Aldosteronism

Aldosteronism 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 approach that includes screening, confirmation of diagnosis, and determination of the specific subtype of primary aldosteronism (PA).

Quick Answers for Clinicians

Which testing algorithms are related to this topic?

Key Points

Measuring Aldosterone-to-Renin Ratio (ARR)

Suggested approach from the Endocrine Society (Funder, 2016)

  • Preparation
    • Attempt to correct hypokalemia
      • Measure plasma potassium in blood collected slowly with syringe and needle (preferably not Vacutainer to minimize risk of spuriously raising potassium)
        • Avoid fist clenching – wait at least 5 seconds after tourniquet release to insert needle
        • Separate plasma from cells within 30 minutes of collection
      • Target plasma potassium of 4 mmol/L
    • Encourage patient to liberalize (rather than restrict) sodium intake
    • Withdraw agents that markedly affect ARR for at least 4 weeks prior to testing
      • Spironolactone, eplerenone, amiloride, triamterene
      • Potassium-wasting diuretics
      • Products derived from licorice root (eg, licorice, chewing tobacco)
    • If ARR testing is not diagnostic after withdrawing above agents and hypertension can be controlled with noninterfering medications, test again in 2 weeks after withdrawing other medications
      • Beta blockers, methyldopa, clonidine, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers
  • If necessary to maintain hypertension control, begin use of other antihypertensive medications that have lesser effects on the ARR
    Medications with Minimal Effects on Plasma Aldosterone Levels that Can Control Hypertension During Case Finding and Confirmatory Testing for PAa
      Verapamil Slow-Release Hydralazine Prazosin Hydrochloride Doxazosin Mesylate Terazosin Hydrochloride
    Class

    Nondihydropyridine slow-release antagonist calcium channel

    Vasodilator

    α-adrenergic blocker

    α-adrenergic blocker

    α-adrenergic blocker

    Usual dose

    90-120 mg

    10-12.5 mgb

    0.5-1 mgb

    1-2 mgb

    1-2 mgb

    Frequency

    2x daily

    2x daily

    2-3x daily

    1x daily

    1x daily

    Comments

    Use singly or in combination with other agents listed in table

    Commence verapamil slow-release first to prevent reflex tachycardia

    Commencement at low doses reduces risk of side effectsc

    Monitor for postural hypotension

    Monitor for postural hypotension

    Monitor for postural hypotension

    aAdapted from Funder, Endocrine Society Guideline, 2016

    bIncreasing as required

    cSide effects include headaches, flushing, and palpitations

  • Oral contraceptives and hormone replacement therapy may lower direct renin concentration (DRC) and cause false-positive ARR (plasma-renin activity [PRA] is unaffected)
    • Recommend renin activity or aldosterone/renin activity ratio in these cases
    • Do not withdraw oral contraceptives unless confident of alternative effect contraception
  • Conditions for blood collection
    • Collect blood midmorning after patient has been sitting, standing, or walking for at least 2 hours and seated for 5-15 minutes
    • Collect carefully and avoid stasis and hemolysis during collection
    • Maintain sample at room temperature (not on ice) during transport to laboratory and prior to centrifugation and rapid freezing of plasma component pending assay
  • Collection and transport requirements
    • Aldosterone and renin
  • Factors affecting results
    • Age
      • >65 years of age – renin can be lowered more than aldosterone by age alone, leading to raised ARR
    • Gender
      • Premenstrual, ovulating females have higher ARR levels than age-matched men during luteal phase of menstrual cycle
        • False positive DRC can occur at this time; PRA is unaffected
    • Time of day, recent diet, posture, length of time in posture
    • Medications
    • Method of blood collection
    • Level of potassium
    • Level of creatinine – renal failure can lead to false positive ARR
  • Interpreting ARR test results
    • Positive or equivocal – requires confirmation
    • Negative – primary aldosteronism unlikely
      Factors That May Lead to False-Positive or False-Negative ARR Resultsa
      Factor Effect on Aldosterone Plasma Levels Effect on Renin Levels Effect on ARR
      Medicationsb
      ACE inhibitors ↑ ↑ ↓ (false negative)
      Angiotensin II type 1 receptor blockers ↑ ↑ ↓ (false negative)
      Potassium-sparing diuretics ↑ ↑ ↓ (false negative)
      Ca2+ blockers (dihydropyridine) → ↓ ↓ (false negative)
      Potassium-wasting diuretics → ↑ ↑ ↑ ↓ (false negative)
      Central alpha-2 agonists (eg, clonidine, α-methyldopa) ↓ ↓ ↑ (false positive)
      Nonsteroidal anti-inflammatory drugs ↓ ↓ ↑ (false positive)
      β-Adrenergic blockers ↓ ↓ ↑ (false positive)
      Renin inhibitors ↓ ↑ ↑ (false positive); ↓ (false negative)
      Potassium status
      Hypokalemia → ↑ ↓ (false negative)
      Potassium loading → ↓
      Dietary sodium
      Sodium loaded ↓ ↓ ↑ (false positive)
      Sodium restricted ↑ ↑ ↑ (false negative)
      Age
      >65 ↓ ↓ ↑ (false positive)
      Premenopausal femalesc
      Compared with males → ↑ ↑ (false positive)
      Other conditions
      Malignant hypertension ↑ ↑ ↓ (false negative)
      Pregnancy ↑ ↑ ↓ (false negative)
      Renovascular hypertension ↑ ↑ ↓ (false negative)
      Pseudohypoaldosteronism type 2 ↑ (false positive)
      Renal impairment ↑ (false positive)

