Primary aldosteronism (PA, or hyperaldosteronism) is a syndrome caused by excessive and inappropriate aldosterone production and is the most common form of endocrine hypertension. The Endocrine Society suggests a three-tiered diagnostic approach for PA that includes initial testing, confirmation, and subtyping.
Indications for Testing
- Endocrine Society Clinical Practice Guidelines (Funder, 2016) recommend case detection of PA in individuals with the following:
- Blood pressure (BP) >150/100 mmHg from three measurements on different days
- Hypertension (>140/90 mmHg) resistant to three conventional antihypertensive drugs (including a diuretic) or controlled BP (<140/90 mmHg) on four or more antihypertensive drugs
- Hypertension and
- Spontaneous or diuretic-induced hypokalemia
- Adrenal incidentaloma
- Sleep apnea
- Family history of early-onset hypertension or cerebrovascular accident at young age (<40 years)
- First-degree relatives of patients with PA
- Aldosterone-renin ratio (ARR) is most reliable.
- Renin testing alone is not recommended.
- Remove any drugs that can interfere with test results 4 weeks before testing.
- Confirmatory testing is recommended.
- Confirmatory testing may not be required for individuals with spontaneous hypokalemia, undetectable renin concentration, and plasma aldosterone concentration >20 ng/dL.
- Recommend adrenal CT as initial study to subtype
Patient preparation is critical for accurate ARR results. Refer to the Aldosterone-Renin Ratio Test Fact Sheet for specific guidance.
- Interpreting ARR test results
- Positive or equivocal: requires confirmation
- Negative: PA unlikely
- Sources of potential interference
|Factor||Impact on Aldosterone Plasma Concentrations||Impact on Renin Concentrations||Impact on ARR||Potential False Result|
|Angiotensin-converting enzyme inhibitors||↓||↑ ↑||↓||False negative|
|Angiotensin II type 1 receptor blockers||↓||↑ ↑||↓||False negative|
|β-adrenergic blockers||↓||↓ ↓||↑||False positive|
|Ca2+ blockers (dihydropyridine)||↔ or ↓||↑||↓||False negative|
|Central alpha-2 agonists (eg, clonidine, α-methyldopa)||↓||↓ ↓||↑||False positive|
|Nonsteroidal anti-inflammatory drugs||↓||↓ ↓||↑||False positive|
|Potassium-sparing diuretics||↓||↑ ↑||↓||False negative|
|Potassium-wasting diuretics||↔ or ↓||↑ ↑||↓||False negative|
False positive (PRA)False negative (DRC)
|Hypokalemia||↓||↔ or ↑||↓||False negative|
|Potassium loaded||↑||↔ or ↓||↑||—|
|Sodium loaded||↓||↓ ↓||↑||False positive|
|Sodium restricted||↑||↑ ↑||↑||False negative|
|>65 yrs of age||↓||↓ ↓||↑||False positive|
|Premenopausal, ovulatinga||↔ or ↑||↓||↑||False positiveb|
|Malignant hypertension||↑||↑ ↑||↓||False negative|
|Pregnancy||↑||↑ ↑||↓||False negative|
|Pseudohypoaldosteronism type 2||↔||↓||↑||False positive|
|Renal impairment||↔||↓||↑||False positive|
|Renovascular hypertension||↑||↑ ↑||↓||False negative|
aIn premenopausal, ovulating individuals, plasma aldosterone concentration is similar to that found in nonovulating individuals (and renin concentrations are lower) in all phases except the luteal phase. ARR is generally higher in ovulating individuals than in nonovulating individuals, and it increases during the luteal phase.
bIf possible, screening during the follicular phase may reduce the likelihood of false-positive results. When screening during the luteal phase, renin should be measured as PRA (rather than DRC) to avoid false-positive results.
