Primary Aldosteronism

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

Diagnosis

Initial Testing

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

Aldosterone-Renin Ratio

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

Factors That May Impact ARR Results
Factor	Impact on Aldosterone Plasma Concentrations	Impact on Renin Concentrations	Impact on ARR	Potential False Result
Medications
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
Renin inhibitors	↓	↓ (PRA) ↑ (DRC)	↑ (PRA) ↓ (DRC)	False positive (PRA) False negative (DRC)
Electrolyte Status
Hypokalemia	↓	↔ or ↑	↓	False negative
Potassium loaded	↑	↔ or ↓	↑	—
Sodium loaded	↓	↓ ↓	↑	False positive
Sodium restricted	↑	↑ ↑	↑	False negative
Demographic Characteristics
>65 yrs of age	↓	↓ ↓	↑	False positive
Premenopausal, ovulating^a	↔ or ↑	↓	↑	False positive^b
Other Conditions
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

Confirmatory Testing

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

PA Confirmatory Test Options^a
Procedure	Positive Interpretation	Comments
Oral sodium loading^b
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
Saline infusion^b
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 Renin, aldosterone, cortisol, and plasma potassium	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
Fludrocortisone suppression^b
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 At 0700 and 1000 hrs, measure plasma cortisol At 1000 hrs, measure plasma aldosterone concentration and plasma renin activity (with patient seated)	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 Is most sensitive for confirming PA Is a less intrusive method of sodium loading than SIT Allows for potentially confounding effects of potassium to be controlled and for ACTH to be detected and monitored Is safe when performed by an experienced practitioner
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 renin activity Plasma aldosterone concentration Cortisol (with patient seated)	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

Subtype Differentiation

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
- Results
  - 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).
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).

Genetics

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
- FH-III
  - KCNJ5 variant
  - Severe hypertension and massive adrenal hyperplasia
Variants in sporadic aldosterone-producing adenomas (Funder, Endocrine Society Guideline, 2016)
- KCNJ5
  - 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