Richard D. Gordon

High incidence of primary aldosteronism in 199 patients referred with hypertension.

1. This study sought to assess the incidence of primary aldosteronism in 199 hypertensives who were normokalaemic and in whom the question of primary aldosteronism had never been raised.

Mutations in Kelch-like 3 and Cullin 3 cause hypertension and electrolyte abnormalities

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K+ and H+ excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin–RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na–Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na–Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K+ and pH homeostasis.

Markers for monitoring overtraining and recovery

Physiological and mood state parameters were monitored during a 6-month swimming season in an attempt to determine markers of overtraining and recovery. Fourteen elite male and female swimmers were tested early-, mid-, and late-season and shortly before and after major competition. Training details and subjective ratings of well-being were compiled by the athletes in daily logs. Three swimmers were classified as stale based upon performance deterioration and prolonged, high fatigue levels. Staleness scores were calculated for each athlete using performance change from early- to late-season and daily fatigue ratings for the season. Regression analysis revealed a battery of well-being ratings which predicted staleness scores, accounting for 76% of the variance. The late-season stress ratings and plasma catecholamine levels at rest predicted staleness scores, accounting for 85% of the variance. During tapering, well-being ratings predicted improvement in competitive performance, accounting for 72% of the variance of the improvement in race times from previous best times. It was concluded that self-reported ratings of well-being may provide an efficient means of monitoring both overtraining and recovery; plasma catecholamine levels at rest may provide an additional objective tool for diagnosis.

Evidence that primary aldosteronism may not be uncommon : 12% incidence among antihypertensive drug trial volunteers

1. Six (12%) out of 52 respondents to newspaper advertisements for antihypertensive drug trials had elevated aldosterone to renin ratio, confirmed by repeated measurement.

The Adrenal Vein Sampling International Study (AVIS) for Identifying the Major Subtypes of Primary Aldosteronism

CONTEXT In patients who seek surgical cure of primary aldosteronism (PA), The Endocrine Society Guidelines recommend the use of adrenal vein sampling (AVS), which is invasive, technically challenging, difficult to interpret, and commonly held to be risky. OBJECTIVE The aim of this study was to determine the complication rate of AVS and the ways in which it is performed and interpreted at major referral centers. DESIGN AND SETTINGS The Adrenal Vein Sampling International Study is an observational, retrospective, multicenter study conducted at major referral centers for endocrine hypertension worldwide. PARTICIPANTS Eligible centers were identified from those that had published on PA and/or AVS in the last decade. MAIN OUTCOME MEASURE The protocols, interpretation, and costs of AVS were measured, as well as the rate of adrenal vein rupture and the rate of use of AVS. RESULTS Twenty of 24 eligible centers from Asia, Australia, North America, and Europe participated and provided information on 2604 AVS studies over a 6-yr period. The percentage of PA patients systematically submitted to AVS was 77% (median; 19-100%, range). Thirteen of the 20 centers used sequential catheterization, and seven used bilaterally simultaneous catheterization; cosyntropin stimulation was used in 11 centers. The overall rate of adrenal vein rupture was 0.61%. It correlated directly with the number of AVS performed at a particular center (P = 0.002) and inversely with the number of AVS performed by each radiologist (P = 0.007). CONCLUSIONS Despite carrying a minimal risk of adrenal vein rupture and at variance with the guidelines, AVS is not used systematically at major referral centers worldwide. These findings represent an argument for defining guidelines for this clinically important but technically demanding procedure.

Review: Diagnosis and management of primary aldosteronism

JRAAS 2001;2:156-69 Introduction Primary aldosteronism (PAL) is characterised by aldosterone production which is excessive to the body’s requirements and relatively autonomous of its normal chronic regulator, angiotensin II (Ang II). Inappropriate aldosterone production results in excessive reabsorption of sodium via the amiloride-sensitive epithelial sodium channels situated within the distal tubule and collecting duct of the kidney (leading to hypertension), and continues in the face of suppression of the reninangiotensin system (RAS). Urinary loss of potassium, which is exchanged for sodium at the distal nephron, may eventually result in hypokalaemia if severe and prolonged enough. Because measurements of plasma aldosterone and plasma renin activity (PRA) have become readily available, it is now feasible to measure their relationship in all hypertensive patients. The wide application of the aldosterone/PRA ratio (ARR) has permitted the diagnosis of PAL in the absence of hypokalaemia,and more commonly, in fact, than in the presence of hypokalaemia. This has led to a new understanding that PAL is not a rare cause of hypertension, to be suspected only when hypokalaemia is present, but is probably the commonest, identifiable, specifically treatable and potentially curable form of hypertension. With most recent studies reporting prevalence rates for PAL that are much higher than those previously described in medical textbooks and reviews on the subject, the diagnosis of PAL is likely to become an increasingly frequent event. The ability to correctly apply diagnostic techniques involved in the workup of PAL and to interpret their results therefore represent skills of increasing importance for physicians who treat hypertension. This review focuses on the rationale and methodology of these diagnostic techniques, and on current approaches to management of patients with PAL.

