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THE MINERALOCORTICOID HORMONE PATHWAYS IN HYPERTENSION WITH HYPERALDOSTERONISM
E.G. Biglieri, C.E. Kater, N. Brust, B. Chang and J. Hirai Medical Service, San Francisco General Hospital Medical Center, and the Department of Medicine, University of California, San Francisco San Francisco, California 94110
ABSTRACT
Simultaneous measurement of the 0800-hr plasma concentrations of deoxycorticosterone (DOC), corticosterone (B), 18-hydroxycortico- sterone (18-OHB), aldosterone, 18-hydroxydeoxycorticosterone (18-OHDOC) and cortisol (F) in four types of primary aldosteronism provides evidence for primary adrenal disease. Elevated DOC with normal F concentrations in the presence of elevated 18-OHB and aldosterone, and suppressed renin concentration suggests a primary adrenal abnormality of the zona glomerulosa (ZG). Steroid production by the zona fasciculata (ZF), F, 18-OHDOC, and most often B, is normal. These patterns exist only for primary adrenal hyperplasia, aldosterone- producing adenoma (APA), and aldosterone-producing adrenocortical carcinoma (AP-Ca). Elevated DOC levels are rarely found in patients with idiopathic hyperaldosteronism (IHA or adrenal hyperplasia) and suggest that IHA is not a primary adrenal disorder and should be excluded from the syndrome of primary aldosteronism as they have been heretofore.
INTRODUCTION
The major mineralocorticoid hormones produced by the adrenal gland have different zones of origin. DOC, B, and 18-OHB comprise the steroid precursors of the late aldosterone bio- synthetic pathway. It is difficult to determine the precise ZG contribution of DOC and B to their peripheral concentrations. Virtually all the peripheral DOC and B originate in the ZF (3).
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Administration of angiotensin II or III stimulates only ZG pro- duction of 18-OHB and aldosterone (7, 10). Adrenocorticotropin (ACTH) is the major regulator of peripheral blood levels of DOC and B. In the setting of a suppressed renin system and normal ACTH production, as occurs in primary aldosteronism, elevations of DOC and B would be indicative of a ZG origin and a marker of an abnormal increase of steroids in the late aldosterone pathway. To examine this possibility, we measured these steroids in 15 patients with an APA, 10 patients with IHA, four patients with proposed primary hyper- plasia, and three with primary aldosteronism due to an adrenocortical carcinoma.
METHODS
Patients were hospitalized in the General Clinical Research Center (RR-00083) at San Francisco General Hospital Medical Center and studied according to protocols approved by the Committee on Human Research at the University of California, San Francisco. All patients, as well as 20 normal subjects, ingested diets of fixed electrolyte content (sodium intake approximately 120 mEq/day) . After equilibration had been achieved, 0800-hr plasma samples were obtained after overnight recumbency.
Aldosterone, 18-OHB, DOC, and 18-OHDOC were measured by a radioimmunoassay developed in our laboratory (3) and F and B were determined by competitive protein binding. Plasma renin concen- tration (PRC) was assessed by radioimmunoassay of angiotensin I generated in the presence of excess heterologous renin substrate
(8). Plasma potassium and sodium were measured by internal standard flame photometry.
MATERIALS
Four groups of patients with hypertension, renal potassium wasting, suppressed PRC levels, and hyperaldosteronism were studied. Idiopathic Hyperaldosteronism (n = 10)
Plasma aldosterone concentration increased with upright posture and was not suppressed by either DOC acetate (DOCA) or saline (2). Computed axial tomography findings were compatible with hyperplasia. Primary Adrenal Hyperplasia (PAH) (n = 4)
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This group has been described (6). Unilateral adrenalectomy corrects hypertension, hypokalemia, suppressed PRC, and hyper- aldosteronism. Plasma aldosterone concentration was elevated without change or fall with upright posture. Aldosterone production was not suppressed by DOCA. Nonsurgical techniques to locate the tumor were equivocal. Hypertension and biochemical abnormalities were corrected by administration of spironolactone.
