CONTEXT:Adrenal venous sampling (AVS) is regarded as the gold standard for diagnosis of primary aldosteronism (PA) subtypes, although some authors have questioned its diagnostic accuracy and highlighted the lack of standardized procedure protocols and interpretation criteria for AVS. In particular, the usefulness of cosyntropin stimulation and benefit of superselective adrenal vein catheterization have been hotly debated.OBJECTIVE:We report a case that highlights the potential pitfalls of superselective sampling and demonstrates a negligible effect of cosyntropin stimulation on aldosterone secretion in nonadenomatous adrenal tissue when an aldosterone-producing adenoma (APA) is present.INTERVENTION AND RESULTS:A 38-year-old man with PA and a single right macroadenoma underwent AVS at our center. The procedure was performed both under basal conditions and during cosyntropin stimulation. Right adrenal vein angiography demonstrated two branches of the main adrenal vein trunk, one draining the nodule and one draining the right adrenal gland. Hormonal assays confirmed adrenal origin of left-sided and all right-sided samples, and were consistent with lateralization on the right side, with suppression of aldosterone secretion in the left adrenal gland and in the nonadenomatous right adrenal tissue. Cosyntropin-stimulated AVS results were similar to those of the unstimulated procedure.CONCLUSIONS:Cosyntropin stimulation does not significantly affect aldosterone secretion from nonadenomatous adrenal tissue when an APA is present and can therefore be used during AVS for PA. Superselective AVS should be performed with caution and interpreted by expert clinicians.

Objective: Despite being widely recognized as the most common form of secondary hypertension, the true prevalence of primary aldosteronism (PA) and its main subtypes, aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH), among the general hypertensive population remains a matter of debate. The present study was undertaken to determine the prevalence and clinical phenotype of PA in a large cohort of unselected hypertensive patients, consecutively referred to our Hypertension Unit, by 19 general practitioners. Design and method: Patients were screened for PA using the serum aldosterone to plasma renin activity ratio after withdrawal from all interfering medications and PA was diagnosed according to the Endocrine Society guidelines. The diagnosis was confirmed/excluded by an i.v. saline infusion test or captopril challenge test and subtype differentiation was performed by adrenal CT scanning and adrenal vein sampling (AVS) using strict criteria to define both successful cannulation and lateralization of aldosterone production. Results: A total of 1,672 primary care hypertensive patients, 569 newly diagnosed hypertensives and 1,103 patients already diagnosed with arterial hypertension, were included in the study. A total of 99 patients (5.9%) were diagnosed with PA and conclusive subtype differentiation by AVS was made in 91 patients (27 patients with an APA and 64 patients with BAH). The overall prevalence of PA increased with the severity of hypertension, from 3.9% in hypertensives stage I to 11.8% in hypertensives stage III. Patients with PA more frequently displayed target organ damage and cardiovascular events compared to non-PA hypertensives, independent of confounding variables. Conclusions: The results from the present study demonstrated that PA is a frequent cause of secondary hypertension even in the general hypertensive population and indicates that the majority of hypertensive patients should be screened for PA.

BACKGROUND:Despite being widely recognized as the most common form of secondary hypertension, among the general hypertensive population the true prevalence of primary aldosteronism (PA) and its main subtypes, aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH), remains a matter of debate. OBJECTIVES:This study sought to determine the prevalence and clinical phenotype of PA in a large cohort of unselected patients with hypertension, consecutively referred to our hypertension unit, by 19 general practitioners from Torino, Italy. METHODS:Following withdrawal from all interfering medications, patients were screened for PA using the ratio of serum aldosterone to plasma renin activity. PA was diagnosed according to Endocrine Society guidelines. The diagnosis was confirmed or excluded by an intravenous saline infusion test or captopril challenge test and subtype differentiation was performed by adrenal computed tomography scanning and adrenal vein sampling, using strict criteria to define successful cannulation and lateralization of aldosterone production. RESULTS:A total of 1,672 primary care patients with hypertension (569 newly diagnosed and 1,103 patients already diagnosed with arterial hypertension) were included in the study. A total of 99 patients (5.9%) were diagnosed with PA and conclusive subtype differentiation by adrenal vein sampling was made in 91 patients (27 patients with an APA and 64 patients with BAH). The overall prevalence of PA increased with the severity of hypertension, from 3.9% in stage 1 hypertension to 11.8% in stage 3 hypertension. Patients with PA more frequently displayed target organ damage and cardiovascular events compared with those without PA, independent of confounding variables. CONCLUSIONS:Our results demonstrated that PA is a frequent cause of secondary hypertension, even in the general population of patients with hypertension, and indicates that most of these patients should be screened for PA.

