldosterone excess on bone health in PA patients.

METHODS:

We studied 226 patients: 116 with PA (46 with an aldosterone-producing adenoma and 70 with bilateral adrenal hyperplasia) and 110 patients with EH. In 40 patients with PA, we evaluated biochemical parameters and bone mass, using the dual-energy X-ray absorptiometry, at baseline and after a mean follow-up of 24 months from treatment.

RESULTS:

In PA patients, compared with EH, PTH levels and urinary calcium excretion significantly increased while serum calcium significantly decreased with comparable vitamin D levels. At follow-up in PA patients, PTH levels were significantly reduced compared with basal evaluation, despite similar vitamin D amounts. At follow-up, we observed a significant improvement of the Z-score at the lumbar spine, femoral neck, and at total hip sites.

CONCLUSIONS:

Our results support previous data showing secondary hyperparathyroidism in PA patients, which is reversible after treatment. Moreover, this targeted treatment appears to be able to determine a significant improvement of BMD both at the spine and hip sites.

Recent data suggest excess circulating aldosterone promotes cardiometabolic decline. Weight loss may lower aldosterone levels, but little longitudinal data is available in normotensive adults. We aimed to determine whether, independent of changes in sodium excretion, reductions in serum aldosterone are associated with favorable changes in obesity-related factors in normotensive overweight/obese young adults. We studied 285 overweight/obese young adult participants (body mass index25 and<40 kg m(-2), age 20-45 years) in a clinical trial examining the effects of a 1-year diet and physical activity intervention with or without sodium restriction on vascular health. Body weight, serum aldosterone, 24-h sodium and potassium excretion and obesity-related factors were measured at baseline, 6, 12 and 24 months. Weight loss was significant at 6 (7%), 12 (6%) and 24 months (4%; all P<0.0001). Decreases in aldosterone were associated with decreases in C-reactive protein, leptin, insulin, homeostasis assessment of insulin resistance, heart rate, tonic cardiac sympathovagal balance and increases in adiponectin (all P<0.05) in models adjusting for baseline age, sex, race, intervention arm, time since baseline, and sodium and potassium excretion. Weight loss and reductions in thigh intermuscular fat (intermuscular adipose tissue area; IMAT) were associated with decreases in aldosterone in the subgroup (n=98) with metabolic syndrome (MetS) at baseline (MetS × weight loss, P=0.04; MetS × change in IMAT, P=0.04). Favorable changes in obesity-related factors are associated with reductions in aldosterone in young adults with no risk factors besides excess weight, an important finding, given aldosterone's emergence as an important cardiometabolic risk factor.Hypertension Research advance online publication, 9 May 2013; doi:10.1038/hr.2013.45.

Incidentally detected adrenal masses occur frequently especially in the elderly. This is due to technical advances as well as to widespread use of radiologic imaging performed for other reasons. After discovery of an adrenal mass two major questions arise: firstly, is the lesion malignant and, secondly, is it hormonally active? Malignancy is only very rarely the cause for incidental adrenal masses. However, in patients with a history of malignant disease these are suspicious for metastases. Imaging may help distinguish adrenal masses in terms of size and signal characteristics. About 10 - 15 % of adrenal incidentalomas are hormonally active. Clinically significant are an overproduction of catecholamines, aldosterone and cortisol. Hormonal evaluation should be considered according to the clinical context: screening for hyperaldosteronism is recommended if hypertension is present and screening for cortisol-excess should be performed in patients with typical clinical signs. In contrast, a pheochromocytoma should be ruled out in almost all patients with adrenal incidentaloma. Often only a combination of different tests can prove hormone-excess. These tests are influenced by a variety of factors and should therefore be interpreted with caution.

Aldosterone plays a major role in regulating sodium and potassium homeostasis, and blood pressure. More recently aldosterone has emerged as a key hormone in mediating end organ damage. In extreme cases, dysregulated aldosterone production leads to primary aldosteronism, the most common form of secondary hypertension. However, even within the physiological range, high levels of aldosterone are associated with an increased risk of developing hypertension over time. Primary aldosteronism represents the most common and curable form of hypertension, with a prevalence that increases with the severity of hypertension. Although genetic causes underlying glucocorticoid remediable aldosteronism, one of the three Mendelian forms of primary aldosteronism, were established some time ago, somatic and inherited mutations in the potassium channel GIRK4 have only recently been implicated in the formation of aldosterone producing adenoma and in familial hyperaldosteronism type 3. Moreover, recent findings have identified somatic mutations in two additional genes, involved in maintaining intracellular ionic homeostasis and cell membrane potential, in a subset of aldosterone producing adenoma.This review summarizes our current knowledge on the genetic determinants that contribute to variations in plasma aldosterone and renin levels in the general population, and the genetics of familial and sporadic primary aldosteronism. Various animal models that have significantly improved our understanding of the pathophysiology of excess aldosterone production will also be discussed. Finally, we will outline the cardiovascular, renal and metabolic consequences of mineralocorticoid excess beyond blood pressure regulation.

