Aldosteronism

Primary Author: Meikle, A. Wayne, MD.

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

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
    • 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
      • Renin testing alone 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

    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

    Related Tests

    Guidelines

    Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, Young WF, Montori VM, 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 LJ, Benjamin N, Haites NE, MacConnachie AA, McLay JS. Is random screening of value in detecting glucocorticoid-remediable aldosteronism within a hypertensive population? J Hum Hypertens. 2001; 15(3): 173-6. PubMed

    Kempers MJ E, Lenders JW M, van Outheusden L, van der Wilt GJan, Kool LJ Schultze, Hermus AR M M, 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

    Stowasser M. Update in primary aldosteronism. J Clin Endocrinol Metab. 2015; 100(1): 1-10. 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 JA, Kushnir MM, Palmer J, Sadjadi S, Rockwood AL, 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: April 2016