Q fever is an infectious disease caused by Coxiella burnetii. Its clinical presentation is often nonspecific and the serological diagnosis difficult to make, especially in the absence of specific and suspected medical history. This article presents a case of fever of unknown origin (FUO), interpreted as an autoimmune hepatitis, later proven by the liver biopsy to be a granulomatous hepatitis caused by C. burnetii. The approach to FUO, the features of granulomatous hepatitis and Q fever are presented and discussed.

Renin-angiotensin-aldosterone system (RAAS) is recognized as the main regulatory system of hemodynamics in man, and its derangements have a key role in the development and maintenance of arterial hypertension. Classification of the hypertensive states according to different patterns of renin and aldosterone levels ("RAAS profiling") allows the diagnosis of specific forms of secondary hypertension and may identify distinct hemodynamic subsets in essential hypertension. In this review, we summarize the application of RAAS profiling for the diagnostic assessment of hypertensive patients and discuss how the pathophysiological framework provided by RAAS profiling may guide therapeutic decision-making, especially in the context of uncontrolled hypertension not responding to multi-therapy.

Objective: The aldosterone to renin ratio(ARR)is currently the most reliable available means of screening for Primary aldosteronism. It could be measured in the supine, seating or upright positions. The Endocrine Society and recent French guidelines recommended screening primary aldosteronism by the measurement of ARR in the seating position. The aim of this work is to study the influence of postural changes on ARR in patients with suspected secondary hypertension & to evaluate sensitivity and specificity of seated ARR compared to supine and upright ARR. Figure. No caption available. Design and method: 43 patients were prospectively hospitalized for secondary hypertension exploration (age 51 ± 16,5; SBP/DBP:139 ± 12/85 ± 9mmHg, number of antihypertensive drugs:2 ± 1). After a conventional washout of drugs interfering with renin angiotensin aldosterone system, plasma aldosterone concentration was measured by RIA method(Normal values: 40–175ng/l)and direct renin concentration(DRC)with CLIA method (Normal values: 4,2–59.7 &mgr;UI/l). Aldosterone and renin samples were collected in the morning, at bed after an overnight supine position, then out of bed after 1 hour of upright position and finally 2 hours later after 15 minutes in seating position. When DRC was <5 &mgr;UI/l it was counted 5 &mgr;UI/l as recommended. Results: Referring to ARR cut-off value of 23pg/&mgr;UI, the sensitivity of seated ARR was 50% with a specificity of 96.5%. The negative predictive value was 80% and the positive predictive value was 87.5%. Compared to these results, a cut-off value of 19pg/&mgr;UI improved sensitivity to 85.7% with a specificity of 89.6%. Negative predictive value and positive predictive value were 92.8%and80% respectively. Seated ARR mean value(17 ± 15pg/&mgr;UI/l) was lower than supine and upright ARR, respectively measured at 23 ± 20pg/&mgr;UI and 24 ± 20pg/&mgr;UI. This could be explained by an overall increase in DRC at seating compared to the supine position with a mean increase by factor 2.2 (53 &mgr;UI/l vs 24 &mgr;UI/l), whereas at the same time, aldosterone just slightly increased by a factor 1.05(235ng/l vs 223ng/l). Seated ARR correlated to supine and upright ARR with correlation coefficients (r)of 0.89 and 0.93 respectively (p < 0,0001). Conclusions: Current recommended measurement of ARR in the seating position is fairly correlated to ARR in supine and upright positions. However, even if the recommended cut-off value of 23pg/&mgr;UI offers a good specificity, a suggested cut-off value of 19pg/&mgr;UI increases the discriminating power of this test.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Context: Adrenal vein sampling (AVS) is the only reliable means to distinguish between aldosterone-producing adenoma and bilateral adrenal hyperplasia, the two most common subtypes of primary aldosteronism (PA). AVS protocols are not standardized and vary widely between centers. Objective: The objective of the study was to retrospectively investigate whether the presence of contralateral adrenal (CL) suppression of aldosterone secretion was associated with improved postoperative outcomes in patients who underwent unilateral adrenalectomy for PA. Setting: The study was carried out in eight different referral centers in Italy, Germany, and Japan. Patients: From 585 consecutive AVS in patients with confirmed PA, 234 procedures met the inclusion criteria and were used for the subsequent analyses. Results: Overall, 82% of patients displayed contralateral suppression. This percentage was significantly higher in ACTH stimulated compared with basal procedures (90% vs 77%). The CL ratio was inversely correlated with the aldosterone level at diagnosis and, among AVS parameters, with the lateralization index (P = .02 and P = .01, respectively). The absence of contralateral suppression was not associated with a lower rate of response to adrenalectomy in terms of both clinical and biochemical parameters, and patients with CL suppression underwent a significantly larger reduction in the aldosterone levels after adrenalectomy. Conclusions: For patients with lateralizing indices of greater than 4 (which comprised the great majority of subjects in this study), CL suppression should not be required to refer patients to adrenalectomy because it is not associated with a larger blood pressure reduction after surgery and might exclude patients from curative surgery.