      aAdapted from Funder, Endocrine Society Guideline, 2016

      bRenin inhibitors lower PRA but raise DRC. This would be expected to result in false-positive ARR levels for renin measured as PRA and false negatives for renin measured at DRC.

      cIn premenopausal, ovulating women, plasma aldosterone levels measured during the menses or the proliferative phase of the menstrual cycle are similar to those of men but rise briskly in the luteal phase. Because renin levels are lower, the ARR is higher than in men for all phases of the cycle, but especially during the luteal phase during which aldosterone rises to a greater extent than renin. False positives can occur during the luteal phase, but only if renin is measured as DRC and not PRA. In preliminary studies, some investigations have found false positives on the current cutoffs for women in the luteal phase. Accordingly, it would seem sensible to screen women at the follicular phase, if practicable.

Confirmatory Testing

  • Insufficient evidence to recommend one strategy over another (Funder, Endocrine Society Guideline, 2016)
    • Captopril challenge (CCT)
    • Fludrocortisone suppression (FST)
    • Saline infusion (SIT)
    • Oral sodium loading
  • Recent study comparing CCT, furosemide upright test (FUT), and SIT in Japanese individuals (Nanba, 2012)
    • Single confirmatory testing is sufficient to confirm PA; SIT is suboptimal when compared to CCT and FUT
    • Although significantly higher results correlate with unilateral subtypes, adrenal vein sampling (AVS) is still recommended before surgery even in patients highly likely to have unilateral PA
Primary Aldosteronism​ (PA) Confirmatory Test Optionsa
Procedure Positive interpretation Concerns
Oral saline 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 (>14 μg/24 hr at the Cleveland Clinic, >12 μg/24 hr at Mayo Clinic) make PA highly likely
  • PA unlikely if urinary aldosterone <10 μg/24 hr in the absence of renal disease where PA may coexist with lower measured urinary aldosterone levels
Do not use for individuals with
  • Severe uncontrolled hypertension
  • Renal insufficiency
  • Cardiac arrhythmia
  • Severe hypokalemia

Inconvenience of 24-hr urine collection (main limitation)

Saline infusion (SIT)b
Administer 2 L 0.9% NaCl infused over 4 hours starting from 0800-0930 hrs

Monitored throughout test − blood pressure and heart rate

Blood samples – baseline and 4 hrs post challenge

  • Renin, aldosterone, cortisol, and plasma potassium
Postinfusion plasma aldosterone levels <5 ng/dL (140 pmol/L) make diagnosis of PA unlikely

