Hyperaldosteronism Workup

Evaluation of a patient in whom hyperaldosteronism is suggested has several distinct stages. The finding of hypertension, hypokalemia, or both most commonly precipitates the decision to screen. The presence of these 2 features together has a 50% predictive value.

The first step in the workup entails confirming that hyperaldosteronism is present and, if it is not present, excluding other conditions that produce a similar picture. The next step involves differentiating primary causes of hyperaldosteronism from secondary causes.

Aldosterone-to-renin ratio

The aldosterone-to-renin ratio (ARR)—that is, the ratio of plasma aldosterone (expressed in ng/dL) to plasma renin activity (PRA, expressed in ng/mL/h)—is the most sensitive means of differentiating primary from secondary causes of hyperaldosteronism. It can be obtained under random conditions of sodium intake.

The principle behind this test is that as aldosterone secretion rises, PRA (which measures the rate of production of angiotensin I from endogenous angiotensinogen) in ex vivo testing should fall because of sodium retention. This negative feedback response should occur when the aldosterone levels are supraphysiologic for that individual patient, and PRA may fall well before plasma aldosterone is clearly increased.

Values obtained in the upright position (ie, with the patient standing for 2 hours) are more sensitive than supine test results. Patients should be normokalemic because hypokalemia suppresses aldosterone secretion. An ARR higher than 20 with a plasma aldosterone exceeding 15 ng/dL is highly suggestive of primary hyperaldosteronism. For screening purposes, plasma aldosterone must be elevated as well as the ARR because with the more sensitive PRA assays, it is possible to have an ARR higher than 20 without an elevated aldosterone.

The most important factors that can interfere with the diagnostic reliability of the ARR test are drugs and renal impairment. Beta blockers can reduce PRA, leading to a falsely elevated ARR, and dihydropyridine calcium antagonists (eg, nifedipine) can reduce aldosterone levels, potentially leading to a falsely normal ARR in some patients with primary hyperaldosteronism. Diuretics tend to induce secondary hyperaldosteronism. Spironolactone, an aldosterone receptor antagonist, can raise plasma renin levels.

Spironolactone and diuretics should be withheld for 6 weeks before testing, and beta blockers and dihydropyridine calcium antagonists should be withheld for 5-7 days. Patients’ hypertension can be controlled with diltiazem and alpha blockers during testing for primary hyperaldosteronism.

Renal impairment can lead to a high ARR in patients without primary hyperaldosteronism because fluid retention suppresses PRA and hyperkalemia stimulates aldosterone secretion.

After a positive screening test result, subsequent testing is directed at confirming aldosterone secretory autonomy and differentiating an aldosterone-producing adenoma (APA), for which surgery is currently first-line treatment, from idiopathic hyperaldosteronism (IHA), which is usually treated medically. The possibility of glucocorticoid-remediable aldosteronism (GRA), which accounts for approximately 1% of cases of primary hyperaldosteronism, should be kept in mind.

Tests for confirming autonomous aldosterone secretion

The saline infusion test can confirm autonomous aldosterone secretion. Other tests described include measurement of urine aldosterone excretion during oral salt loading and the fludrocortisone suppression test. All tests rely on the principle that a lack of suppression of aldosterone excretion with intravascular expansion is indicative of aldosterone production.

Saline infusion test

The saline infusion test is performed by infusing 0.9% saline in a dose of 1140 mL/m² body surface area (BSA) over 4 hours. Plasma aldosterone and cortisol are measured before and at the end of infusion. In individuals without primary hyperaldosteronism, plasma aldosterone levels should fall to less than 10 ng/dL. Plasma aldosterone values higher than 10 ng/dL confirm primary hyperaldosteronism, and levels between 5 and 10 ng/dL may be considered borderline.

Cortisol levels are taken to exclude an adrenocorticotropic hormone (ACTH)–mediated rise in aldosterone. Consider the risks of fluid expansion or hypokalemia in susceptible patients.

Oral salt loading test

The oral salt loading test consists of administration of 12 g/1.7 m² BSA of sodium chloride tablets with an ad libitum diet for 3 days, followed by a 24-hour urinary aldosterone measurement. Urinary aldosterone values higher than 10-14 µg/day with urine sodium excretion exceeding 250 nmol/day are considered diagnostic of primary hyperaldosteronism.

Captopril test

The captopril test has also been used for screening. Its use is based on the principle that inhibition of angiotensin II production should not affect autonomous secretion of aldosterone in primary aldosteronism.

Determination of the 60-minute ARR after oral administration of captopril 25 mg yielded a sensitivity of 100% and specificity of 83% for diagnosis of primary hyperaldosteronism, but the test was only marginally better than baseline values. Somewhat lower sensitivity was noted in a larger study using the aldosterone level and PRA 90 minutes after a 50-mg dose of captopril.

Fludrocortisone suppression test

The fludrocortisone suppression test uses fludrocortisone (0.1 mg every 6 hours) and salt loading. First described by Gordon et al in 1995, it currently is less frequently performed.^{[8, 9]}

Tests for differentiating aldosterone-producing adenoma from other primary hyperaldosteronism

Postural testing

Postural testing is best performed after overnight recumbency. An intravenous (IV) catheter is inserted at 7 AM, and baseline aldosterone, cortisol, and PRA values are obtained at 8 AM. After 2 hours of ambulation, these values are obtained again.