Primary aldosteronism comprises subtypes that need different therapeutic strategies. Adrenal vein sampling is recognised by Endocrine Society guidelines as the only reliable way to correctly diagnose the subtype of primary aldosteronism. Unfortunately, despite being the gold-standard procedure, no standardised procedure exists either in terms of performance or interpretation criteria. In this Personal View, we address several questions that clinicians are presented with when considering adrenal vein sampling. For each of these questions we provide responses based on the available evidence, and opinions based on our experience. In particular, we discuss the most appropriate way to prepare the patient, whether adrenal vein sampling can be avoided for some subgroups of patients, the use of ACTH (1-24) during the procedure, the most appropriate criteria for interpretation of adrenal vein cannulation and lateralisation, the use of contralateral suppression, and strategies to improve success rates of adrenal vein sampling in centres with little experience.

BACKGROUNDAldosterone plays a detrimental role on the cardiovascular system and PA patients display a higher risk of events compared with EH.OBJECTIVESThe objectives of the study were to compare cardio- and cerebrovascular events in patients with primary aldosteronism (PA) and matched essential hypertension (EH).METHODSWe retrospectively compared the percentage of patients experiencing events at baseline and during a median follow-up of 12 years in 270 PA patients case-control matched 1:3 with EH patients and in PA subtypes [aldosterone-producing adenoma (n = 57); bilateral adrenal hyperplasia (n = 213)] vs matched EH.RESULTSA significantly higher number of PA patients experienced cardiovascular events over the entire period of the study (22.6% vs 12.7%, P < .001). At the diagnosis of PA, a higher number of patients had experienced total events (14.1% vs 8.4% EH, P = .007); furthermore, during the follow-up period, PA patients had a higher rate of events (8.5% vs 4.3% EH, P = .008). In particular, stroke and arrhythmias were more frequent in PA patients. During the follow-up, a higher percentage of PA patients developed type 2 diabetes. Parameters that were independently associated with the occurrence of all events were age, duration of hypertension, systolic blood pressure, presence of diabetes mellitus, and PA diagnosis. After division into PA subtypes, patients with either aldosterone-producing adenoma or bilateral adrenal hyperplasia displayed a higher rate of events compared with the matched EH patients.CONCLUSIONSThis study demonstrates in a large population of patients the pathogenetic role of aldosterone excess in the cardiovascular system and thus the importance of early diagnosis and targeted PA treatment.

