Idiopathic bilateral adrenocortical hyperplasia of the zona glomerulosa (idiopathic hyperaldosteronism) is characterized by features similar to those associated with APAs, although they are less pronounced in many patients.29 The reported prevalence of idiopathic hyperaldosteronism has ranged from a high of 70% of those patients with primary hyperaldosteronism14 to a low of 8%.20 The true prevalence probably is somewhere between these two extremes and may be ˜30%.

Although the etiology of idiopathic aldosteronism has not been established, the belief that a circulating stimulatory factor is responsible for hyperfunction of the zona glomerulosa is generally accepted. Extracts of urine from normal persons contain a protein fraction that selectively stimulates the production of aldosterone and produces hypertension when injected into rats.30 Subsequent studies of one of these extracts have shown that (a) it is a peptide of pituitary origin, (b) it is increased in patients with idiopathic hyperaldosteronism but not in those with an APA, and (c) it is not suppressed by dexamethasone.31 The specific peptide has not been identified. In other studies, plasma concentrations of γ-melanotropin32 and of β-endorphin33 were increased in patients with idiopathic hyperaldosteronism but not in those with an aldosterone-producing adenoma. These two peptides are fragments of a larger peptide, pro-opiomelanocortin, which is formed in the pituitary; they may stimulate the secretion of aldosterone or increase the sensitivity of the adrenal gland to angiotensin II, or both. The report of an enlargement of the intermediate lobe of the pituitary in a patient with idiopathic hyperaldosteronism,34 together with the observations that central serotoninergic stimulation of aldosterone secretion may occur35 and that cypro-heptadine, which is an inhibitor of central serotonin release, may decrease plasma aldosterone in patients with idiopathic hyperaldosteronism,36 is consistent with a possible role for the pituitary in the pathogenesis of idiopathic hyperaldosteronism. It should be noted, however, that a pathogenetic schema for idiopathic hyperaldosteronism has to account for the hypertension as well as the hyperaldosteronism because adrenalectomy rarely lowers blood pressure. Therefore, a putative aldoster-one-stimulating factor of pituitary or other origin, orchanges proximal to its release, must be responsible for the hypertension in idiopathic hyperaldosteronism, unless the hypertension is a separate process. The effects of the putative aldosterone-stimulating factors on blood pressure are not known. As in an APA, the overproduction of aldosterone in idiopathic hyperal-dosteronism causes increased sodium reabsorption and potassium secretion by the renal tubule, expansion of the volume of extracellular fluid, suppression of plasma renin activity, and hypokalemia.

Although the features that characterize prolonged aldosterone excess may be as prominent in patients with idiopathic hyperal-dosteronism as in patients with an APA, they usually are less pronounced and more subtle.29 (It has been suggested that approximately half the patients with hypertension and suppressed plasma renin activity who show a decrease in plasma aldosterone to values between 5 and 10 ng/dL in response to saline infusion may have idiopathic hyperaldosteronism, even though baseline plasma aldosterone and serum potassium values may be normal.14 When these diagnostic criteria are used, it may be difficult to distinguish between idiopathic hyperaldo-steronism and low-renin essential hypertension. Such a sharp distinction between idiopathic hyperaldosteronism and low-renin essential hypertension may not be made with certainty until the pathogenesis of both disorders is more clearly delineated.) More important distinctions are those between idiopathic hyperaldosteronism and an APA, and between idiopathic hyperaldosteronism and primary bilateral adrenal hyperplasia, because therapy for these disorders is different. The response to saline infusion may be helpful because the aldosterone/cortisol ratio increases in an APA but remains unchanged or decreases, with a value of 2.2 or less, in idiopathic hyperaldosteronism37 (Fig. 80-5). A value for plasma 18-hydroxycorticosterone less than 50 ng/dL at 8:00 a.m. after overnight bedrest is the usual finding in idiopathic hyperaldosteronism.8,21 In patients with an APA, as well as in most patients with primary hyperplasia, values for 18-hydroxycorticosterone are >50 ng/dL and may exceed 100 ng/dL.5,21,38 An increase in plasma aldosterone levels associated with a decrease in plasma cortisol levels after 2 hours of ambulation in the morning favors a diagnosis of idiopathic
hyperaldosteronism but also may occur in association with an APA.22 An increase in plasma aldosterone levels is more difficult to interpret than is a paradoxic decrease. Because of the number of false-positive and false-negative results, the test, as originally described, is not sufficiently dependable to be a reliable tool.8 A refinement in the interpretation of the postural stimulation test (i.e., correction of the percentage increase in aldosterone by subtraction of the percentage increase in cortisol with standing) and acceptance of an increase in levels of plasma aldosterone with standing of <30% as a positive response for an adenoma has improved the predictive value of the test.39 The response of plasma aldosterone to a single dose of a converting enzyme inhibitor, such as captopril, is more helpful in discriminating between hyperaldosteronism and low-renin essential hypertension than in separating patients with idiopathic hyperaldosteronism from those with an APA.16 Interestingly, others have observed a decrease in aldosterone levels and blood pressure in patients with idiopathic hyperaldosteronism who are given larger doses of converting enzyme inhibitors for longer periods.40 In contrast to the results obtained with a single dose of a converting enzyme inhibitor, testing with saralasin, which is an angiotensin II antagonist, correctly identified 15 patients with aldosteronism. After infusing saralasin, 10 μg/kg per minute for 30 minutes, plasma aldosterone levels increased in eight patients with idiopathic hyperaldosteronism but did not change in six patients with an adenoma.41 Most important, thesemethods of evaluation assess adrenal function indirectly. Therefore, the more concordance there is among the results of several tests, the more confidence one can have in the diagnosis. The best procedure for resolving uncertainty and making a more definitive diagnosis is adrenal vein catheterization. This procedure provides a direct assessment of adrenal biology; hence, bilateral supernormal secretion of aldosterone is readily distinguished from supernormal secretion of aldosterone by one adrenal gland with suppression of secretion from the contralateral gland. The results of adrenal vein catheterization in a representative patient with idiopathic hyperaldosteronism are shown in Table 80-2.