John C. Rutherford

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.

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: Are we diagnosing and operating on too few patients?

Many cases of potentially curable primary aldosteronism are currently likely to be diagnosed as essential hypertension unless screening tests based on suppression of renin are carried out in all hypertensive patients. More than half of the patients with primary aldosteronism detected in this way have normal circulating potassium levels, so measurement of potassium is not enough to exclude primary aldosteronism. When primary aldosteronism is diagnosed, fewer than one-third of patients are suitable for surgery as initial treatment, but this still represents a significant percentage of hypertensive patients. After excluding glucocorticoid-suppressible primary aldosteronism, adrenal venous sampling is essential to detect unilateral production of aldosterone and diagnose angiotensin-responsive aldosterone-producing adenoma. One cannot rely on the computed tomography scan. If all hypertensive patients are screened for primary aldosteronism and the workup is continued methodically in those with a positive screening test, patients with unilateral overproduction of aldosterone who potentially can be cured surgically are not denied the possibility of cure. Beaucoup de patients ayant un hyperaldostéronisme primitif potentiellement curables seraient classé atteints d’hypertension artérielle essentielle, si on ne réalise pas des tests de dépistage basés sur la suppression de rénine chez tous les patients hypertendus. Plus de la moitié des patients ayant un hyperaldostéronisme primitif détecté de cette manière ont un taux de kaliémie normale si bien que le dosage de la kaliémie n’est pas suffisant pour exclure un hyperaldostéronisme primitif. Lorsqu’on fait le diagnostic d’hyperaldostéronisme primitif, moins d’un tiers de ces patients sont candidats à la chirurgie comme traitement initial, mais ceci représente encore un pourcentage important de patients hypertendus. Après avoir exclus un certain nombre de patients ayant un hyperaldostéronisme primitif glucocorticoïdesuppressible, il faut avoir un échantillon du sang veineux provenant de la surrénale pour faire le diagnostic d’adénome produisant de Faldostérone angiotensine-dépendant. On ne peut compter sur la tomodensitométrie. Si l’on fait un test de dépistage chez tous les patients hypertendus pour l’hyperaldostéronisme primitif, et le bilan est continué de façon méthodique chez ceux qui sont positifs au premier bilan, on ne doit pas manquer de détecter tous les patients ayant une hyperproduction unilatérale d’aldostérone potentiellement curables et ensuite opérés. En la actualidad muchos pacientes con aldosteronismo primario potencialmente curable aparecen cobijados bajo el sello de hipertensión esencial, a menos que se realicen pruebas de tamizaje basadas en la supresión de renina en todo paciente hipertenso. Más de la mitad de los pacientes con aldosteronismo primario así detectados muestran niveles normales de potasio, de modo que la determinatión del potasio no es suficiente para descartar el aldosteronismo primario. Cuando se diagnostica el aldosteronismo primario, menos de la tercera parte de los pacientes resultan candidatos para cirugía como tratamiento inicial, y éste sigue representando un porcentaje significativo de los pacientes hipertensos. Luego de excluir un aldosteronismo primario supresible por glucocorticoides, es esencial el muestreo venoso para detectar la producción unilateral de aldosterona y para el diagnóstico de un adenoma productor de aldosterona que responda a la angiotensina. La tomografla computadorizada no es un método confiable. Si todo paciente hipertenso es sometido a tamizaje para aldosteronismo primario y se continua con una evaluación metódica en los que presenten prueba positiva, no se debe negar la posibilidad de curación mediante cirugía a aquellos con producción unilateral de aldosterona.