Levels >10 ng/dL (280 nmol/L) sign of very probable PA

5-10 ng/dL – indeterminate

For seated SIT, postinfusion plasma aldosterone of >6 ng/dL confirms PA, provided plasma cortisol concentration is lower than the value obtained basally to exclude confounding ACTH effect

Do not use for individuals with
  • Severe uncontrolled hypertension
  • Renal insufficiency
  • Cardiac arrhythmia
  • Severe hypokalemia
Fludrocortisone suppressionb
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 − plasma cortisol
  • At 1000 hrs – plasma aldosterone and PRA (patient seated)
Upright plasma aldosterone >6 ng/dL (170 nmol/L) on day 4 at 1000 hrs confirms PA (provided PRA 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 argue
  • It is most sensitive for confirming PA
  • Less intrusive method of sodium loading than SIT
  • Allows for potentially confounding effects of potassium to be controlled and for ACTH to be monitored and detected
  • Safe when performed by experienced hands
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 post-challenge with patient remaining seated during this period

  • Plasma renin activity (PRA)
  • Plasma aldosterone
  • Cortisol (patient seated)
Plasma aldosterone normally suppressed by captopril (>30%)

In patients with PA, it remains elevated and PRA remains suppressed

Some decrease of aldosterone levels is occasionally seen in patients with idiopathic adrenal hyperplasia (IAH)

Reports of substantial number of false-negative or equivocal results
aAdapted from Funder, Endocrine Society Guideline, 2016

bInsufficient direct evidence to recommend one test over the others

Subtype Differentiation

Diagnosis

Indications for Testing

Refer to Screening.

Laboratory Testing

Refer to Key Points.

Imaging Studies

  • Adrenal CT or MRI to screen for tumor if testing confirms aldosteronism
    • Most useful to rule out adrenocortical cancer
    • Lack specificity, sensitivity
    • MRI offers no diagnostic advantage over CT
    • Nonfunctional adrenal “incidentalomas” appear identical on imaging to functional tumors
    • Results (Chao, 2013)
      • Normal, micronodularity, or bilateral masses on imaging
        • Refer to bilateral adrenal vein sampling (AVS) below
      • Unilateral hypodense nodule ≥1 cm but <4 cm on imaging
        • ≥40 years – bilateral AVS (see below)
        • <40 years – aldosterone-producing adenoma (APA) or primary adrenal hyperplasia (PAH); unilateral laparoscopic adrenalectomy
      • Unilateral mass ≥ 4 cm on imaging – likely adrenal carcinoma
  • Bilateral AVS
    • Gold standard to distinguish unilateral (APA or UAH) from bilateral (IAH) disease
    • Indicated in patients where surgical treatment is considered
    • 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 PAH; unilateral laparoscopic adrenalectomy
      • No lateralization – consider genetic testing for glucocorticoid-remediable aldosteronism (GRA)

Differential Diagnosis

  • Essential hypertension
  • Cushing syndrome
  • Obstructive sleep apnea
  • Pheochromocytoma
  • Liddle syndrome
  • Excessive licorice ingestion
  • Renal artery stenosis
  • Aortic coarctation

Screening

  • Endocrine Society Clinical Practice Guidelines (Funder, 2016) recommends case detection of primary aldosteronism (PA) in individuals with
    • Blood pressure >150/100 mmHg on 3 measurements on different days
    • Hypertension (HTN) (>140/90 mmHg) resistant to 3 conventional antihypertensive drugs (including a diuretic) or controlled BP (<140/90 mmHg) on ≥4 antihypertensive drugs
    • HTN and
      • Spontaneous or diuretic-induced hypokalemia
      • Adrenal incidentaloma
      • Sleep apnea
      • Family history of early onset HTN or cerebrovascular accident at young age (<40 years)
      • First degree relatives of patients with primary aldosteronism
  • Initial screen – aldosterone-renin ratio (ARR) most reliable
    • Renin testing alone not recommended as screen
    • Remove any drugs that can interfere with test results 4 weeks before test
    • ARR increase is not diagnostic – proceed with confirmatory testing
  • Recommend adrenal CT as initial study in subtype testing