Adrenal incidentalomas (AI) are detected in approximately 4-7% of patients in imaging studies. Majority are benign, but careful evaluation is warranted to rule out carcinoma and functional adenomas.The purpose of presenting these cases is to highlight the approach to management of AI in terms of diagnosis, follow-up, and treatment.Seven patients presenting in the endocrine clinic with AI were evaluated for their presenting clinical features and investigated.Case 1 was a 49-year-old female, with adrenal androgen secreting adrenocortical carcinoma with amenorrhoea which was mistaken as menopause. She had minimal hirsutism, which was mistaken as postmenopausal hirsutism. Case 2 was a 39-year-old male, presenting with hyperglycemia found to have Conns' syndrome with aldosterone producing adenoma on routine ultrasound. Case 3 was a 32-year-old male, presenting with gastritis and bloating, where ultrasound showed bilateral large adrenal masses revealed as diffuse large B cell lymphoma on biopsy. Case 4 was a 21-year-old boy, who had pheochromocytoma misdiagnosed as benign intracranial hypertension (HTN). Case 5 was a 59-year-old hypertensive male, presenting with fever had pheochromocytoma with catecholamine excess, producing fever. Case 6 was isolated adrenal tuberculosis who presented with chronic diarrhea.AI are common, though prevalence varies depending on the reason for scanning, the characteristics of the population studied, and the radiological techniques used. Most are non-secreting cortical adenomas. AI should be evaluated both biochemically and radiologically. When a hormonal disorder is suspected clinically, targeted, diagnostic testing for autonomous cortisol secretion, pheochromocytoma, and hyperaldosteronism is indicated.

There is a high incidence of metabolic syndrome among patients with primary aldosteronism (PA), which has recently been associated with an unfavorable cardiometabolic profile. However, the underlying mechanisms have not been clarified in detail. Characterizing aldosterone (Ald) target genes in adipocytes will help us to elucidate the deleterious effects associated with excess Ald. Apelin, a novel adipokine, exerts beneficial effects on obesity-associated disorders and cardiovascular homeostasis. The objective of this study was to investigate the effects of high Ald levels on apelin expression and secretion and the underlying mechanisms involved in adipocytes. In vivo, a single-dose Ald injection acutely decreased apelin serum levels and adipose tissue apelin production, which demonstrates a clear inverse relationship between the levels of plasma Ald and plasma apelin. Experiments using 3T3-L1 adipocytes showed that Ald decreased apelin expression and secretion in a time- and dose-dependent manner. This effect was reversed by glucocorticoid receptor (GR) antagonists or GR (NR3C1) knockdown; furthermore, putative HREs were identified in the apelin promoter. Subsequently, we verified that both glucocorticoids and mineralocorticoids regulated apelin expression through GR activation, although no synergistic effect was observed. Additionally, detailed potential mechanisms involved a p38 MAPK signaling pathway. In conclusion, our findings strengthen the fact that there is a direct interaction between Ald and apelin in adipocytes, which has important implications for hyperaldosteronism or PA-associated cardiometabolic syndrome and hoists apelin on the list of potent therapeutic targets for PA.

Context:

Primary aldosteronism (PA) represents the most frequent cause of secondary arterial hypertension. Conflicting data have been published regarding the effect of aldosterone excess on glucose metabolism.

Objective:

Our aim was to analyze insulin sensitivity and beta cell function in a cohort of PA patients. Prospective follow-up investigations were performed in a subgroup of patients before and after adrenalectomy to assess the metabolic outcome.

Design:

Oral glucose tolerance test, combined intravenous glucose tolerance test (ivGTT) - hyperinsulinaemic-euglycaemic glucose clamp test and arginine test were carried out after a 12-hour fasting period.

Patients:

22 consecutive patients with both unilateral aldosterone producing adenoma and bilateral idiopathic adrenal hyperplasia were recruited through the Munich center of the German Conn's Registry. The control group of patients with essential hypertension (EH, n=11) of corresponding age and BMI was recruited from our hypertension unit. A normotensive cohort (n=11) served as a further control group.