Success of Surgery for Primary Aldosteronism Judged by Residual Autonomous Aldosterone Production

AbstractSince February 1996 we have prospectively assessed residual adrenal autonomy by the fludrocortisone suppression test (FST) in 23 patients 3 months after unilateral adrenalectomy for Conn syndrome and in 45 patients after a longer interval. In regard to blood pressure, 36 (53%) patients were cured of hypertension and the remaining 32 (47%) patients had improved hypertension control at the time of their latest postoperative clinical assessment. In regard to the outcome of surgery, patients who achieved normal suppressibility of aldosterone were regarded as cured, and those who had greater suppressibility after surgery were considered improved. Time since surgery for the whole group averaged 26 months. By these biochemical criteria, 42 patients (62%) were cured by surgery, and the rest improved; 16 (76%) of 21 women were cured, and 26 (55%) of 47 men. The women (mean ± SD age 47 ± 11 years) were significantly ( p < 0.05) younger than the men (52 ± 9 years). Preoperative aldosterone levels before and after FST were similar in the cured and improved groups and fell significantly (p < 0.01) in both groups following surgery. After surgical reduction of autonomous aldosterone production, mean plasma renin activity levels increased sixfold in the cured group and threefold in the improved group. Surgical mortality in this group of 68 patients with Conn syndrome was zero.

LAPAROSCOPIC ADRENALECTOMY FOR ADRENAL TUMOURS CAUSING HYPERTENSION AND FOR ‘INCIDENTALOMAS’ OF THE ADRENAL ON COMPUTERIZED TOMOGRAPHY SCANNING

1. In a 19 month period from June 1993 to December 1994, 60 patients (mean age 54.8 ±.5 years s.e.m.; 32 males, 28 females) underwent unilateral laparoscopic adrenalectomy by one of us (JCR) for the treatment of hypertension due to primary aldosteronism (n = 48), phaeochromocytoma (n = 3) and cortisol‐producing adenoma (n = 1) or to remove adrenal masses incidentally discovered on abdominal computerized tomography scanning (‘incidentaloma’) performed for other reasons (seven adenomas without biochemical evidence of excessive steroid hormone or catecholamine secretion and one carcinoma autonomously producing cortisol).

Karyotypic abnormalities in benign adrenocortical tumors producing aldosterone

Because familial hyperaldosteronism type II (FH-II) includes tumor formation, we examined the karyotypes of benign adrenocortical aldosterone-producing adenomas (APAs), including those from patients with FH-II. Cell culture was successful in 12 of 14 tumors removed, two of which were from patients with FH-II. Five of the 12 tumors cultured (one from a patient with FH-II) had abnormal karyotypes. All were from male patients, and loss of the Y chromosome was observed in each. One showed loss of chromosome 19, and another showed an unbalanced t(6;7) producing partial trisomy 7q. Oncogenes are present at these breakpoints, and loss of the Y chromosome and monosomy 19 have previously been reported in neoplasia. This is the first report of cytogenetic abnormalities in benign adrenocortical tumors.

Adrenal cortico-medullary interactions: pheochromocytoma-associated cortical hyperplasia and benign neoplasia

