Who Should Be Screened?

• Modern guidelines consistently recommend testing for hyperaldosteronism in patients with adrenal incidentalomas and either hypertension or hypokalemia.(1–4)

How Should Screening Be Performed?

• Measurement of the serum aldosterone-to-renin ratio (ARR) is universally recommended as the preferred screening test for hyperaldosteronism caused by an adrenal lesion.(1–4)

• The only sets of guidelines to address the manner in which this testing should be performed in any detail were released by the Endocrine Society in 20164 and the Canadian Urological Association in 2023, with the latter largely referring back to the former.(2) Other algorithms have also been proposed by expert reviews.(5)

• A nearly complete list of the medications and conditions which are thought to influence the ARR can be found in Table 3 of the Endocrine Society guidelines. These guidelines also discuss avoiding licorice and chewing tobacco and drawing levels when patients have been out of bed for over two hours and have been seated for 5-15 minutes, but they do not explicitly discuss how these are thought to affect the ARR.4 A summary of the most significant of these

• Lower ARR (can cause false negative screen for hyperaldosteronism)

• Diuretics, especially direct aldosterone receptor blockers (e.g. spironolactone), and generally potassium sparing more so than potassium wasting

• Hypokalemia

• Sodium restriction

• Lesser effects: ACE inhibitors, angiotensin receptor blockers (Although mechanistically one might think these would strongly interfere with the ARR, evidence suggests that their effects on ARR are minimal)2

• Raise ARR (can cause false positive screen for hyperaldosteronism)

• Beta blockers

• Alpha-2 adrenergic agonists (e.g. clonidine)

• Lesser effects: Sodium loading, renal impairment

• Ensuring ideal testing conditions and withdrawing all potentially confounding medications is too burdensome to implement in the screening setting, so both the Endocrine Society and the Canadian Urological Association have suggested simplified approaches for preparing patients for ARR testing.(2,4)

• Both organizations recommend

• Liberalizing sodium intake (if patient is on a low-sodium diet)

• Repleting potassium if hypokalemia is present (to a goal of >4.0)

• Stopping mineralocorticoid antagonists (e.g. spironolactone, eplerenone) and potassium sparing diuretics (e.g. triamterene, amiloride) for 4 weeks prior to the ARR draw

• Drawing the sample after the patient has been out of bed for at least 2 hours and seated for at least 5-15 minutes

• For the purposes of this site, we recommend the first 3 of these interventions in preparation for ARR measurement for the following reasons:

• Many patients with adrenal incidentalomas are not tested for hyperaldosteronism at all.6  We believe a simpler approach is more conducive to broader testing. This is in line with other experts who have recommended immediate ARR testing at the time of suspicion without any patient preparation for similar reasons.(5) 

• Withdrawing other medications, including oral contraceptives and additional antihypertensive classes, may subject patients to additional risk, even if the intent is to substitute these (e.g. for barrier contraception or other classes of antihypertensives).

• These three recommendations address the testing conditions which have been most convincingly associated with false negative results. Addressing conditions which can lead to false positive results can be safely left to the confirmatory setting.

• If it is highly desirable to avoid stopping mineralocorticoid antagonists and potassium sparing diuretics, some have suggested checking an initial ARR before holding these medications. If the renin level is low on this check, the ARR can be interpreted as if the patient were not on these medications.(5)

• Either the plasma renin activity (generally measured in ng/mL/hr or pmol/L/min) or the direct renin concentration (measured in mU/L or ng/L) may be measured, but the former is generally favored as measurement of the latter can lead to false positive screening during the luteal phase of ovulation.(4)

How should the aldosterone-to-renin ratio be interpreted?

• No guideline attempts to propose a single cutoff or algorithm for interpreting ARRs.

• The Canadian Urological Association highlights that an ARR > 20 ng/dL per ng/mL/hr has been shown in some studies to have sensitivity and specificity >90%,(2) which is consistent with the most sensitive cutoff mentioned as possibility by the Endocrine Society(4) and the cutoff used by the American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons,(7) so we present this as a reasonable cutoff to use for screening purposes, though of course in the setting of a high clinical suspicion a lower threshold could be considered for confirmatory testing.

• Most patient with primary hyperaldosteronism will have a fully suppressed or nearly fully suppress renin activity.  Aldosterone levels are usually >10ng/dL.

What confirmatory testing is required (prior to adrenal vein sampling)?

• In general, we recommend confirmatory testing for primary hyperaldosteronism with an experienced endocrinologist.

• The Endocrine Society guidelines are the only guidelines to address the question of additional confirmatory testing prior to adrenal vein sampling. They recommend confirmation of primary hyperaldosteronism in any patient with an elevated ARR, although they suggest that this is likely not necessary in patients with hypokalemia, plasma renin activity below the level of detection, and plasma aldosterone concentration >20 ng/dL.4 Thus, in the absence of conflicting guidelines, this is our recommendation as well. Confirmatory testing should be considered even for patients who meet all these criteria if their ARR was measured with only the simplified testing conditions described above, especially if the patient is taking beta blockers or centrally acting adrenergic agonists (e.g clonidine), which are known to be strongly associated with false positive results. 

• These guidelines discuss seven possible confirmatory tests (oral sodium loading, seated saline infusion, recumbent saline infusion , fludrocortisone suppression, dexamethasone-enhanced fludrocortisone suppression, captopril challenge, and furosemide upright test) in addition to simple repetition of ARR measurement under more ideal measurement conditions. To date there is no clear evidence suggesting superiority of one test over another.

When is adrenal vein sampling required?

• In general, adrenal vein sampling is recommended prior to adrenalectomy for primary hyperaldosteronism to confirm a unilateral source of the aldosterone excess, although clear consensus does not exist as demonstrated in the table below.

• Details regarding performance and interpretation of adrenal vein sampling can be found in the Endocrine Society guidelines,(4) although these should generally be performed at expert centers.

Last update: 8/5/2024 by Marshall Strother, Julie Hallanger-Johnson, and Ben Ristau