Aldosterone regulation for 18 years in a case of primary aldosteronism

Primary aldosteronism is a cause of secondary hypertension, resulting from excessive production and release of the mineralcorticoid hormone from the zona glomerulosa of the adrenal cortex.1 The etiology is usually attributable to an aldosterone-producing adrenocortical adenoma or bilateral adrenal hyperplasia (also called idiopathic hyperaldosteronism),2 but can rarely be caused by a unilateral adrenal hyperplasia.3 Much less frequently, glucocorticoid-remediable hyperaldosteronism may be diagnosed in young adults with a family history of hypertension with hypokalemia.4 Herein we present a patient with an aldosterone-producing adenoma causing primary hyperaldosteronism, who displayed intriguing changes in the hormonal characteristics during our 18-year observation. This extended follow-up of nearly two decades demonstrates the natural course of the development of an aldosterone adenoma. A 50-year-old hypertensive Japanese man was admitted to our hospital for a detailed examination regarding hyperaldosteronism. When he was first examined for severe hypertension (180 to 203/95 to 100 mm Hg) and coexisting hypokalemia (3.0 to 3.2 mEq/L) in 1984, the systemic aldosterone levels were 200 pg/mL (normal at recumbency, 30 to 159 pg/mL; Fig. 1) and the plasma renin activity (PRA) was suppressed at less than 0.5 ng/mL/h (normal at recumbency, 0.2 to 2.7 mg/mL/h). Both adrenals exhibited no significant abnormalities by computed tomography (CT; Fig. 2) and the unilateral excess of aldosterone secretion was not proven by selective adrenal venous sampling (the ratio of aldosterone [pg/mL]/cortisol [μg/dL] from left and right adrenal venous sampling, 12.1 and 14.9, respectively) as well as iodocholesterol scintigraphy. At that time there was no aldosterone secretion response to exogenously administered adrenocorticotorpin (ACTH; 0.25 mg of intravenous 1–24 ACTH) (Fig. 3A) and there were no circadian changes in aldosterone levels (Fig. 3B). Renin stimulation tests using intravenous furosemide (40 mg) with a 2-h upright posture significantly increased the PRA levels (Fig. 3C), whereas oral captopril (25 mg) administration was less effective in inducing the increase in PRA (Fig. 3D). These endocrine profiles obtained in 1985 were consistent with idiopathic hyperaldosteronism, possibly due to bilateral adrenal hyperplasia, although both adrenals were radiologically normal (see Fig. 2). Meanwhile, his hypertension and hypokalemia were treated with spironolactone (25 to 100 mg), potassium supplement and calcium antagonists.5 Throughout the 18-year observation period, the systemic levels of aldosterone increased exponentially to approximately 1000 pg/mL (see Fig. 1), concomitant with the gradual enlargement of left adrenal mass as determined by CT examinations (see Fig. 2). A sensitive diagnostic marker of primary aldosteronism, the ratio of aldosterone (ng/dL) to PRA (ng/mL/h; ARR),6 was also steadily elevated (see Fig. 1) indicating the progress of autonomous secretion of aldosterone. The endocrine profile was therefore reevaluated in 2002. As a result, the ACTH stimulation test markedly enhanced aldosterone levels (Fig. 3A) and the daily levels of aldosterone changed in parallel with endogenous ACTH (Fig. 3B), whereas PRA totally failed to respond to renin stimulation tests, including fulosemide-upright and captopril administration (Fig. 3C, D). These results were clearly distinct from those obtained in 1985. Adrenal venous sampling further confirmed the unilateral production of aldosterone from the left adrenal gland (the ratio of aldosterone-to-cortisol from the left and right adrenal vein, 34.3 and 17.6, respectively). After laparoscopic removal of the left adrenocortical adenoma (Fig. 4), the patient’s aldostereone and potassium levels normalized without medication, although a reduced calcium antagonist regimen was still required to maintain normal blood pressure. Reliable criteria for the differential diagnosis of the subsets of primary aldosteronism have been established.1,2 However, the main issues in evaluating primary aldosteronism are to differentiate adrenocortical adenomas from bilateral adrenal hyperplasia and to determine the laterality of the endocrine source. This evaluation is clinically necessary because surgical treatment is curative for aldosterone-producing adenomas, whereas patients with bilateral hyperplasia should be treated with aldosterone antagonists such as spironolactone. Determining the type of primary aldosteronism requires imaging examinations of adrenal glands by CT or magnetic resonance imaging (MRI). When a solitary unilateral macroadenoma (more than 1 cm in diameter) and normal contralateral adrenal are found by CT/MRI in patients with primary aldosteronism, unilateral adrenalectomy is a reasonable therapeutic option. However, the imaging study often shows normal-appearing adrenals or equivocal changes such as minimal thickening of the adrenal limb and unilateral or bilateral microadenomas. The microadenomas may be labeled incorrectly as bilateral hyperplasia on the basis of CT findings of bilateral enlargement or normal-appearing adrenals.7,8 Adrenal microadenomas may also represent some portions of bilateral hyperplasia. In these cases such as our patient, additional testing is required to determine the source of the aldosterone excess. Although iodocholesterol scintigraphy during dexamethasone inhibition is used, it does not seem to have any advantage over CT examination with the accuracy of 72% to 92%.9 With the addition of adrenal venous sampling, unilateral adenoma can be discovered in 36% of patients who have clinically high probable adenomas with normal-appearing adrenals by CT.10 It is also suggested that adrenal venous sampling is essential to direct appropriate therapy in patients with primary aldosteronism who have a high probability of aldosterone adenomas11,12 or unilateral micronodules.13 In the present case, the results from aderenal venous sampling were compatible with bilateral hyperplasia when the adrenal mass was radiologically undetectable. Once the adrenal adenoma was clearly detected by CT, the results of the sampling showed unilateral aldostereone secretion from the adenoma. The aldosterone secretion of adenomas is sensitive to endogenous and exogenous ACTH, unlike the cases of bilateral hyperplasia, which are predominantly regulated by the renin-angiotensin system. A decrease in systemic aldosterone can be shown at noon after 4 h of ambulation in parallel with the endogenous ACTH secretion, forming the circadian rhythm in a day.14 Furthermore, acute studies of aldosterone response to exogenous ACTH stimulation have demonstrated exaggerated increases of aldosterone levels compared with healthy subjects.15–18 Upright posture stimulation can markedly elevate the aldosterone levels of bilateral hyperplasia,19 in contrast to the reduction shown in aldosterone-producing adenomas.9 Enhanced sensitivity of bilateral hyperplasia to the small change in angiotensin II occurs during upright posture,20 whereas patients with adenomas fail to release aldosterone in the upright posture because adenomas are functionally insensitive to angiotensin II,21 owing to autonomy from the renin-angiotensin axis and their responsiveness to the circadian rhythm of plasma ACTH. On the basis of our present case, the responsiveness of ACTH and abolishment of renin responsiveness are critical factors to determine the existence of a developed aldosterone-producing adenoma, although a small part of the aldosterone-producing adenomas could be renin or angiotensin responsive.22,23 Collectively, it is very difficult to find the predictors of adenoma or bilateral hyperplasia. This case suggests the difficulty in identifying the types of primary aldosteronism at the earlier stage, even with adrenal venous sampling. It may also be important to notice, however, that these two common types are not mutually exclusive. To uncover the change in hormonal regulators of aldosterone secretion, the loss of renin suppression and the acquirement of ACTH responsiveness are clinically diagnostic for typing the aldosterone-producing adenomas based on the present observation.