DRC, direct renin concentration; PRA, plasma renin activity
↔, normal; ↑, increased; ↓, decreased; ↑ ↑, more significant increase; ↓ ↓, more significant decrease
Source: Funder, 2016
- Insufficient evidence to recommend one strategy over another (Funder, Endocrine Society Guideline, 2016)
- Oral sodium loading
- Saline infusion (SIT)
- Fludrocortisone suppression (FST)
- Captopril challenge (CCT)
- Study comparing CCT, furosemide upright test (FUT), and SIT in Japanese individuals (Nanba, 2012)
- Single confirmatory test is sufficient to confirm PA; SIT is suboptimal when compared with CCT and FUT
- Adrenal vein sampling (AVS) is still recommended before surgery even in patients highly likely to have unilateral PA
Oral sodium loadingb
Administer 200 mmol/dL Na x 3 days; KCl supplementation
Urine sample (24-hr urine sodium content measurement finalized on morning of day 3 to the morning of day 4)
Elevated urinary aldosterone excretion makes PA highly likely
PA is unlikely if urinary aldosterone <10 μg/24 hrs in the absence of renal disease where PA may coexist with lower measured urinary aldosterone concentrations
Do not use for individuals with severe uncontrolled hypertension, renal insufficiency, cardiac arrhythmia, or severe hypokalemia
Administer 2 L 0.9% NaCl infused over 4 hrs starting from 0800-0930 hrs
Monitored throughout test: blood pressure and heart rate
Blood samples: baseline and 4 hrs postchallenge
Postinfusion plasma aldosterone concentrations of <5 ng/dL (140 pmol/L) make diagnosis of PA unlikely
Concentrations >10 ng/dL (280 nmol/L) are a sign of very probable PA
5-10 ng/dL: indeterminate
For seated SIT, postinfusion plasma aldosterone concentrations of >6 ng/dL confirm PA, provided plasma cortisol concentration is lower than the value obtained basally to exclude confounding ACTH effect
Do not test individuals with severe uncontrolled hypertension, renal insufficiency, cardiac arrhythmia, or severe hypokalemia
Administer 0.1 mg oral fludrocortisone every 6 hrs x 4 days along with KCl, slow-release NaCl supplementation (30 mmol 3 times daily)
Blood samples on day 4
Upright plasma aldosterone concentrations of >6 ng/dL (170 nmol/L) on day 4 at 1000 hrs confirm PA (provided plasma renin activity is <1 ng/mL/h and plasma cortisol concentration is lower than the value obtained at 0700 hrs [to exclude a confounding ACTH effect])
Proponents of FST claim it
Captopril challenge test (CCT)b
Administer captopril 25-50 mg orally after patient has been sitting or standing for ≥1 hr
Blood samples: baseline and 1 or 2 hrs postchallenge with patient remaining seated during this period
Plasma aldosterone concentrations normally suppressed by captopril (>30%)
In patients with PA, it remains elevated and plasma renin activity remains suppressed
Some decrease of aldosterone concentrations is occasionally seen in patients with IAH
Numerous false-negative or equivocal results reported
aAdapted from Funder, Endocrine Society Guideline, 2016.
bInsufficient direct evidence to recommend one test over the others.
IAH, idiopathic adrenal hyperplasia
Confirmatory testing, localization studies, and genetic testing (Funder, Endocrine Society Guideline, 2016)
- If confirmatory test for PA is positive
- All patients with PA should undergo adrenal CT as initial study in subtype testing to exclude large masses that may represent adrenocortical carcinoma; magnetic resonance imaging (MRI) may also be considered.
- Localization studies
- Bilateral AVS
- Should be performed when surgical treatment is being considered
- Gold standard to distinguish unilateral (ie, aldosterone-producing adrenal adenoma [APA] or unilateral adrenal hyperplasia [UAH]) from bilateral (ie, idiopathic hyperaldosteronism) disease
- May be useful if scans are negative and high suspicion remains or patient >40 years with unilateral hypodense nodule >1 cm but <4 cm
- Blood samples collected simultaneously from adrenal veins and the inferior vena cava
- Concurrent serum cortisol sampling to rule out dilution at site of right adrenal vein
- Lateralization present: APA or primary adrenal hyperplasia (PAH); unilateral laparoscopic adrenalectomy
- No lateralization: Consider genetic testing for glucocorticoid-remediable aldosteronism (GRA).
- Bilateral AVS
- Genetic testing
- Test for familial hyperaldosteronism type 1 (FH-I).
- Patients with onset of confirmed PA before 20 years of age and in those who have a family history of PA or stroke at a young age (<40 years)
- Test for germline variants in KCNJ5 causing familial hyperaldosteronism type 3 (FH-III).
- Test for familial hyperaldosteronism type 1 (FH-I).
- Three forms of familial hyperaldosteronism (FH)
- FH-I autosomal dominant (AD)
- Unequal recombination between CYP11B1 and CYP11B2
- Glucocorticoid-remediable aldosteronism (GRA)
- FH-II AD
- Associated with region chromosome 7p22
- Familial occurrence of adenoma or hyperplasia
- Not glucocorticoid remediable
- KCNJ5 variant
- Severe hypertension and massive adrenal hyperplasia
- FH-I autosomal dominant (AD)
- Variants in sporadic aldosterone-producing adenomas (Funder, Endocrine Society Guideline, 2016)
- Tends to be detected in female individuals and younger individuals
- Higher occurrence in Japanese individuals
- Associated with more severe PA
- ATP1A1, ATP2B3, CACNA1D
- These variants tend to be more common in male individuals
ARUP Laboratory Tests
Chao CT, Wu VC, Kuo CC, et al. Diagnosis and management of primary aldosteronism: an updated review. Ann Med. 2013;45(4):375-383.
Funder JW, Carey RM, Mantero F, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916.
Gates LJ, Benjamin N, Haites NE, et al. Is random screening of value in detecting glucocorticoid-remediable aldosteronism within a hypertensive population? J Hum Hypertens. 2001;15(3):173-176.
Kempers MJE, Lenders JWM, van Outheusden L, et al. Systematic review: diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism. Ann Intern Med. 2009;151(5):329-337.
Monticone S, Viola A, Tizzani D, et al. Primary aldosteronism: who should be screened? Horm Metab Res. 2012;44(3):163-169.
Nanba K, Tamanaha T, Nakao K, et al. Confirmatory testing in primary aldosteronism. J Clin Endocrinol Metab. 2012;97(5):1688-1694.
Nishikawa T, Saito J, Omura M. Prevalence of primary aldosteronism: should we screen for primary aldosteronism before treating hypertensive patients with medication? Endocr J. 2007;54(4):487-495.
Tomaschitz A, Pilz S. Aldosterone to renin ratio--a reliable screening tool for primary aldosteronism? Horm Metab Res. 2010;42(6):382-391.