There are two types of familial hyperaldosteronism: FH-I and FH-II. FH-I is caused by a hybrid CYP11B1/CYP11B2 gene mutation. The genetic cause of FH-II, which is more common, is unknown. Adrenal hyperplasia and adenomas are features. We reported linkage of FH-II to a 4 Mb region on chr 7p22. Candidate genes at 7p22 involved in cell cycle control include retinoblastoma-associated Kruppel-associated box gene (RBaK), postmeiotic segregation increased 2 (PMS2) and guanine nucleotide-binding protein alpha-12 (GNA12). RBaK interacts with the retinoblastoma gene product to repress expression of genes activated by E2F transcription factors. PMS2 is involved in DNA mismatch repair and tumor predisposition. GNA12 is a transforming oncogene. We previously reported finding no causative mutations in RBaK and PMS2 coding regions. In the current study, (1) GNA12 exons and proximal promoter were examined in two affected (A1, A2) and two unaffected (U1, U2) subjects from FH-II family 1, and a normotensive control. No mutations were found. (2) The RBaK promoter was sequenced to -1300bp from the transcription start site. Two unreported single nucleotide polymorphisms (SNPs; C-1034G and T-1021C) were found in subjects A1, A2 but not in U1, U2 or the control. Additional subjects from 7p22-linked FH-II families 1, 2 and 3 and 68 controls were therefore genotyped. Results (see table) suggest that the –1034C/-1021T allele may be in linkage disequilibrium with the causative mutation in family 1. Its frequency among controls does not exclude it, since, based on recent data from the Framingham offspring study linking aldosterone/renin ratio to rising BP and chr 7p, it could indicate those predisposed to become hypertensive. Since this sequence alters the binding sites for several transcription factors in the RBaK promoter and may contribute to FH-II phenotype, these SNPs will be genotyped in additional FH-II subjects.Due to differences in pressure amplification, central BP can differ greatly between individuals with similar brachial BP. Recent large trials have highlighted an independent role of central BP for predicting CV events. However, measuring central BP requires extra effort and dedicated equipment. This study sought to identify individuals most likely to clinically benefit from assessment of central BP. Supine brachial BP was recorded by sphygmomanometry and central BP by validated radial tonometry in a heterogeneous population of 765 people (214 healthy, 207 with known or suspected CAD, 219 with type 2 diabetes, 125 at increased risk of CVD). Normal central SBP was defined as 115 mmHg (men) or 109 mmHg (women) based on Framingham data. Amplification of SBP (SBPamp) was the difference between brachial and central SBP. Across all levels of brachial BP, there was wide variation in SBPamp (2 – 33 mmHg, mean SD, 12 5 mmHg). Normal or high-normal brachial SBP was evident in 68% (n 521) of the population. However, 47% (n 246) of these 521 people had above normal central SBP. There was no additional value (in terms of categorizing individuals as having “normal” or “high” BP) in assessing central BP in people with brachial SBP 160 mmHg because central SBP was high (139 mmHg) in all. The table shows individuals grouped according to brachial SBP and the impact of central SBP measurement on BP categorization in. In terms of further assessing whether patients have, or do not have, elevated SBP, people with normal to mild hypertension (160 mmHg) are those most likely to benefit from central BP monitoring. This does not exclude central BP monitoring as being useful in selected individuals from these or other groups.AVS plays a critical role in the diagnostic workup of primary aldosteronism (PAL) as it is the most reliable means of differentiating unilateral forms (e.g. aldosterone-producing adenoma) correctable by unilateral adrenalectomy, from bilateral forms usually treated with aldosterone antagonist medications. Examination of the adrenal/peripheral venous (AV/PV) cortisol ratio permits assessment of the adequacy of AVS. Ratios of 3 indicate adequate sampling. The right adrenal vein (RAV) is often harder to locate than the left (LAV) as it usually is smaller and empties into the inferior vena cava (IVC) rather than the renal vein at a level ranging from upper T11 to mid L1. Thus, even in highly experienced hands, the RAV cannulation success rate (87% at Princess Alexandra Hospital) is lower than that for LAV (94%). Use of contrast CT prior to AVS has contributed to high success rates achieved in our institutions by permitting visualization of the RAV at its point of entry into the IVC. We recently instituted an on-the-spot method of measuring plasma cortisol that permits determination of AV levels within 12 min of collection. Rapid cortisol estimation was performed by competitive fluorescence polarization assay using a TDx analyser and the TDx reagent system for cortisol. The standard assay for cortisol was modified by reducing the original 16 min incubation time to 6 min by following a test protocol on the analyser originally used for measuring ethosuximide. The requirement for only 50 L sample volumes allowed rapid centrifugation (4 min). Measurement of RAV and simultaneously collected PV cortisol levels was undertaken while the radiologist collected samples from the LAV, resulting in minimal or no prolongation of the AVS procedure. Cortisol levels of 1500 nmol/L could be estimated accurately, permitting reliable assessment of cannulation success provided PV levels were 500 nmol/L (which was almost always the case). This method proved accurate when compared with an established competitive chemiluminescent immunoassay (ADVIA Centaur). This approach offers a means of definitively establishing, at the time of AVS, whether AV cannulation has been successful, and thereby promises to reduce the number of samples required and the need for repeat procedures.