Sven Diederich

Cardiovascular and Cerebrovascular Comorbidities of Hypokalemic and Normokalemic Primary Aldosteronism: Results of the German Conn’s Registry

CONTEXT Primary aldosteronism (PA) is associated with vascular end-organ damage. OBJECTIVE Our objective was to evaluate differences regarding comorbidities between the hypokalemic and normokalemic form of PA. DESIGN AND SETTING This was a retrospective cross-sectional study collected from six German centers (German Conns registry) between 1990 and 2007. PATIENTS Of 640 registered patients with PA, 553 patients were analyzed. MAIN OUTCOME MEASURES Comorbidities depending on hypokalemia or normokalemia were examined. RESULTS Of the 553 patients (61 +/- 13 yr, range 13-96), 56.1% had hypokalemic PA. The systolic (164 +/- 29 vs. 155 +/- 27 mm Hg; P < 0.01) and diastolic (96 +/- 18 vs. 93 +/- 15 mm Hg; P < 0.05) blood pressures were significantly higher in hypokalemic patients than in those with the normokalemic variant. The prevalence of cardiovascular events (angina pectoris, myocardial infarction, chronic cardiac insufficiency, coronary angioplasty) was 16.3%. Atrial fibrillation occurred in 7.1% and other atrial or ventricular arrhythmia in 5.2% of the patients. Angina pectoris and chronic cardiac insufficiency were significantly more prevalent in hypokalemic PA (9.0 vs. 2.1%, P < 0.001; 5.5 vs. 2.1%, P < 0.01). Overall, cerebrovascular comorbidities were not different between hypokalemic and normokalemic patients, however, stroke tended to be more prevalent in normokalemic patients. CONCLUSIONS Our data indicate a high prevalence of comorbidities in patients with PA. The hypokalemic variant is defined by a higher morbidity than the normokalemic variant regarding some cardiovascular but not cerebrovascular events. Thus, PA should be sought not only in hypokalemic but also in normokalemic hypertensives because high-excess morbidity occurs in both subgroups.

Risk factors associated with a low glomerular filtration rate in primary aldosteronism.

CONTEXT Primary aldosteronism (PA) is associated with vascular end organ damage. OBJECTIVE We evaluated the newly established German Conns Registry for evidence of renal impairment and compared the data with those from hypertensive subjects of a population-based survey. DESIGN We conducted a case-control study. PATIENTS AND CONTROLS A total of 408 patients with PA from the Conns registry treated in five German centers were matched for age, sex, and body mass index in a 1:1 ratio with 408 hypertensive control subjects from the population-based F3 survey of the Kooperative Gesundheitsforschung in the region of Augsburg (KORA). MAIN OUTCOME MEASURES We measured serum creatinine and calculated glomerular filtration rate (GFR). RESULTS The percentage of patients with a serum creatinine concentration above the normal range of 1.25 mg/dl was higher in patients with PA than in hypertensive controls (29 vs. 10%; P < 0.001). Regression analysis showed that age, male sex, low potassium, and high aldosterone concentrations were independent predictors of a lower GFR. Adrenalectomy reduced systolic blood pressure from a mean of 160 to 144 mm Hg. In parallel, we observed an increase in serum creatinine and a decrease of GFR from 71 to 64 ml/min (P < 0.001). A similar trend was seen after spironolactone treatment. CONCLUSIONS In a large cohort of patients with PA, markers of disease activity such as plasma aldosterone and serum potassium are independent predictors of a lower GFR. Specific interventions, such as adrenalectomy or spironolactone treatment, are associated with a further decline in GFR.