Typically, APAs (aldosteronomas) are unresponsive to angiotensin II, and a fall in aldosterone over 2 hours is observed in parallel with reduced circadian ACTH and cortisol release. In IHA, however, a rise in aldosterone is observed. Cortisol levels are used to validate the test; a rise in cortisol release suggests an ACTH surge, which invalidates the test. A diagnostic accuracy of 85% is reported.

18-Hydroxycorticosterone level

levels of 18-hydroxycorticosterone are typically elevated (>100 ng/dL) in patients with APAs and are significantly lower in patients with IHA. Although a diagnostic accuracy of 82% is reported, 18-hydroxycorticosterone levels have been noted to parallel the severity of hyperaldosteronism, and levels of aldosterone and clinical severity are greater in APAs than in IHA.

Dexamethasone suppression test

In cases of bilateral aldosterone secretion or when the diagnosis is suspected on the basis of the family history, GRA can be excluded by means of a 4-day dexamethasone suppression test (using a dosage of 0.5 mg every 6 hours).

The aldosterone and renin levels can be measured before suppression testing, after 2 days of testing, and after 4 days of testing. In patients without GRA, aldosterone levels typically fall by approximately 50% and return to the reference range by the end of testing; however, persistent suppression of aldosterone levels to less than 4 ng/dL are reported in patients with GRA. Compared with direct genetic testing, this test achieves a sensitivity of 92% and a specificity of 100% for the diagnosis of GRA.

Biochemically unique, markedly elevated levels of 18-oxocortisol and 18-hydroxycortisol (>100 nmol/day) are also observed in GRA.

Mutation analysis for the hybrid gene that gives rise to GRA can now be accomplished by means of Southern blotting or a long polymerase chain reaction (PCR) technique. This study is likely to supersede the time-intensive dexamethasone suppression test.

Computed tomography (CT) of the adrenal gland has a 70% sensitivity in the detection of APAs. In one large series, the mean APA size was 1.8 cm; however, 19% of these tumors were smaller than 1 cm. Aldosteronomas are typically lipid-rich and commonly appear as homogeneous lesions with a low Hounsfield number consistent with this high lipid content.

When a solitary adrenal mass is identified on a CT scan from a child or young adult with hyperaldosteronism, it is very likely to be the cause of the hyperaldosteronism, because the prevalence of nonfunctioning adrenal adenomas is very low in childhood.

The diagnostic accuracy of adrenal scintigraphy is insufficient to permit its routine use in diagnosing adrenal adenomas.

Adrenal venous sampling requires considerable skill. It can be performed as an outpatient procedure, though younger children may need general anesthesia. Ideally, the procedure should be performed in centers with appropriate expertise. Adrenal veins are often small, and the right vein tends to be difficult to cannulate.

ACTH may be infused into a peripheral vein (at a dosage of 50 µg/h, starting 30 minutes before sampling) to mask the effects of confounding ACTH peaks during sampling. To reduce the risk of adrenal hemorrhage, adrenal venography is avoided.

Comparison of simultaneous aldosterone-to-cortisol ratios in the adrenal veins and the inferior vena cava allows detection of unilateral or bilateral sources of aldosterone hypersecretion. Although the cut-off value for lateralization is controversial, both 5:1 and 10:1 have been advocated. Nevertheless, adrenal venous sampling remains the standard test for the differential diagnosis of primary aldosteronism.

Adrenal venous sampling is not without risk and can lead to damage of the adrenal gland if not performed correctly. Similarly, failure to cannulate the right adrenal vein can lead to an incorrect diagnosis of unilateral disease when, in fact, both glands are affected.

Unlike cortisol-producing adrenocortical tumors, in which the remaining ipsilateral and contralateral glands are commonly atrophic, APAs may show hyperplasia of the zona glomerulosa in the nontumorous cortex, either forming a broad zone locally or thickening the entire cortex, with tongues of glomerulosalike cortex extending inward from the subcapsular region.

This appearance has been reported in as many as one third of patients with APAs and suggests that the tumor has arisen from within an area that was hyperplastic, though to date, neither an external stimulus nor an intrinsic defect has been found.

IHA is a disease of the zona glomerulosa with a variable macroscopic appearance that can range from hyperplasia with micronodules and macronodules to hyperplasia without nodules to normal-appearing zona glomerulosa with micronodules. The glands may be normal in weight or heavy.

The normal microscopic appearance of the zona glomerulosa is of small discontinuous subcapsular nests of cells. In hyperplasia, the zona glomerulosa may contain continuous bands of cells that may be visibly thickened, either forming a continuous sheet or focally extending as tongues into the adjacent cortex. This process may be focal or diffuse and may vary from one part of the gland to another, requiring multiple sections.

GRA, or familial hyperaldosteronism (FH) type I (FH-I), results from the formation of a hybrid gene that leads to ACTH-mediated mineralocorticoid synthesis by the zona fasciculata. Histologically, evidence suggests hyperplasia of this zone in addition to the zona glomerulosa.

FH type II (FH-II) has been linked to a locus on chromosome 7p22. Histologically, evidence suggests adrenocortical hyperplasia or hypertrophy and the presence of adenomas.