Primary Aldosteronism

Medical Experts

Contributor

Doyle

Kelly Doyle, PhD, DABCC, FADLM

Associate Professor of Pathology (Clinical), University of Utah

Medical Director, Special Chemistry, Endocrinology, and Mass Spectrometry, ARUP Laboratories

Contributor

Straseski

Joely A. Straseski, PhD, MS, MT(ASCP), DABCC, FAACC

Professor of Pathology (Clinical), University of Utah

Head of Clinical Operations for Clinical Chemistry, Toxicology, and Biochemical Genetics; Medical Director, Endocrinology; Co-Director, Automated Core Laboratory, ARUP Laboratories

Contributor

Young

Brittany A. Young, MD, PhD

Associate Professor of Pathology (Clinical), University of Utah

Director, University Hospital Clinical Laboratories and Farmington Clinical Laboratories; Medical Director, Client Services and Point-of-Care Testing, ARUP Laboratories

Primary aldosteronism (PA, or hyperaldosteronism) is a syndrome caused by excessive and inappropriate aldosterone production and is the most common form of endocrine hypertension.^, PA is associated with an increased risk of cardiovascular morbidity and mortality compared to essential hypertension.^, Furthermore, PA is likely underdetected and undertreated.^, The Endocrine Society suggests that increased PA case detection is warranted. It is suggested that all individuals with hypertension undergo screening for PA by measurement of aldosterone-renin ratio (ARR), confirmation of results and subtyping as indicated, and possible genetic testing.

Quick Answers for Clinicians

Who should be screened for primary aldosteronism?

Current guidelines from the Endocrine Society recommend that all individuals with hypertension be screened for primary aldosteronism (PA). This approach benefits more individuals, allowing for targeted therapies and decreasing long-term cardiovascular risks.

What are the appropriate sampling conditions for aldosterone-renin ratio testing?

The sample for aldosterone-renin ratio (ARR) testing is ideally collected in the morning with the patient in the seated posture.^, In premenopausal ovulating individuals, testing should be performed during the follicular phase of the menstrual cycle, if possible. Care should be taken to avoid hemolysis and stasis during collection (e.g., by having the patient avoid clenching their fist). The sample should be held at room temperature during transport and before centrifugation because cold temperatures will cause inactive renin to convert to active renin.^, The plasma component should be rapidly frozen after centrifugation until the assay is performed.

How should individuals be prepared for aldosterone-renin ratio testing?

Potassium concentrations should be measured together with aldosterone-renin ratio (ARR) testing and corrected by supplementation if necessary.^, Licorice root products should be avoided for at least a month before testing. Unrestricted sodium intake is recommended.^, Potentially interfering medications, particularly mineralocorticoid receptor antagonists and beta (β)-blockers, should be either withdrawn or substituted with a treatment that has minimal effects on ARR for 2-4 weeks, depending on the medication.^, However, this is not always feasible; if medications cannot be withdrawn or substituted, ARR testing may still be performed with results considered in the context of potential effects from medication.^, Refer to the Factors That May Impact ARR Results table for more information about the effects of different medications on ARR test results.

When is one renin measurement technique (direct renin concentration or plasma renin activity) preferred over another?

In some situations, the choice to measure renin using the direct renin concentration (DRC) versus plasma renin activity (PRA) can affect the aldosterone-renin ratio (ARR), potentially yielding false-negative or false-positive results. For example, renin inhibitors increase the DRC but decrease the PRA. With an increased DRC, ARR is decreased, resulting in a potential false-negative result if DRC is used. With a decreased PRA, ARR is increased, resulting in a potential false-positive result if PRA is used. Also, DRCs in ovulating individuals are generally higher than in nonovulating individuals, particularly during the luteal phase of the menstrual cycle. Aldosterone concentrations are similar in all phases of the menstrual cycle in both ovulating and nonovulating individuals. Therefore, the ARR is increased in ovulating individuals and false-positive results may occur during the luteal phase if a DRC is used. For more information about the impact of various factors on the ARR, refer to the Factors That May Impact ARR Results table.