Results:

At baseline, first phase insulin reaction in ivGTT was significantly reduced in patients with PA as compared to normal controls (36.0 [24.0;58.7] vs. 90.1 [52.6;143.8] μU/ml, p=0.031) and lower in comparison to EH without reaching statistical significance (53.2 [30.8;73.3] μU/ml, p=0.123). The study was repeated 6 months after unilateral adrenalectomy in 9 consecutive patients with aldosterone producing adenoma. At this time point, blood pressure had been normalized in the majority of patients while BMI remained unchanged (26.9 [25.5;37.6] vs. 27.5 [25.1;35.6] kg/m2, p=0.401). First phase insulin reaction in response to glucose significantly increased at follow-up (from 36.0 [25.5;58.7] to 48.5 [40.4;95.2] μU/ml, p=0.038, n=9). In contrast, insulin sensitivity and response to i.v. arginine did not differ before and after adrenalectomy.

Conclusion:

Aldosterone excess has a direct negative effect on beta cell function in patients with PA. After adrenalectomy, glucose induced first phase insulin secretion improves significantly in the patients.

Blessed were the days when it all made sense and the apparent mechanism for edema formation in nephrotic syndrome was straightforward: the kidneys lost protein in the urine, which lowered the plasma oncotic pressure. Thus, fluid leaked into the interstitium, depleting the intravascular volume with subsequent activation of renin/aldosterone and consequent avid renal sodium retention. As simple as that! Unfortunately, a number of clinical and laboratory observations have raised serious concerns about the accuracy of this "underfill" hypothesis. Instead, an "overfill" hypothesis was generated. Under this assumption, the nephrotic syndrome not only leads to urinary protein wasting, but also to primary sodium retention with consequent intravascular overfilling, with the excess fluid spilling into the flood plains of the interstitium, leading to edema. Recently, an attractive mechanism was proposed to explain this primary sodium retention: proteinuria includes plasma proteinases, such as plasmin, which activate the epithelial sodium channel in the collecting duct, ENaC. In this edition, further evidence for this hypothesis is being presented by confirming increased plasmin content in the urine of children with nephrotic syndrome and demonstrating ENaC activation. If correct, this hypothesis would provide a simple treatment for the edema: pharmacological blockade of ENaC, for instance, with amiloride. Yet, how come clinicians have not empirically discovered the presumed power of ENaC blockers in nephrotic syndrome? And why is it that some patients clearly show evidence of intravascular underfilling? The controversy of over- versus underfilling demonstrates how much we still have to learn about the pathophysiology of nephrotic syndrome.

BACKGROUND:

In primary aldosteronism (PA), lateralized aldosterone excess can be treated with aldosterone antagonists or surgery, which raises the question as to whether surgery or medications should be the preferred management. A difference in required patient follow-up/clinic resource utilization might provide a surrogate estimate of the comparative outcome efficacy of medical versus surgical therapy.

METHODS:

From a retrospective review of our adrenal vein sampling (AVS) database June 2005 to August 2011, we chose all patients with PA who were surgical candidates and investigated with AVS. There were 77 subjects; 38 (with aldosteronoma) had unilateral adrenalectomy, and 39 (7 aldosteronoma and 32 hyperplasia) were treated with primary medical therapy. After AVS, patients with nonsurgical disease immediately started mineralocorticoid antagonists and follow-up measured from the AVS date. Surgical patients were seen in the clinic immediately after hospital discharge and follow-up measured from the operative date. Target BP was <140/90 before discharge to the community.

RESULTS:

Total follow-up ranged from 1 to 55 months, and 4 subjects were lost to follow-up. Mean follow-up in the medical and surgical groups was 13.4 versus 6.5 months (p < 0.004). There was a trend toward more clinic visits for the medical group (7.0 vs 5.2, p = 0.17).

CONCLUSIONS:

Most PA patients can be managed by medical or surgical approaches. Medically treated patients require much longer-term follow-up to manage their condition, whereas most surgical patients can be successfully discharged shortly after surgery. When possible, surgical management may represent a more expeditious means of treating PA.

In patients with primary aldosteronism who have bilateral adrenal incidentalomas, it is important to identify which adrenal gland is secreting excess aldosterone. Traditionally, adrenal vein sampling (AVS) has been performed for lateralization despite its invasiveness. Here we report a case of bilateral adrenal incidentaloma in which 18-Fluorodeoxyglucose (FDG)-positron emission tomography (PET) was used to identify the functional adrenal mass. A 53-yr-old man was referred to our clinic due to bilateral adrenal incidentalomas (right: 1 cm, left: 2.5 cm) on computed tomography (CT). Given his history of colon cancer, FDG-PET/CT scanning was used to rule out metastasis. Although there was focal hot uptake lesion in the right adrenal gland, the patient was suspected primary aldosteronism clinically more than metastasis because of the patient's underlying hypertension with hypokalemia. It was consistent with the results of AVS. Based on these findings, we propose that FDG-PET/CT can be used instead of AVS to identify the source of primary aldosteronism between two bilateral adrenal incidentalomas.