Mining for Genes

Primary aldosteronism is the most common form of secondary hypertension and is present in about 8% to 10% of patients with hypertension. In primary aldosteronism, aldosterone secretion is excessive and relatively autonomous of the normal regulatory mechanisms.1,2 It was originally described by Jerome Conn from the University of Michigan3 and is thought to be due to an aldosterone-producing adenoma (APA) causing hypertension and hypokalemic alkalosis. Primary aldosteronism is now recognized to include a spectrum of disorders from unilateral APA to bilateral zona glomerulosa (ZG) hyperplasia, or idiopathic hyperaldosteronism. The diagnosis of all forms of primary aldosteronism is based on the finding of elevated levels of aldosterone and suppressed renin secretion.1 Differentiation between unilateral and bilateral aldosteronism is done by a combination of adrenal imaging (computed tomography or MRI) and bilateral adrenal sampling.1,2 Diagnosis of an APA is attractive because surgical therapy with unilateral adrenalectomy should cure the disease, and mechanistically, APA would suggest a single etiology of a benign neoplastic transformation of cells of the ZG producing aldosterone, regardless of the molecular mechanism. However, the histological characteristics of most adrenal tumors classified as APA are heterogeneous when one considers the surrounding adrenal cortex4 and include varying proportions of 4 different types of cells: clear cells with large vacuolated lipid–laden cytoplasm and central round nuclei similar to zona fasciculata cells; lipid-poor ZG-like cells; compact eosinophilic cells similar to those of the zona reticularis; and cells with cytological features of both ZG and zona fasciculata cells, designated hybrid cells.4 The lipid-laden fasciculata-like cells usually predominate, giving the tumors a characteristic golden yellow color, but some have more glomerulosa-like characteristics.4 However, the histological picture is far more complex, as most patients with APA also have hyperplasia of the rest of the adrenal ZG (40%) or hyperplastic nodules of ZG cells within the ZG (56%). In situ hybridization for the aldosterone synthase enzyme expression was done to demonstrate that the dominant nodule in 22 of 27 patients with the diagnosis of an adenoma was functionally significant.5 In 14 of these patients, significant but lower aldosterone synthase expression was also found in other areas of the ZG, and adrenalectomy resulted in a cure. However, in one of these patients with high aldosterone synthase expression outside the dominant adenoma, the syndrome recurred after adrenalectomy.5 Two patients in whom the expression was in smaller nodules rather than the dominant one were also not cured by adrenalectomy.2,5 APAs have been separated into the more common adenomas that are angiotensin II nonresponsive and 10% to 30% that are angiotensin II responsive, but from a diagnostic point of view they are very similar.1,2 Definition of an APA requires the presence of a unilateral adrenal mass and the lateralization of aldosterone secretion by adrenal vein sampling, as well as a therapeutic response to adrenalectomy. A high ratio of aldosterone to cortisol in the effluent from the affected, compared with unaffected, adrenal is the hallmark for diagnosis, although the exact ratio for diagnosis has been controversial,1,2 as most often aldosterone production from the unaffected adrenal is not completely suppressed. Unfortunately, a therapeutic response to adrenalectomy is frequently partial,1,2 yet some cases of clear bilateral disease have responded to unilateral adrenalectomy.6 Half to two thirds of APA patients treated surgically continue to require antihypertensive medications, albeit at lower doses or with fewer drugs.2 Partial surgical response in APA might depend on whether patients are selected on the basis of adrenal vein sampling, extent of contralateral aldosterone suppression, duration and severity of the hypertension, or age of the patient. This preamble indicates that the diagnosis of APA is not simple and that the tumors comprise a number of disparate histological and pathological entities. Several studies in the literature have attempted to determine the molecular characteristics of adrenal adenomas by using transcriptosome analysis to identify expressed genes that participate in the pathogenesis of the adenoma.7–9 The regulated genes have differed greatly between studies; in one study even aldosterone synthase was not found to be upregulated in the supposed APA of some patients!7 Such discrepant results might be due to patient selection, use of insufficiently stringent criteria for lateralization of aldosterone secretion, or inclusion of dominant nodules that did not express aldosterone synthase, rather than smaller nodules which were likely to be producing the aldosterone, as shown by other studies.5 A few studies have searched for G-protein–coupled receptor expression not normally present in adrenal gland that might be responsible for aberrant responses, and although expression is frequently present in APA, the response of patients to the hormone ligands has not been studied in most cases.2,8 The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Endocrinology, G.V. (Sonny) Montgomery VA Medical Center, and the University of Mississippi Medical Center, Jackson, Miss. Correspondence to Celso E. Gomez-Sanchez, Division of Endocrinology, G.V. (Sonny) Montgomery VA Medical Center, 1500 East Woodrow Wilson Drive, Jackson, MS 39110. E-mail [email protected] (Hypertension. 2010;55:1306-1307.) © 2010 American Heart Association, Inc.