Indications for Testing

Screening for PA is suggested in all individuals with hypertension. The feasibility of this approach may depend on factors such as local resources and expertise.

Diagnosis

Initial Testing: Aldosterone-Renin Ratio

The recommended initial testing for PA is calculation of the ARR.^, The ARR is more sensitive than a standalone measurement of aldosterone or potassium and is more specific than a standalone measurement of renin.^, An ARR test that reports both serum/plasma aldosterone concentration and plasma renin (concentration or activity) in addition to the ARR should be used. Potassium levels should also be assessed to aid in the accurate interpretation of results. Because there is variability between tests, assay-specific cutoff values should be used in ARR interpretation.^, Because the ARR may show variability from one day to the next, testing should be measured at least twice in individuals with low renin concentrations.

Aldosterone concentrations may be affected by adrenocorticotropic hormone (ACTH) concentrations, which are highest early in the day. ACTH concentrations may also be affected by other factors such as stress and posture. To avoid ACTH effects on aldosterone, testing in the morning after a rest in the sampling position (recumbent or seated) is recommended.

Techniques used to measure aldosterone include immunometric testing and ultrahigh performance liquid chromatography/tandem mass spectrometry (LC-MS/MS). Renin may be measured with either a direct renin concentration (DRC) or plasma renin activity (PRA).^, The DRC is more commonly used, and immunoassays are suitable for either DRC or PRA. Tandem mass spectrometry is also suitable for measuring the PRA. Assays must be sensitive enough to detect 2 mU/L (with DRC) or 0.2-0.3 ng/mL/h (with PRA). Radioimmunoassays should not be used.

ARR testing should be repeated if sampling conditions were not appropriate, results are difficult to interpret or inconclusive, or if a strong clinical suspicion remains despite negative test results.Results may be affected by a number of factors, including an individual’s age, whether they are ovulating, electrolyte status, medications, or other conditions, potentially yielding false-negative or false-positive results.^, Refer to the Factors That May Impact ARR Results table for more information.

Factors That May Impact ARR Results
Factor	Impact on Aldosterone Plasma Concentrations	Impact on Renin Concentrations	Impact on ARR	Potential False Result
Demographic Characteristics
Premenopausal, ovulating^a	Normal or increased	Decreased	Increased	Positive
Age >65 yrs	Decreased	Significantly decreased	Increased	Positive
Electrolyte Status
High dietary sodium	Decreased	Significantly decreased	Increased	Positive
Low dietary sodium	Increased	Significantly increased	Increased	Negative
High dietary potassium	Increased	Normal or decreased	Increased	None
Hypokalemia	Decreased	Normal or Increased	Decreased	Negative
Medications
Angiotensin-converting enzyme inhibitors	Decreased	Significantly increased	Decreased	Negative
Angiotensin II type 1 receptor blockers	Decreased	Significantly increased	Decreased	Negative
Beta (β)-adrenergic blockers	Decreased	Significantly decreased	Increased	Positive
Ca²+ blockers (dihydropyridine)	Normal or decreased	Increased	Decreased	Negative
Central alpha (α)-2 agonists	Decreased	Significantly decreased	Increased	Positive
Nonsteroidal anti-inflammatory drugs	Decreased	Significantly decreased	Increased	Positive
Potassium-sparing diuretics	Decreased	Significantly increased	Decreased	Negative
Potassium-wasting diuretics	Normal or decreased	Significantly increased	Decreased	Negative
Renin inhibitors	Decreased	Decreased (if PRA used) Increased (if DRC used)	Increased (if PRA used) Decreased (if DRC used)	Positive (if PRA used) Negative (if DRC used)
Other Conditions
Malignant hypertension	Increased	Significantly increased	Decreased	Negative
Pregnancy	Increased	Significantly increased	Decreased	Negative
Pseudohypoaldosteronism type 2	Normal	Decreased	Increased	Positive
Renal impairment	Normal	Decreased	Increased	Positive
Renovascular hypertension	Increased	Significantly increased	Decreased	Negative
^aPlasma aldosterone concentrations are similar between ovulating and nonovulating individuals except in the luteal phase of the menstrual cycle in ovulating individuals. Renin concentrations are lower in premenopausal individuals. Therefore, ARR is generally higher in ovulating individuals than in nonovulating individuals, particularly during the luteal phase. Testing during the follicular phase may reduce the likelihood of false-positive results. If testing is performed during the luteal phase, PRA should be measured instead of DRC. Sources: Adler, 2025; Mulatero, 2020; Funder, 2016

