STEP 2: Confirmatory Testing
Since the aldosterone renin ratio tends to yield false-positives, a second step is needed to confirm or rule out the presence of primary aldosteronism.
Just as the aldosterone renin ratio is not a standardized test, there is no standard way of confirming primary aldosteronism. Four options are commonly available, and their use vary across the US, Europe, and Japan.
In the absence of consensus, the choice of test depends on physicians and diagnostic centers.
How Confirmatory Testing Differs From ARR
The goal of confirmatory testing is to show that excess aldosterone is “autonomous,” i.e. that it is produced independently of the renin-angiotensin system. To demonstrate this, patients are administered agents which suppress the regulator of aldosterone production. Hormones and electrolytes are measured before and after the test. If aldosterone is again found in excess, the dysfunction is “confirmed” to originate in the adrenal glands.
The most common tests are oral sodium loading, saline infusion, fludrocortisone suppression, and Captopril challenge. How the tests are performed, and their associated risks and costs vary widely. Patients should discuss with their physicians which test is most appropriate for them based on their comorbidities, insurance coverage, and methods available at their diagnostic center.
What ARRs and Confirmatory Tests Have in Common
Confirmatory tests have their own sensitivity and specificity, and can also lead to false-positives and false-negatives. Like ARRs, their results are influenced by sodium intake, potassium level, and blood pressure medications. Preparation for confirmatory testing is the same as for ARR. Compliance with these recommendations has a direct impact on the accuracy of results, and should be optimized by physicians and patients alike.
Can Confirmatory Testing Be Omitted?
Confirmatory testing is mandatory to confirm or rule out the presence of primary aldosteronism. While Japanese guidelines do not entertain any exception to this rule, American and European guidelines consider avoiding confirmatory testing when the following factors are present:
- Elevated plasma aldosterone concentration (above 20 ng/dL or 550 pmol/L), and
- Spontaneous hypokalemia, and
- Undetectable plasma renin activity.
An Important Factor Shared by all Confirmatory Tests
Stress can increase a hormone called adrenocorticotropic hormone (ACTH) which, in turn, can increase aldosterone and cause false-positive results. Whether this is happening to patients must be determined. To do so, cortisol is monitored during testing, and levels are taken into consideration when interpreting results.
By the time they are diagnosed (years, if not decades, after disease onset), primary aldosteronism patients are usually quite ill, and their reaction to stress considerably impaired by excess aldosterone. The complexity of the disease and its treatment, along with lengthy and challenging testing which is poorly — if ever — explained to them, are all aggravating stress factors. Patients should thus be vigilant, and make sure their cortisol levels are accounted for during confirmatory testing. This is even more relevant that a form of primary aldosteronism – Connshing syndrome – involves excess cortisol and excess aldosterone. The incidence of the syndrome is unknown, and the disease is even less recognized than hyperaldosteronism. Making sure that cortisol levels are properly assessed during the diagnosis process, is thus critical to ensure the syndrome is not overlooked.
Oral Sodium Loading
What the Test Involves |
What Results Mean |
What the Risks Are |
|---|---|---|
The test is performed at home where, together with potassium supplementation, patients ingest 6 g of sodium chloride per day for 3 consecutive days. Starting on day 3 at 8:00 AM, patients collect their urine for 24 hours (until 8:00 AM on day 4), and deliver the collected urine to their laboratory. |
Primary aldosteronism is confirmed if urinary aldosterone exceeds 12 µg/24 h or 33 nmol/24 h. A result less than 10 µg/24 h or 28 nmol/24 h makes primary aldosteronism unlikely. |
While inexpensive, the test involves a fair amount of risk considering that primary aldosteronism is a salt-sensitive form of hypertension, and that the test is not performed under medical supervision. At a minimum, it should be avoided in the presence of severe hypertension and hypokalemia, kidney impairment, and arrhythmia. |
Saline Infusion
What the Test Involves |
What Results Mean |
What the Risks Are |
|---|---|---|
Saline infusion is performed in a hospital setting, and involves the administration of 2 L of 0.9% saline by IV over 4 hours. The test is started between 8 and 9 AM. Aldosterone and renin are measured prior to starting and at the end of the 4 hour infusion. |