Bone Mineral Density Is Not Significantly Reduced in Adult Patients on Low-Dose Glucocorticoid Replacement Therapy

CONTEXT Patients with primary adrenal insufficiency (PAI) and patients with congenital adrenal hyperplasia (CAH) receive glucocorticoid replacement therapy, which might cause osteoporosis. OBJECTIVES Questions addressed by this study were: 1) Is bone mineral density (BMD) reduced in PAI and CAH on lower glucocorticoid doses than previously reported? 2) Is BMD in PAI influenced by the type of glucocorticoid used? and 3) Does DHEA treatment affect BMD in PAI women? DESIGN AND PATIENTS We conducted a prospective, cross-sectional study including 81 PAI patients and 41 CAH patients. MAIN OUTCOME MEASURES BMD was measured by dual-energy x-ray absorptiometry. Serum levels of bone turnover markers, minerals, vitamins, hormones, and urinary crosslinks were measured. RESULTS PAI and CAH patients received average daily hydrocortisone doses of 12.0 ± 2.7 mg/m(2) (range, 4.9-19.1) and 15.5 ± 7.8 mg/m(2) (range, 5.7-33.7), respectively. BMD varied within the normal reference range (-2 to +2) in both cohorts. However, lower Z-scores for femoral neck and Wards region were found in CAH compared to PAI women, but not in men. Prednisolone treatment showed significant lower osteocalcin levels and lower Z-scores for lumbar spine and femoral neck compared to PAI patients on hydrocortisone. PAI women treated with DHEA had significantly lower urinary collagen crosslinks and bone alkaline phosphatase, and significantly higher Z-scores in lumbar spine and femoral Wards region compared to non-DHEA-treated women. CONCLUSIONS Adult PAI and CAH patients on low glucocorticoid doses showed normal BMD within the normal reference range. The use of longer acting prednisolone resulted in significantly lower BMD in PAI. In addition, DHEA treatment may have a beneficial effect on bone in Addisons women.

Intravenous Lipid and Heparin Infusion-Induced Elevation in Free Fatty Acids and Triglycerides Modifies Circulating Androgen Levels in Women: A Randomized, Controlled Trial

BACKGROUND The polycystic ovarian syndrome (PCOS) is characterized by hyperandrogenism and associated with obesity and impaired glucose metabolism. Despite the high prevalence of PCOS and the considerable clinical impact, the precise interplay between metabolism and hyperandrogenemia is not entirely clear. OBJECTIVE The objective of the study was to analyze the effects of iv lipid and heparin infusion on circulating androgen levels in healthy women. DESIGN This was a randomized, controlled, crossover trial. SETTING The study was conducted at an endocrinology center. PATIENTS Patients included 12 healthy young women during the early follicular phase of two subsequent cycles. INTERVENTION After an overnight fast, a 20% lipid/heparin or a saline/heparin infusion was administered in random order for 330 min. MAIN OUTCOME MEASURES A detailed characterization of androgen metabolism was performed. RESULTS Elevations in free fatty acids and triglycerides, induced by lipid/heparin infusion, elevates the levels of androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), testosterone, 5alpha-dihydrotestosterone, estrone, and 17beta-estradiol. Urinary excretion of DHEA, DHEAS, 5-androstene-3beta,17beta-diol, and the sum of urinary excreted DHEA and its 16-hydroxylated downstream metabolites, 16alpha-hydroxy-DHEA and 5-androstene-3beta,16alpha,17beta-triol, were reduced. CONCLUSION The mechanism of iv lipid and heparin infusion-induced elevation of circulating androgens described here might contribute to the development of hyperandrogenism in women with PCOS and suggests that lowering of hyperlipidemia might be a potential therapeutic target in patients with PCOS to treat hyperandrogenemia.

Clinical validation for the aldosterone-to-renin ratio and aldosterone suppression testing using simultaneous fully automated chemiluminescence immunoassays