Primary aldosteronism (PA) is now recognized as the most frequent form of secondary arterial hypertension. The importance of a correct and prompt diagnosis of PA is determined by its relevant prevalence, its increased cardiovascular risk compared to essential hypertension and by the possibility of reversing this increased risk with a targeted therapy. Surgical treatment of unilateral forms of PA (mainly aldosterone-producing adenomas) is at present recommended in well-selected patients because of its cost-effectiveness. Therefore, subtype differentiation of PA forms is of fundamental importance, and available guidelines recommend contrast-enhanced CT-scanning and adrenal venous sampling (AVS) as the main diagnostic tests for this purpose. In this review, we discuss the value of adrenal non-invasive imaging and AVS, the recent advances in complementary tests and, finally, the available data on the outcome of surgical treatment for PA.

Adrenal vein sampling (AVS) is fundamental for subtype diagnosis in patients with primary aldosteronism. AVS protocols vary between centers, especially for diagnostic indices and for use of adrenocorticotropic hormone (ACTH) stimulation. We investigated the role of both continuous ACTH infusion and bolus on the performance and interpretation of AVS in a sample of 76 patients with confirmed primary aldosteronism. In 36 primary aldosteronism patients, AVS was performed both under basal conditions and after continuous ACTH infusion, and in 40 primary aldosteronism patients, AVS was performed both under basal conditions and after ACTH IV bolus. Both ACTH protocols determined an increase in the rate of successful cannulation of the adrenal veins. Both ACTH infusion and bolus determined a significant increase in selectivity index for the right adrenal vein and ACTH bolus for the left adrenal vein. Lateralization index was not significantly different after continuous ACTH infusion and IV bolus. In 88% and 78% of the patients, the diagnosis obtained was the same before and after ACTH infusion and IV bolus, respectively. However, the reproducibility of the diagnosis was reduced using less stringent criteria for successful cannulation of the adrenal veins. This study shows that ACTH use during AVS may be of help for centers with lower success rates, because a successful adrenal cannulation is more easily obtained with this protocol; moreover, this technique performs at least as well as the unstimulated strategy and in some cases may be even better. Stringent criteria for cannulation should be used to have a high consistency of the diagnosis.

Primary aldosteronism is the most frequent cause of endocrine hypertension. Three forms of familial hyperaldosteronism (FH) have been described, named FH-I to -III. Recently, a mutation of KCNJ5 has been shown to be associated with FH-III, whereas the cause of FH-II is still unknown. In this study we searched for mutations in KCNJ5 in 46 patients from 21 families with FH, in which FH-I was excluded. We identified a new germline G151E mutation in 2 primary aldosteronism–affected subjects from an Italian family and 3 somatic mutations in aldosterone-producing adenomas, T158A described previously as a germline mutation associated with FH-III, and G151R and L168R both described as somatic mutations in aldosterone-producing adenoma. The phenotype of the family with the G151E mutation was remarkably milder compared with the previously described American family, in terms of both clinical and biochemical parameters. Furthermore, patients with somatic KCNJ5 mutations displayed a phenotype indistinguishable from that of sporadic primary aldosteronism. The functional characterization of the effects of the G151E mutation in vitro showed a profound alteration of the channel function, with loss of K + selectivity, Na + influx, and membrane depolarization. These alterations have been postulated to be responsible for voltage gate Ca 2+ channel activation, increase in cytosolic calcium, and stimulation of aldosterone production and adrenal cell proliferation. In conclusion, we describe herein a new mutation in the KCNJ5 potassium channel associated with FH-III, responsible for marked alterations of channel function but associated with a mild clinical and hormonal phenotype.

Primary aldosteronism (PA) is the most frequent cause of secondary ­hypertension and its prevalence increases with the severity of hypertension. The importance of PA diagnosis is not just related to offering a targeted treatment, that is, adrenalectomy, for aldosterone-producing adenoma and medical therapy with mineral­ocorticoid receptor antagonists for bilateral adrenal hyperplasia, but also because it has been demonstrated extensively that patients affected by PA are more susceptible to cardiovascular events and target organ damage compared to essential hypertensives. Herein, we review the pathophysiology of PA and its clinical features and potential complications; the three step approach employed in the diagnosis of PA, established by the Endocrine Society Guidelines, that is, screening, confirmation/exclusion, and subtype diagnosis are discussed; the rarer, familial, and sporadic genetic forms of PA are explained and we conclude with a section on targeted PA therapy.