| Aldosterone ng/dl | 18-OHB ng/dl | B ng/dl | DOC ng/dl | 18-OHDOC ng/dl | |
|---|---|---|---|---|---|
| IHA (n=10) | 16.4±1.5 | 28.4+4.1 | 160±28 | 7.9±1.3 | 3.8±0.6 |
| PAH (n=4) | 33.7±3.2 | 64.4±15.6 | 400±132 | 18.8±2.5 | 7.2±3.3 |
| APA (n=15) | 52.5±9.9 | 137.4±22.2 | 365±57 | 19.3±3.6 | 8.8±1.6 |
| AP-Ca (n=3) | 105.2+56.0 | - | 218±60 | 46.5±2.1 | - |
| NCS* (n=20) | 7.8+0.4 | 18.5±1.8 | 258±31 | 7.8+0.6 | 5.6±0.8 |
Mean ± SEM
*NCS = normal control subjects
Aldosterone-Producing Adenoma (n = 15)
Unilateral adrenalectomy was performed and histologically confirmed APA removed.
Aldosterone-Producing Adrenocortical Carcinoma (n = 3)
Surgical confirmation was obtained after unilateral adrenal- ectomy for an adrenal mass and metastatic spread resulted in death (5).
RESULTS
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Plasma aldosterone and 18-OHB concentrations are elevated in all types of hyperaldosteronism. Slightest increases above normal are present in patients with IHA and highest in those with AP-Ca.
B concentrations are usually in the upper limits of the normal range but they are frequently elevated in patients with APA, PAH, and AP-Ca.
DOC levels are normal in patients with IHA but usually increased in those with APA, PAH, and AP-Ca.
18-OHDOC concentrations are normal in all types. Basal F levels, not reported, were normal in all patients.
DISCUSSION
DOC and B are precursors for 18-OHB and aldosterone in the ZG. Endogenous increases or exogenous administration of angiotensin II does not effect increased production of B or DOC. In fact, there are only two disorders in which increases in DOC may be identified as originating in the ZG: the simple virilizing form of congenital adrenal hyperplasia (3) and possibly the salt-losing
B methyl oxidase type II deficiency (9). In the former, the elevated DOC cannot be of ZF origin because the 21-hydroxylase defect is in the ZF. DOC and the steroids distal to it in the ZF, 18-OHDOC and B, are normal but unresponsive to ACTH stimulation. In the latter, the defect is only in the ZG with an exaggerated renin drive. In both of these conditions, F levels are within the normal range. Thus, a discrepancy between the levels of DOC and F suggests that when DOC is increased in the presence of normal F levels, it most likely originates in the ZG. Normally, when ACTH is increased, both DOC and F levels are elevated (1).
In patients with IHA the normal levels of B, DOC, 18-OHDOC and F, ZF steroids, suggest normalcy of that zone. The fact that DOC, in particular, is not increased, whereas in the other types of primary aldosteronism it is significantly increased in the presence of normal F levels and suppressed PRC levels, could be considered further evidence that IHA may not be a primary adrenal disorder and, therefore, that there may be another cause of the hypertension observed. Subtotal or total adrenalectomy does not cure the hypertension.
The PAH group is an emerging subset that may explain the occasional sustained cure of hypertension and hypokalemia after surgical removal of adrenal hyperplastic tissue. Their precursor patterns show an elevation in DOC in association with high levels of 18-OHB and aldosterone but normal F concentrations. In the presence of suppressed PRC and normal ZF steroid levels, the presumption is that the DOC is of ZG origin and implies a primary disorder of this zone.
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The same reasoning applies to patients with APA and AP-Ca. The further elevation of DOC in these two types further strengthens this argument because they both clearly are primary adrenal disorders. DOC is always elevated in AP-Ca (5).
The levels of B tend to be normal or slightly elevated in PAH, APA, and AP-Ca. The B levels may represent a minor contribution from the ZG.
The coupling of elevated DOC levels with elevated 18-OHB and aldosterone concentrations but a normal F level provides strong evidence that a primary adrenal disorder is present. Inclusion of its measurement may provide the necessary information to tighten the diagnosis of primary aldosteronism by excluding IHA from this classification (4).
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ACKNOWLEDGMENTS
Supported in part by U.S. Public Health Service Research Grants HL-11046 from the National Heart, Lung, and Blood Institute and AM-06415 from the National Institute of Arthritis, Metabolism, and Digestive Diseases. The studies were carried out in the General Clinical Research Center at San Francisco General Hospital Medical Center (RR-00083), with support by the Division of Research Resources, National Institutes of Health.
Dr. Kater is the recipient of a Postgraduate Research Fellowship from CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brasil, under contract 200.046/80-CL.
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RIGHTSLINK
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