Background

Epidemiology

  • Prevalence – >5% and possibly >10% of hypertensive patients (Funder, Endocrine Society Guideline, 2016)
  • Age – 30s-40s
  • Sex – M<F, 1:2

Etiologies

  • Unilateral or bilateral cortical nodular hyperplasia
  • Aldosterone-producing adenoma (Conn syndrome)
  • Aldosterone-producing adrenocortical carcinoma (rare)
  • Familial syndromes (refer to Genetics)
  • Ectopic aldosterone-producing adenoma or carcinoma

Genetics

  • Three forms of familial hyperaldosteronism (FH)
    • FHI autosomal dominant (AD)
      • Unequal recombination between CYP11B1 and CYP11B2
      • Glucocorticoid-remediable aldosteronism (GRA)
    • FHII AD
      • Associated with region chromosome 7p22
      • Familial occurrence of adenoma or hyperplasia
      • Not glucocorticoid remediable
    • FHIII
      • KCNJ5 mutation
      • Severe hypertension and massive adrenal hyperplasia
  • Mutations in sporadic aldosterone-producing adenomas (Funder, Endocrine Society Guideline, 2016)
    • KCNJ5
      • Tends to be female and younger
      • Higher in Japanese
      • More severe primary aldosteronism
    • ATP1A1, ATP2B3, CACNA1D
      • These mutations tend to be more common in males

Pathophysiology

  • Hypersecretion of aldosterone increases the reabsorption of sodium for potassium and hydrogen by the renal distal tubule
    • Excess sodium reabsorption leads to hypertension
    • Progressive depletion of potassium and hydrogen leads to hypokalemia and metabolic alkalosis
  • Classification
    • Primary – excessive aldosterone secretion by the adrenal glands
    • Secondary – renin-mediated secretion

Clinical Presentation

  • Constitutional – weakness, fatigue
  • Renal – polyuria, proteinuria, renal failure
  • Cardiac – hypertension, cardiac hypertrophy
  • Edema – rarely exists
  • Electrolyte abnormalities – hypokalemia not the usual presenting abnormality

ARUP Lab Tests

Primary Tests

Screen and diagnose hyperaldosteronism

Refer to Key Points for patient preparation information, a complete list of agents that can affect the ARR, and alternative medications

Positive/equivocal results require confirmation

Screen and diagnose hyperaldosteronism

Refer to Key Points for patient preparation information, a complete list of agents that can affect the ARR, and alternative medications

Positive/equivocal results require confirmation

The combined aldosterone/renin tests are preferred when screening for hyperaldosteronism; refer to aldosterone/renin activity ratio test or the aldosterone and renin, direct with ratio tests

Refer to Key Points for patient preparation information, a complete list of agents that can affect the ARR, and alternative medications

Screen and diagnose hyperaldosteronism

Related Tests

Use in aldosterone stimulation testing

Use in aldosterone stimulation testing

The combined aldosterone/renin tests are preferred when screening for hyperaldosteronism; refer to the aldosterone/renin activity ratio test or the aldosterone and renin, direct with ratio test

Refer to Key Points for patient preparation information, a complete list of agents that can affect the ARR, and alternative medications

The combined aldosterone/renin tests are preferred when screening for hyperaldosteronism; refer to the aldosterone/renin activity ratio test or the aldosterone and renin, direct with ratio tests

Refer to Key Points for patient preparation information, a complete list of agents that can affect the ARR, and alternative medications

Investigate primary and secondary aldosteronism

Investigate primary and secondary aldosteronism

Distinguish between bilateral idiopathic hyperaldosteronism (IHA) and aldosterone-producing adenomas (APA)

Investigate primary and secondary aldosteronism

Distinguish between bilateral idiopathic hyperaldosteronism (IHA) and aldosterone-producing adenomas (APA)

Initial screen to identify electrolyte abnormalities associated with aldosteronism

Panel includes anion gap, carbon dioxide, chloride, potassium, and sodium

Monitor disease

Monitor disease

Medical Experts

Contributor
Contributor

Young

Brittany A. Young, MD, PhD
Assistant Professor of Clinical Pathology at University of Utah
Co-Director of Clinical Laboratories at University Hospital, ARUP Laboratories

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®