Confirmatory Testing

Although false-positive results become less likely as the ARR increases, confirmatory testing is recommended for those individuals in whom screening results indicate an intermediate probability of lateralizing PA and who are able and willing to pursue surgical adrenalectomy.^, Confirmatory testing is not necessary in individuals determined to have resistant hypertension or hypertension with spontaneous hypokalemia with plasma renin below the limit of detection and a plasma aldosterone concentration above 20 ng/dL; in these cases, it is reasonable to proceed directly to subtyping.^,

There are no standardized confirmatory tests for PA. Four confirmatory tests are commonly used: the captopril challenge test (CCT), the fludrocortisone suppression test (FST), the oral sodium suppression test, and the saline suppression test.^, Additional confirmatory tests that may be performed include the dexamethasone-captopril-valsartan test and the furosemide upright test. The choice of which confirmatory test to use depends on factors such as available expertise, cost, institutional protocols, and patient needs.

All confirmatory tests should be performed only after potassium concentrations have been tested and hypokalemia corrected if necessary. Interfering medications should be considered when interpreting results.

Captopril Challenge Test

The CCT procedure entails administration of 25-50 mg of oral captopril after a sitting or standing period of at least 1 hour. The individual being tested stays seated and blood is taken at 0 and 2 hours postcaptopril administration. Cortisol, plasma aldosterone, and PRA are measured. PA is confirmed if PRA is low but plasma aldosterone remains high as long as plasma cortisol is lower than the baseline (to account for possible ACTH effects). False-negative and equivocal results have been reported with this test. This test may be a good choice for individuals with potential fluid overload (e.g., heart failure or renal insufficiency).

Fludrocortisone Suppression Test

The FST involves 0.1 mg of oral fludrocortisone and a slow-release potassium chloride supplement taken every 6 hours for 4 days, slow-release sodium chloride supplements taken three times daily with meals, and ample dietary salt. Plasma potassium is measured four times per day and supplementation is provided to maintain concentrations near 4.0 mmol/L. Urinary sodium excretion is tested and maintained at a minimum of 3 mmol/kg of body weight. Blood is collected at 7 a.m. and 10 a.m. while the individual is seated. Plasma cortisol is measured at 7 a.m., and plasma cortisol, plasma aldosterone, and PRA are all measured at 10 a.m. PA is confirmed if plasma aldosterone exceeds 6 ng/dL if PRA is lower than 1 ng/mL/h and plasma cortisol is lower than the baseline (to account for possible ACTH effects). This test is sensitive and may have fewer confounding effects than other confirmatory test methods but may be difficult to perform outside the hospital setting.

Oral Sodium Suppression Test

The oral sodium suppression test is performed by instructing individuals to consume 4-5 g of sodium per day for 3-4 days. Sodium concentrations are confirmed by 24-hour urine sodium tests and potassium by plasma potassium tests. Twenty-four-hour urine from the morning of day 3 to the morning of day 4 is collected and tested for urinary aldosterone. An elevated urinary aldosterone concentration likely confirms PA (cutoffs vary), whereas a urinary aldosterone concentration <10 μg/24 hours likely excludes PA unless renal disease is present. This test is not suitable for patients with cardiac arrhythmias, renal insufficiency, severe hypokalemia, or uncontrolled hypertension.

