Aldosteronism

Primary Author Meikle, A. Wayne, MD.

Key Points

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
    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

PA Confirmatory Test Options  (Endocrine Society Guidelines, 2008)

ProcedurePositive InterpretationConcerns
Captopril Challenge (CCT)*

Captopril 25-50 mg orally after sitting or standing for ≥1 hour

Blood samples

Hours 0 and 1 or 2 hours post-challenge – PRA, plasma aldosterone, and cortisol  (patient seated)

Post-captopril ARR >12 ng/dL

OR

Post-captopril aldosterone >12 ng/dL

Reports of substantial number of false negative or equivocal results
Fludrocortisone Suppression*

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

7 am and 10 am − plasma cortisol

10 am – plasma aldosterone and plasma renin activity (PRA)   (patient seated)

Plasma aldosterone >6 ng/dL, normal serum potassium, urine Na >3 mmol/kg/day, 7 am cortisol <10 am

Do not use for individuals with

  • Severe uncontrolled hypertension
  • Renal insufficiency
  • Cardiac insufficiency
  • Cardiac arrhythmia
  • Severe hypokalemia
Saline Infusion (SIT)*

2 L 0.9% NaCl infused over 4 hours

Starting at 8:00 to 9:30 am

Blood samples

Hours 0 and 4 − renin, aldosterone, cortisol, and plasma potassium

Monitored throughout test − blood pressure and heart rate

Plasma aldosterone >10 ng/dL (Indeterminate 5-10 ng/dL)

May require several days of hospitalization for the testing (monitoring of potassium)

Avoid in patients with heart diesease

Oral Saline Loading*

200 mmol/dL Na/day x 3 days; KCl supplementation

Urine sample

24-hour urine sodium content measurement finalized on morning of day

Urine aldosterone >14 μg/24 hr (grey zone 12-14 ug)

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

  • 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
    • Genetic testing for familial types (I and II) – patients with family history of PA, young onset (<20 years), PA with family history of stroke (Gates, 2001)

Diagnosis

Indications for Testing 

  • Refer to Screening tab

Laboratory Testing

  • Refer to Key Points tab

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 
      • Normal, micronodularity, or bilateral masses on imaging
        • Refer to bilateral 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 differentiate APA from bilateral adrenal hyperplasia 
    • 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

Screening

  • Endocrine Society Clinical Practice Guidelines (2008)
    • Stage 2 or 3 hypertension (BP >160/100)
    • Drug-resistant hypertension
    • Hypertension with diuretic-induced or spontaneous hypokalemia
    • Hypertension with adrenal incidentaloma
    • Hypertension with family history of early onset hypertension or cerebrovascular accident <40 years
    • Hypertension with primary aldosteronism in first-degree relative
  • Initial screen – aldosterone-renin ratio (ARR) most reliable
    • Direct renin test not recommended as screen
    • Remove any drugs 4 weeks before test that can interfere with test results
      • α1-antagonists used in hypertension do not affect ARR
      • Secondary agent can be used – nondihydropyridine calcium channel blocker (eg, verapamil) or α1-antagonist (eg, prazosin)
    • ARR increase is not diagnostic – proceed with confirmatory testing

Clinical Background

Aldosteronism is a syndrome caused by excessive and inappropriate aldosterone production and is the most common form of endocrine hypertension. 

Epidemiology

  • Prevalence – >10% of random hypertensive patients (Endocrine Society, 2008)
  • 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 (see Genetics section)
  • Ectopic aldosterone-producing adenoma or carcinoma

Genetics

  • Three forms of familial hyperaldosteronism (FH)
    • FHI (AD)
      • Unequal recombination between CYP11B1 and CYP11B2
      • Glucocorticoid-remediable aldosteronism (GRA)
    • FHII (AD)
      • Linkage chromosome 7p22 mutation
      • Familial occurrence of adenoma or hyperplasia
      • Not glucocorticoid-remediable
    • FHIII
      • KCNJ5 mutation
      • Severe hypertension and massive adrenal hyperplasia

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

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Aldosterone/Renin Activity Ratio 0070073
Method: Quantitative Chemiluminescent Immunoassay
Diagnose and screen for primary hyperaldosteronism  

Positive/equivocal results require confirmation

Aldosterone and Renin, Direct with Ratio 2002582
Method: Quantitative Chemiluminescent Immunoassay/Quantitative Immunoradiometry

Diagnose and screen for primary hyperaldosteronism

 

Positive/equivocal results require confirmation

Aldosterone 60 Minute 0070017
Method: Quantitative Chemiluminescent Immunoassay

Use in suppression or loading tests

Hypokalemia should be corrected before testing

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Renin Activity 0070105
Method: Quantitative Radioimmunoassay
Electrolytes, Urine 0020498
Method: Quantitative Ion-Selective Electrode

Monitor disease

Potassium, Plasma or Serum 0020002
Method: Quantitative Ion-Selective Electrode

Monitor disease

Aldosterone, Urine 0070480
Method: Quantitative Chemiluminescent Immunoassay
Aldosterone 30 Minute 0070016
Method: Quantitative Chemiluminescent Immunoassay
Renin, Direct 2001575
Method: Quantitative Immunoradiometry

Not recommended

Electrolyte Panel 0020410
Method: Quantitative Ion-Selective Electrode/Enzymatic

Initial screen to identify electrolyte abnormalities associated with aldosteronism

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