Background: As larger numbers of hypertensive patients are screened for primary aldosteronism with the aldosterone-to-renin ratio (ARR), automated analyzers present a practical solution for many laboratories. We report the method-specific ARR cutoff determined with direct, automated chemiluminescence immunoassays allowing the simultaneous measurement of plasma aldosterone concentrations (PACs) and plasma renin concentrations (PRCs). Methods: Method comparisons to commonly employed assays and tandem mass spectrometry were undertaken. Patients were previously diagnosed based on the local ARR cutoff of 1.2 (ng/dl)/(&mgr;IU/ml) in samples collected in upright seated position. Lack of aldosterone suppression in response to salt load to less than 5 ng/dl confirmed primary aldosteronism. For the new assays, the optimal ARR cutoff was established in 152 patients with essential hypertension, 93 with primary aldosteronism and 147 normotensive patients. Aldosterone suppression was assessed in 73 essential hypertensive and 46 primary aldosteronism patients. Results: PAC and PRC were significantly correlated to values determined with currently available methods (P < 0.001). In patients with primary aldosteronism, patients with essential hypertension and controls, mean (95% confidence interval) PAC was 28.4 (25.4–31.8), 6.4 (5.9–6.9) and 6.2 (5.6–6.9) ng/dl, respectively. In the same groups, PRC was 6.6 (5.6–7.7), 12.9 (11.2–14.8) and 26.5 (22.2–31.5) &mgr;IU/ml. An ARR cutoff of 1.12 provided 98.9% sensitivity and 78.9% specificity. Employing the new assay aldosterone suppression confirmed the diagnosis of primary aldosteronism and essential hypertension using the cutoff of 5 ng/dl. Conclusion: Our data demonstrate that the new assays present a convenient alternative for the measurement of PAC and PRC on a single automated analyzer. Availability of these simultaneous assays should facilitate screening and diagnosis of primary aldosteronism.

Rosiglitazone decreases 11β-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue

Objective  The peroxisome proliferator‐activated receptor‐γ (PPARγ) agonist rosiglitazone increases insulin sensitivity, which, in animal models, is comparable to the effect of a reduction in 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) activity. We therefore investigated whether rosiglitazone‐induced insulin sensitivity is associated with changes in 11β‐HSD1 activity in different tissues.

BclI polymorphism of the glucocorticoid receptor gene is associated with increased bone resorption in patients on glucocorticoid replacement therapy

Patients with primary adrenal insufficiency (PAI) and patients with congenital adrenal hyperplasia (CAH) receive weight‐adapted standard glucocorticoid replacement therapy. Clinically, some patients appear more sensitive to therapeutic administration of glucocorticoids than others. Glucocorticoid sensitivity is at least partially genetically determined by polymorphisms of the glucocorticoid receptor (GR) and might influence bone mineral density (BMD).

Diagnosis of primary hyperaldosteronism

ZusammenfassungDer primäre Hyperaldosteronismus ist die häufigste sekundäre Hypertonieform. Eine entsprechende Diagnostik wird bei hypokaliämischer Hypertonie, therapieresistenter Hypertonie (mindestens drei Medikamente und RR > 140/90 mmHg) und beim adrenalen Inzidentalom (= zufällig entdeckter Nebennierentumor) empfohlen.Zum Screening wird der Quotient aus Plasmaaldosteron- (PAC) und Plasmareninkonzentration (PRC) bestimmt. Bei der Beurteilung des PAC/PRC-Quotienten sind das Einhalten von Medikamentenpausen und die assayspezifischen Cut-off-Werte zu beachten.Nach positivem Screeningtest muss zur Diagnosesicherung ein Kochsalzbelastungstest durchgeführt werden. Bei Kontraindikationen/Undurchführbarkeit dieses Tests kann als alternativer Bestätigungstest eine 24-h-Urinsammlung auf Aldosteron-18-Glucuronid unter kochsalzreicher Ernährung eingesetzt werden.Nach Diagnosesicherung des primären Hyperaldosteronismus muss die Differentialdiagnostik zwischen aldosteronproduzierendem Adenom und idiopathischem Hyperaldosteronismus erfolgen. Hierzu stehen CT oder MRT der Nebennieren, Renin-Aldo-Orthostasetest und als Goldstandardtest die seitengetrennte Nebennierenvenenkatheterisierung zur Verfügung.Die Therapie des aldosteronproduzierenden Adenoms erfolgt operativ, die des idiopathischen Hyperaldosteronismus medikamentös mit Spironolacton.AbstractPrimary hyperaldosteronism is the most common secondary form of hypertension. Diagnosis of this entity is recommended in hypokalemic hypertension, in therapy-resistant hypertension (at least three 3 drugs and RR > 140/90 mmHg), and in adrenal incidentalomas (= incidentally discovered adrenal tumors).For screening, the ratio between plasma aldosterone (PAC) and plasma renin concentration (PRC) should be measured. In the assessment of PAC/PRC ratio, the discontinuation of some antihypertensive medication and assay-specific cutoff values must be noticed.After a positive screening test, saline infusion test should be done as confirmatory test. In contraindications/impracticability of this test, 24-h urine collection for aldosterone-18-glucuronide under high-sodium diet can be used as alternative confirmatory test.After confirmation of primary hyperaldosteronism, differential diagnosis between aldosterone-producing adenoma and idiopathic hyperaldosteronism has to be done. For this approach, adrenal CT or MRT, posture test and adrenal vein catheterization as gold standard test are available.Whereas therapy of aldosterone-producing adenoma is surgery, idiopathic hyperaldosteronism is to be treated medically by spironolactone.