Saline Suppression Test

The saline suppression test (also known as the saline infusion test) requires that patients receive an intravenous infusion of 2 L of 0.9% saline over the course of 4 hours after sitting for 1 hour.There are two options for body positioning: The first is for the individual to remain recumbent throughout the infusion after a 1-hour recumbent rest; the second is for the individual to remain seated throughout the infusion after a half-hour seated rest. Blood is taken at 0 and 4 hours, and plasma aldosterone and serum potassium concentrations are measured. Results are interpreted based on the protocol used (refer to the Interpretation of Saline Suppression Test Results table). This test is not suitable for patients with cardiac arrhythmias, renal insufficiency, severe hypokalemia, or uncontrolled hypertension. The seated protocol saline suppression test may be easier to perform than the FST or sodium suppression test.

Interpretation of Saline Suppression Test Results
Postsuppression Plasma Aldosterone Concentration	Interpretation
Recumbent Protocol
<5 ng/dL	PA unlikely
5-10 ng/dL	Indeterminate
>10 ng/dL	PA likely
Seated Protocol
>6 ng/dL	PA confirmed (if plasma cortisol lower than baseline to account for potential ACTH effects)
Source: Funder, 2016

Determination of Laterality

Imaging is recommended for all individuals with confirmed PA to determine whether PA is bilateral or unilateral, thereby informing treatment. Adrenal venous sampling is recommended if surgical treatment is being considered, although this testing may not be necessary in patients younger than 35 years with marked aldosterone excess, imaging findings consistent with a unliteral cortical adenoma, and spontaneous hypokalemia.^,

Genetic Testing

Up to 5% of individuals with PA have an identified genetic association. There are four known types of familial hyperaldosteronism, I-IV, and several other genetic associations with PA. Genetic testing is indicated in individuals with early onset PA (<20 years of age) or a consistent family history.^,

Genetic Syndromes Associated With PA	Associated Genes	Testing Recommendations
Familial hyperaldosteronism type I (glucocorticoid remediable aldosteronism)	CYP11B1::CYP11B2 fusion	Perform genetic testing (e.g., PCR) for all individuals with confirmed PA and at least 1 of the following: Age of onset <20 yrs Family history of PA Family history of stroke at <40 yrs Biochemical testing is not recommended Offer genetic testing to first-degree relatives with hypertension
Familial hyperaldosteronism type II	CLCN2	Sequence CLCN2 in individuals with confirmed PA with age of onset <20 yrs and/or family history of PA Offer genetic testing to first-degree relatives with hypertension
Familial hyperaldosteronism type III	KCNJ5	Sequence KCNJ5 in individuals with confirmed PA with age of onset <20 yrs and/or family history of PA Offer genetic testing to first-degree relatives with hypertension
Familial hyperaldosteronism type IV	CACNA1H	Sequence CACNA1H in individuals with confirmed PA with either age of onset <20 yrs and/or family history of PA Offer genetic testing to first-degree relatives with hypertension
Primary aldosteronism with seizures and neurologic abnormalities (PASNA)	CACNA1D	—
Multiple endocrine neoplasia type 1	Refer to the ARUP Consult Multiple Endocrine Neoplasias - MEN topic for more information
PCR, polymerase chain reaction Sources: Mulatero, 2020; Funder, 2016

Somatic ATP1A1, ATP2B3, CACNA1D, and KCNJ5 gene variants have been observed in sporadic aldosterone-producing adenomas, but there are currently no recommendations for somatic genetic testing in PA.

Treatment Monitoring

Laboratory Monitoring for Surgical Treatment of Primary Aldosteronism

Glomerular filtration rate and serum creatinine may be measured before surgery, and serum creatinine and urine albumin after surgery, to predict postoperative hyperkalemia. Postoperative measurement of plasma aldosterone and renin activity is recommended soon after surgery to assess biochemical response. Serum potassium levels should be checked periodically for a few weeks after surgery to determine if potassium supplementation is required. The FST (or potentially the seated saline suppression test) may be performed 3 or more months after surgery to determine if PA has been successfully treated from a biochemical perspective.

Laboratory Monitoring for Glucocorticoid Treatment of Familial Hyperaldosteronism Type I

Measurement of aldosterone concentrations and PRA may be useful for monitoring treatment effectiveness and preventing overtreatment in individuals with familial hyperaldosteronism type I treated with a glucocorticoid.