Primary aldosteronism is confirmed if Plasma Aldosterone Concentration exceeds 10 ng/dL or 280 pmol/L. A result less than 5 ng/dL or 140 pmol/L rules out the presence of primary aldosteronism. A result between 5 and 10 ng/dL or 140 and 280 pmol/L is considered inconclusive. |
The test is considered safe, and is the most widely used. It nonetheless requires potassium supplementation even if patients’ potassium level is found to be low-normal prior to starting the test. Blood pressure should be monitored on an hourly basis. |
Fludrocortisone Suppression
What the Test Involves |
What Results Mean |
What the Risks Are |
|---|---|---|
Over the course of a 4-day hospital stay, patients ingest 0.1 mg of fludrocortisone every 6 hours, and 6 g of sodium chloride per day. Urine is collected for 24 hours during day 3 and 4. On day 4, plasma cortisol is measured at 7:00 AM, and again at 10:00 AM, together with Plasma Aldosterone Concentration and Plasma Renin Activity. |
Primary aldosteronism is confirmed if:
|
The test is believed to be highly sensitive, but is however the most expensive due to the required hospitalization. More importantly, it involves a high risk of hypokalemia, and therefore requires continuous potassium monitoring and supplementation. |
Captopril Challenge
What the Test Involves |
What Results Mean |
What the Risks Are |
|---|---|---|
The Captopril challenge involves oral intake of 25 to 50 mg of Captopril (an ACE inhibitor) after being seated for 1 hour. Plasma Aldosterone Concentration, Plasma Renin Activity, and plasma cortisol are measured prior to and 2 hours after the medication intake. |
Primary aldosteronism is confirmed if 2 hours after administration of the drug, the Plasma Aldosterone Concentration either does not change or drops by less than 30% since prior to starting the test. An ARR greater than 200 pg/mL/ng/mL/h can also be used to confirm primary aldosteronism. |
The test is fairly inexpensive, is overall considered safe, and is well-suited for patients with compromised renal or cardiac function. The test accuracy is however controversial. Blood pressure monitoring is advised in the presence of angioedema and renovascular hypertension. |
Another Important Test
Some forms of primary aldosteronism are inherited. One of them, called glucocorticoid-remediable aldosteronism (GRA), is caused by gene duplication. Although rare, it must be ruled out if clinical history indicates early onset hypertension and presence of the disease in 1st degree relatives. It may also be indicated when imaging of the adrenals is negative.
The dexamethasone suppression test (DST) is used to this effect, and consists in taking 0.5 mg of dexamethasone orally every 6 hour for 2 days. If positive for GRA, the test will result in nearly undetectable aldosterone thereby confirming that ACTH alone controls its production.
Both aldosterone and cortisol must be measured concurrently to document adequate suppression of ACTH (i.e., if dexamethasone is not administered properly, the test may cause false negative results).
An aldosterone level below 4 ng/dL post-DST is indicative of GRA, and is considered a highly sensitive and specific measurement. Some patients with APA (less than 7%) may however be misclassified as having GRA. Only direct genetic testing can avoid this downside, and offers 100% sensitivity and 100% selectivity.
Complete Health Investigation
Primary aldosteronism is a systemic disease, its deleterious effects are pervasive across systems throughout the body. Kidneys and the cardiovascular system are affected the most, but damage extends far beyond to include dyslipidemia, diabetes, and musculoskeletal disease, to name a few. Patients must thus be vigilant, particularly if they are diagnosed long after the onset of the disease, and should require a full investigation of their health if their physician is not proactively inquiring about possible damage.
If confirmatory testing returns negative or inconclusive results, your physician may consider other endocrine causes of hypertension.
References
- Funder, J. W., Carey, R. M., Mantero, F., Murad, M. H., Reincke, M., Shibata, H., Stowasser, M., & Young Jr, W. F. (2016). The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 101(5), 1889–1916.
- Morera, J., & Reznik, Y. (2019). Management of endocrine disease: the role of confirmatory tests in the diagnosis of primary aldosteronism. European Journal of Endocrinology, 180(2), R45-R58.
- Lin, C., Yang, J., Fuller, P. J., Jing, H., Song, Y., He, W., Du, Z., Luo, T., Cheng, Q., Yang, S., Wang, H., Li, Q., & Hu, J. (2020). A combination of captopril challenge test after saline infusion test improves diagnostic accuracy for primary aldosteronism. Clinical Endocrinology, 92(2), 131-137.
- Litchfield, W. R., New, M. I., Coolidge, C., Lifton, R. P., & Dluhy, R. G. (1997). Evaluation of the dexamethasone suppression test for the diagnosis of glucocorticoid-remediable aldosteronism. The Journal of Clinical Endocrinology & Metabolism, 82(11), 3570–3573.