Diagnostik des primären Hyperaldosteronismus

ZusammenfassungDer primäre Hyperaldosteronismus ist die häufigste sekundäre Hypertonieform. Eine entsprechende Diagnostik wird bei hypokaliämischer Hypertonie, therapieresistenter Hypertonie (mindestens drei Medikamente und RR > 140/90 mmHg) und beim adrenalen Inzidentalom (= zufällig entdeckter Nebennierentumor) empfohlen.Zum Screening wird der Quotient aus Plasmaaldosteron- (PAC) und Plasmareninkonzentration (PRC) bestimmt. Bei der Beurteilung des PAC/PRC-Quotienten sind das Einhalten von Medikamentenpausen und die assayspezifischen Cut-off-Werte zu beachten.Nach positivem Screeningtest muss zur Diagnosesicherung ein Kochsalzbelastungstest durchgeführt werden. Bei Kontraindikationen/Undurchführbarkeit dieses Tests kann als alternativer Bestätigungstest eine 24-h-Urinsammlung auf Aldosteron-18-Glucuronid unter kochsalzreicher Ernährung eingesetzt werden.Nach Diagnosesicherung des primären Hyperaldosteronismus muss die Differentialdiagnostik zwischen aldosteronproduzierendem Adenom und idiopathischem Hyperaldosteronismus erfolgen. Hierzu stehen CT oder MRT der Nebennieren, Renin-Aldo-Orthostasetest und als Goldstandardtest die seitengetrennte Nebennierenvenenkatheterisierung zur Verfügung.Die Therapie des aldosteronproduzierenden Adenoms erfolgt operativ, die des idiopathischen Hyperaldosteronismus medikamentös mit Spironolacton.AbstractPrimary hyperaldosteronism is the most common secondary form of hypertension. Diagnosis of this entity is recommended in hypokalemic hypertension, in therapy-resistant hypertension (at least three 3 drugs and RR > 140/90 mmHg), and in adrenal incidentalomas (= incidentally discovered adrenal tumors).For screening, the ratio between plasma aldosterone (PAC) and plasma renin concentration (PRC) should be measured. In the assessment of PAC/PRC ratio, the discontinuation of some antihypertensive medication and assay-specific cutoff values must be noticed.After a positive screening test, saline infusion test should be done as confirmatory test. In contraindications/impracticability of this test, 24-h urine collection for aldosterone-18-glucuronide under high-sodium diet can be used as alternative confirmatory test.After confirmation of primary hyperaldosteronism, differential diagnosis between aldosterone-producing adenoma and idiopathic hyperaldosteronism has to be done. For this approach, adrenal CT or MRT, posture test and adrenal vein catheterization as gold standard test are available.Whereas therapy of aldosterone-producing adenoma is surgery, idiopathic hyperaldosteronism is to be treated medically by spironolactone.

In vivo activity of 11β-hydroxysteroid dehydrogenase type 1 and free fatty acid-induced insulin resistance

Introduction  Free fatty acids (FFAs) induce hepatic insulin resistance and enhance hepatic gluconeogenesis. Glucocorticoids (GCs) also stimulate hepatic gluconeogenesis. The aim of this study was to investigate whether the FFA‐induced hepatic insulin resistance is mediated by increased activity of hepatic 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1), accompanied by elevated hepatic cortisol levels.