Aldosteronism

Primary Author: Meikle, A. Wayne, MD.

  • Key Points
  • Diagnosis
  • Algorithms
  • Screening
  • Background
  • Lab Tests
  • References
  • Related Content

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)
  • 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

  • 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)

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

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

Hyperaldosteronism Testing Algorithm

  • 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

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

Aldosterone/Renin Activity Ratio 0070073
Method: Quantitative Chemiluminescent Immunoassay

Follow Up

Positive/equivocal results require confirmation

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

Follow Up

Positive/equivocal results require confirmation

Aldosterone 60 Minute 0070017
Method: Quantitative Chemiluminescent Immunoassay

Limitations

Hypokalemia should be corrected before testing

Additional Tests Available

Renin Activity 0070105
Method: Quantitative Radioimmunoassay

Comments

The combined aldosterone/renin tests are preferred (refer to Aldosterone/Renin activity ratio or Aldosterone and Renin, direct with ratio) when screening for primary hyperaldosteronism

Electrolytes, Urine 0020498
Method: Quantitative Ion-Selective Electrode

Comments

Monitors disease

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

Comments

Monitors disease

Aldosterone, Urine 0070480
Method: Quantitative Chemiluminescent Immunoassay

Comments

For screening and diagnosing for primary hyperaldosteronism, order this urine test concurrently with the serum renin testing

Aldosterone 30 Minute 0070016
Method: Quantitative Chemiluminescent Immunoassay

Comments

Use in aldosterone suppression or loading testing

Renin, Direct 2001575
Method: Quantitative Immunoradiometry

Comments

Not recommended

The combined aldosterone/renin tests are preferred (refer to Aldosterone/Renin activity ratio or Aldosterone and Renin, direct with ratio) for diagnosing hyperaldosteronism

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

Comments

Initial screen to identify electrolyte abnormalities associated with aldosteronism

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

Aldosterone, Serum 0070015
Method: Quantitative Chemiluminescent Immunoassay

Comments

The combined aldosterone/renin tests are preferred (refer to Aldosterone/Renin activity ratio or Aldosterone and Renin, direct with ratio) for diagnosing hyperaldosteronism

Guidelines

Funder J, Carey R, Fardella C, Gomez-Sanchez C, Mantero F, Stowasser M, Young W, Montori V, Endocrine Society. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008; 93(9): 3266-81. PubMed

General References

Chao C, Wu V, Kuo C, Lin Y, Chang C, Chueh J, Wu K, Pimenta E, Stowasser M. Diagnosis and management of primary aldosteronism: an updated review. Ann Med. 2013; 45(4): 375-83. PubMed

Gates L, Benjamin N, Haites N, MacConnachie A, McLay J. Is random screening of value in detecting glucocorticoid-remediable aldosteronism within a hypertensive population? J Hum Hypertens. 2001; 15(3): 173-6. PubMed

Kempers M, Lenders J, van Outheusden L, van der Wilt G, Kool L, Hermus A, Deinum J. Systematic review: diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism. Ann Intern Med. 2009; 151(5): 329-37. PubMed

Monticone S, Viola A, Tizzani D, Crudo V, Burrello J, Galmozzi M, Veglio F, Mulatero P. Primary aldosteronism: who should be screened? Horm Metab Res. 2012; 44(3): 163-9. PubMed

Nanba K, Tamanaha T, Nakao K, Kawashima S, Usui T, Tagami T, Okuno H, Shimatsu A, Suzuki T, Naruse M. Confirmatory testing in primary aldosteronism. J Clin Endocrinol Metab. 2012; 97(5): 1688-94. PubMed

Nishikawa T, Saito J, Omura M. Prevalence of primary aldosteronism: should we screen for primary aldosteronism before treating hypertensive patients with medication? Endocr J. 2007; 54(4): 487-95. PubMed

Sukor N. Primary aldosteronism: from bench to bedside. Endocrine. 2012; 41(1): 31-9. PubMed

Tomaschitz A, Pilz S. Aldosterone to renin ratio--a reliable screening tool for primary aldosteronism? Horm Metab Res. 2010; 42(6): 382-91. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Malabanan A, Meikle A, Swenson L, Bope E, Blackwell E. Suspected Hyperaldosteronism. In Choose the Right Tests: Endocrine Disorders, Columbus, Ohio: Anadem Publishing, 2004.

Ray J, Kushnir M, Palmer J, Sadjadi S, Rockwood A, Meikle W. Enhancement of specificity of aldosterone measurement in human serum and plasma using 2D-LC-MS/MS and comparison with commercial immunoassays. J Chromatogr B Analyt Technol Biomed Life Sci. 2014; 970: 102-7. PubMed

Medical Reviewers

Last Update: December 2015