Primary aldosteronism - careful investigation is essential and rewarding

Once considered rare, primary aldosteronism (PAL) is now regarded as the commonest potentially curable and specifically treatable form of hypertension. At Greenslopes Hospital Hypertension Unit (GHHU), the decision in 1991 to screen all (and not just hypokalemic or resistant) hypertensives by aldosterone/renin ratio (ARR) testing led to a 10-fold increase in detection rate of PAL and four-fold increase in removal rate of aldosterone-producing adenomas (APAs). The GHHU/Princess Alexandra Hospital Hypertension Unit PAL series stands at 977 patients and 250 APAs removed with hypertension cured in 50-60% (remainder improved). Reliable detection requires that interfering medications are withdrawn (or their effects considered) before ARR measurement, and reliable methods (such as fludrocortisone suppression testing) to confirm PAL. Adrenal venous sampling is the only dependable way to differentiate APA from bilateral adrenal hyperplasia. Genetic testing has facilitated detection of glucocorticoid-remediable, familial PAL. Identification of mutations causing the more common familial variety described by GHHU in 1991 should further aid in detection of PAL.

Hormonal, immunological, and hematological responses to intensified training in elite swimmers

The purpose of this study was to compare the responses of selected hormonal, immunological, and hematological variables in athletes showing symptoms of overreaching with these variables in well-trained athletes during intensified training. Training volume was progressively increased over 4 wk in 24 elite swimmers (8 male, 16 female); symptoms of overreaching were identified in eight swimmers based on decrements in swim performance, persistent high ratings of fatigue, and comments in log books indicating poor adaptation to the increased training. Urinary excretion of norepinephrine was significantly lower (P < 0.05, post hoc analysis) in overreached (OR) compared with well-trained (WT) swimmers throughout the 4 wk. There were no significant differences between OR and WT swimmers for other variables including: concentrations of plasma norepinephrine, cortisol, and testosterone, and the testosterone/cortisol ratio; peripheral blood leukocyte and differential counts, neutrophil/lymphocyte ratio, and CD4/CD8 cell ratio; serum ferritin and blood hemoglobin concentrations, erythrocyte number, hematocrit, and mean red cell volume (MCV). MCV increased significantly over the 4 wk in both groups, suggesting increased red blood cell turnover. These data show that, of the 16 hormonal, immunological, and hematological variables measured, urinary norepinephrine excretion appears to be the only one to distinguish OR from WT swimmers during short-term intensified training. Low urinary norepinephrine excretion was observed 2 to 4 wk before the appearance of symptoms of overreaching, suggesting the possibility that neuroendocrine changes may precede, and possibly contribute to, development of the overreaching/overtraining syndromes.

Hormonal Responses of Elite Swimmers to Overtraining

Fourteen elite swimmers had measurements of stress hormones taken at five points during a 6-month season: early-, mid- and late-season, during tapering for National Trials, and 1-3 d after the Trials. Training details and subjective ratings of fatigue were recorded daily in log books. Plasma norepinephrine and epinephrine concentrations were significantly correlated with swim training volume (r = 0.37 and 0.33, respectively, P < 0.05 for each). No significant differences were seen in norepinephrine or cortisol concentrations at the five sampling times. Epinephrine levels were significantly lower (P < 0.05) after competition compared with values early in the season and shortly before competition. Symptoms of the overtraining syndrome were identified in three of the swimmers, based on performance decrements and high, prolonged levels of fatigue. In these three swimmers, norepinephrine levels tended to be higher than those of the other swimmers from mid-season onward and were significantly higher (P < 0.01) during tapering. If these findings can be confirmed in larger numbers and different types of athletes, norepinephrine level may provide a useful marker of the overtraining syndrome.

Clinical and pathological diversity of primary aldosteronism, including a new familial variety.

1. Of 93 patients with primary aldosteronism seen during a 20 year period, 52 had an aldosterone‐producing adenoma (APA) removed (five more await surgery), 14 had bilateral adrenal hyperplasia (BAH), three had glucocorticoid‐suppressible hyperaldosteronism (GSH), one had adrenal carcinoma and 18 are yet to be categorized.