Primary aldosteronism (PA) has a prevalence in the general hypertensive population from 5 to 10%, and is widely recognized as the most frequent form of secondary hypertension. The 2 main PA subtypes are aldosterone producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) that account for 95% of all PA cases. The diagnosis of PA is a 3-step process that comprises screening, confirmatory testing, and subtype differentiation. The different categories of patients at an increased risk of PA who should thus undergo a screening test were described in the first Endocrine Society (ES) Practice Guidelines for diagnosis and treatment of PA published in 2008. These categories include patients with Joint National Committee Stage 2, Stage 3, or drug-resistant hypertension; hypertension, and spontaneous or diuretic-induced hypokalemia; hypertension with adrenal incidentaloma; hypertension and a family history of early-onset hypertension or cerebrovascular accident at a young age and all hypertensive first degree relatives of patients with PA. Recently, a growing number of studies have linked PA with the metabolic syndrome, diabetes, and obstructive sleep apnea that may be partly responsible for the higher rate of cardio and cerobrovascular accidents in PA patients. The aim of this review is to discuss, which patients should be screened for PA, focusing not only on the well-established categories of the ES Guidelines, but also on additional other group of patients with a potentially high prevalence of PA that has emerged from recent research.

BACKGROUND:Primary aldosteronism is the most frequent cause of secondary hypertension and is responsible for an increased risk of cardiometabolic complications. A concomitant subtle cortisol hyperproduction could enhance cardiovascular risk. We prospectively estimated the occurrence of subclinical hypercortisolism in primary aldosteronism patients. METHODS:In a large population of hypertensive patients without clinical signs of hypercortisolism, 76 consecutive patients with primary aldosteronism were investigated. Differential diagnosis between unilateral and bilateral aldosterone hypersecretion was made by computed tomography/MRI and/or adrenal venous sampling (AVS). Subclinical hypercortisolism was defined as failure to suppress plasma cortisol to less than 50 nmol/l after 1 mg-overnight dexamethasone, used as screening test, and at least one of two other abnormal hormonal parameters, that is, adrenocorticotrophin (ACTH) less than 2 pmol/l and urinary cortisol more than 694 nmol/24 h. RESULTS:Three out of 76 patients had postdexamethasone plasma cortisol more than 50 nmol/l. Only one also showed low-normal ACTH and mildly elevated urinary cortisol. The patient had a right 4 cm adrenal mass. Laparoscopic adrenalectomy was followed by short-term steroid replacement to prevent adrenal insufficiency. In-situ hybridization showed CYP11B1 expression exclusively in tumoral tissue, whereas CYP11B2 was expressed only in a peritumoral region composed of zona glomerulosa-like cells, suggesting the co-existence of a cortisol-producing adenoma and an aldosterone-producing hyperplasia in the same adrenal. The restoration of hormone abnormalities to normal levels was confirmed at 12 months of follow-up. CONCLUSION:Concurrent aldosterone and subclinical cortisol hypersecretion seems to be a rare event in primary aldosteronism patients; however, its detection by appropriate testing is important to avoid AVS misinterpretation.

Methods In a large population of hypertensive patients without clinical signs of hypercortisolism, 76 consecutive patients with primary aldosteronism were investigated. Differential diagnosis between unilateral and bilateral aldosterone hypersecretion was made by computed tomography/MRI and/or adrenal venous sampling (AVS). Subclinical hypercortisolism was defined as failure to suppress plasma cortisol to less than 50 nmol/l after 1 mgovernight dexamethasone, used as screening test, and at least one of two other abnormal hormonal parameters, that is, adrenocorticotrophin (ACTH) less than 2 pmol/l and urinary cortisol more than 694 nmol/24 h.