Aldosteronism

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
• 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 hypertension control

• Confirmatory testing
  • PA confirmatory testing in common use; insufficient evidence to recommend one over the others (Endocrine Society)
    • 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 (see table below)

Subtype Differentiation

• If confirmatory test is positive
  • MRI/CT adrenals
    • Lacks sensitivity, specificity
    • Most useful to rule out adrenocortical cancer
  • Adrenal vein sampling (AVS)
    • Should be performed in all patients considering surgery
    • Gold standard to differentiate aldosterone producing adenoma from bilateral adrenal hyperplasia  
  • Genetic testing for glucocorticoid-remediable aldosteronism (GRA) in patients with confirmed PA who have a family history of PA or of strokes at young age 

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 all 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

Clinical Background

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

Epidemiology

• Prevalence – 5-15% of random hypertensive patients
• Age – 30s-40s
• Sex – M<F, 1:2  

Etiologies

• Unilateral or bilateral cortical nodular hyperplasia
• Aldosterone-producing tumor (Conn syndrome)
• Adrenal carcinoma (rare in the general population)

Genetics

• Three forms of familial hyperaldosteronism (FH)
  • FHI – unequal recombination between CYP11B1 and CYP11B2
  • FHII – linkage in 7922 region; nonglucocorticoid remediable
  • FHIII – aggressive form; medication resistant

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
    • Seen in congestive heart failure, nephritic syndrome, cirrhosis, renal artery hypertension, severe arteriolar nephrosclerosis, rare renin-secreting tumors

Clinical Presentation

• Constitutional – weakness, fatigue
• Renal – polyuria, proteinuria, renal failure
• Cardiac – hypertension, cardiac hypertrophy
• Edema – rarely exists

Treatment

• Often involves surgical excision if tumor present
• Aldosterone antagonists (spironolactone) may be successful therapy

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
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 Radioimmunoassay
Aldosterone 30 Minute 0070016 Method: Quantitative Radioimmunoassay
Renin, Direct 2001575 Method: Quantitative Immunoradiometry	Not recommended

Diagnostic Algorithm

  Hyperaldosteronism Testing Algorithm