Aldosteronism

Confirmation Testing for Primary Aldosteronism (PA)

The Endocrine Society suggests a three-tiered approach that includes screening, confirmation of diagnosis, and determination of the specific subtype of PA (Endocrine Society Clinical Practice Guidelines, 2008).

Confirmation of Clinical Suspicion/Screening

• Initial testing − ARR (plasma aldosterone-renin ratio); positive or equivocal results requires confirmation
  • Negative result – good evidence for absence of primary aldosteronism (PA)
• ARR testing protocol

  • Preparation
    • Correct hypokalemia 4 weeks prior – discontinue drugs and interfering substances
    • Potassium-wasting diuretics
      • Products derived from liquorice root (eg, confectionary licorice, chewing tobacco)
      • Aldosterone antagonists (eg, spironolactone, eplerenone)
  • Perform ARR Testing
    • Conditions for collecting blood samples − perform test in the morning
    • If ARR testing is not diagnostic – withdraw other medications that may affect the ARR and retest in 2 weeks
      • Beta blockers, methyldopa, clonidine, calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers
    • Substitute interfering hypertensive medications with relatively noninterfering medications (eg, prazosin, hydralazine, verapamil) for blood pressure control
• Confirmatory testing

  • Insufficient evidence to recommend one strategy over another (Endocrine Society, 2008)
    • Captopril challenge (CCT)
    • Fludrocortisone suppression (FUT)
    • Saline infusion (SIT)
    • Oral saline loading
  • Recent study comparing CCT, 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

  PA Confirmatory Test Options (Endocrine Society Guidelines, 2008)
  Procedure	Positive Interpretation	Concerns
  Captopril Challenge (CCT)*
  Administer captopril 25-50 mg orally after sitting or standing for ≥1 hr Blood samples – baseline and 1 or 2 hrs post-challenge Plasma renin activity (PRA) Plasma aldosterone Cortisol (patient seated)	Post-captopril plasma aldosterone-renin ratio (ARR) – >12 ng/dL OR Post-captopril aldosterone – >12 ng/dL	Reports of substantial number of false-negative or equivocal results
  Fludrocortisone Suppression*
  Administer 0.1 mg oral fludrocortisone acetate every 6 hrs x 4 days along with KCl, slow-release Na supplementation (30 mmol 3 times daily) Blood samples on day 4 At 0700 and 1000 − plasma cortisol At 1000 – plasma aldosterone and PRA (patient seated)	Plasma aldosterone – >6 ng/dL Normal serum potassium Urine Na – >3 mmol/kg/day At 0700 cortisol level <1000 cortisol level	Do not use for individuals with Severe uncontrolled hypertension Renal insufficiency Cardiac insufficiency Cardiac arrhythmia Severe hypokalemia
  Saline Infusion (SIT)*
  Administer 2 L 0.9% NaCl infused over 4 hours starting from 0800-0930 Monitored throughout test − blood pressure and heart rate Blood samples – baseline and 4 hrs post-challenge Renin, aldosterone, cortisol, and plasma potassium	Positive plasma aldosterone – >10 ng/dL Indeterminate plasma aldosterone – 5-10 ng/dL	May require several days of hospitalization for the testing (monitoring of potassium) Avoid in patients with heart disease
  Oral Saline Loading*
  Administer 200 mmol/dL Na/day x 3 days; KCl supplementation Urine sample 24-hr urine sodium content measurement finalized on morning of day 3	Urine aldosterone – >14 μg/24 hr (grey zone 12-14 μg) Urine Na – >200 mmol/24 hr	Do not use for individuals with Severe uncontrolled hypertension Renal insufficiency Cardiac insufficiency Cardiac arrhythmia Severe hypokalemia Inconvenience of 24-hr urine collection (main limitation) Avoid in patients with heart failure
  *Insufficient direct evidence to recommend one test over the others

Subtype Differentiation

• Confirmatory testing, localization studies, and molecular testing

  • If confirmatory test for hyperaldosteronism is positive
    • MRI/CT adrenals
      • Lacks sensitivity, specificity
      • Most useful to rule out adrenocortical cancer
  • Localization studies
    • Adrenal vein sampling (AVS)
      • Should be performed in all patients considering surgery
      • Gold standard to differentiate aldosterone producing adenoma from bilateral adrenal hyperplasia
  • Molecular testing
    • Familial types – patients with family history of PA, young onset (<20 years), PA with family history of stroke (Gates, 2001)