Aldosteronism

Primary Author: Straseski, Joely A., PhD, MS, MT(ASCP), DABCC.

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

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

Suggested approach to measuring aldosterone-to-renin ratio (ARR) (Funder, Endocrine Society Guideline, 2016)

  • ARR test results
    • Positive or equivocal – requires confirmation
    • Negative – PA unlikely

Confirmatory testing

  • Insufficient evidence to recommend one strategy over another (Funder, Endocrine Society Guideline, 2016)
    • Captopril challenge (CCT)
    • Fludrocortisone suppression (FST)
    • Saline infusion (SIT)
    • Oral sodium loading
  • Recent study comparing CCT, furosemide upright test (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

Primary Aldosteronism (PA) Confirmatory Test Options

Primary Aldosteronism​ (PA) Confirmatory Test Options*

Procedure

Positive interpretation

Concerns

Oral saline loading**

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

Urine sample

  • 24-hr urine sodium content measurement finalized on morning of day 3 to the morning of day 4
  • Elevated urinary aldosterone excretion (>14 μg/24 hr at the Cleveland Clinic, >12 μg/24 hr at Mayo Clinic) make PA highly unlikely
  • PA unlikely if urinary aldosterone <10 μg/24 hr in the absence of renal disease where PA may coexist with lower measured urinary aldosterone levels 

Do not use for individuals with

  • Severe uncontrolled hypertension
  • Renal insufficiency
  • Cardiac arrhythmia
  • Severe hypokalemia

Inconvenience of 24-hr urine collection (main limitation)

Saline infusion (SIT)**

Administer 2 L 0.9% NaCl infused over 4 hours starting from 0800-0930 hrs

Monitored throughout test − blood pressure and heart rate

Blood samples – baseline and 4 hrs post challenge

  • Renin, aldosterone, cortisol, and plasma potassium

Postinfusion plasma aldosterone levels <5 ng/dL (140 pmol/L) make diagnosis of PA unlikely

Levels >10 ng/dL (280 nmol/L) sign of very probable PA

5-10 ng/dL – indeterminate

For seated SIT, postinfusion plasma aldosterone of >6 ng/dL confirms PA, provided plasma cortisol concentration is lower than the value obtained basally to exclude confounding ACTH effect

Do not use for individuals with

  • Severe uncontrolled hypertension
  • Renal insufficiency
  • Cardiac arrhythmia
  • Severe hypokalemia

Fludrocortisone suppression**

Administer 0.1 mg oral fludrocortisone every 6 hrs x 4 days along with KCl, slow-release NaCl supplementation (30 mmol 3 times daily)

Blood samples on day 4

  • At 0700 and 1000 hrs − plasma cortisol
  • At 1000 hrs – plasma aldosterone and PRA (patient seated)

Upright plasma aldosterone >6 ng/dL (170 nmol/L) on day 4 at 1000 hrs confirms PA (provided PRA is <1 ng/mL/h and plasma cortisol concertation is lower than the value obtained at 0700 hrs (to exclude a confounding ACTH effect)

Proponents of FST argue

  • It is most sensitive for confirming PA
  • Less intrusive method of sodium loading than SIT
  • Allows for potentially confounding effects of potassium to be controlled and for ACTH to be monitored and detected
  • Safe when performed by experienced hands

Captopril challenge test (CCT)**

Administer captopril 25-50 mg orally after patient has been sitting or standing for ≥1 hr

Blood samples – baseline and 1 or 2 hrs post-challenge with patient remaining seated during this period

  • Plasma renin activity (PRA)
  • Plasma aldosterone
  • Cortisol (patient seated)

Plasma aldosterone normally suppressed by captopril (>30%)

In patients with PA, it remains elevated and PRA remains suppressed

Some decrease of aldosterone levels is occasionally seen in patients with idiopathic adrenal hyperplasia (IAH)

Reports of substantial number of false-negative or equivocal results

*Adapted from Funder, Endocrine Society Guideline, 2016

**Insufficient direct evidence to recommend one test over the others

Subtype Differentiation

Indications for Testing

  • Refer to Screening section

Laboratory Testing

  • Refer to Key Points section

Imaging Studies

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 (Funder, 2016) recommends case detection of primary aldosteronism (PA) in the individuals with
    • Blood pressure >150/100 mmHg on 3 measurements on different days
    • Hypertension (HTN) (>140/90 mmHg) resistant to 3 conventional antihypertensive drugs (including a diuretic) or controlled BP (<140/90 mmHg) on ≥4 antihypertensive drugs
    • HTN and
      • Spontaneous or diuretic-induced hypokalemia
      • Adrenal incidentaloma
      • Sleep apnea
      • Family history of early onset HTN or cerebrovascular accident at young age (<40 years)
      • First degree relatives of patients with primary aldosteronism
  • Initial screen – aldosterone-renin ratio (ARR) most reliable
    • Renin testing alone not recommended as screen
    • Remove any drugs that can interfere with test results 4 weeks before test
    • ARR increase is not diagnostic – proceed with confirmatory testing
  • Recommend adrenal CT as initial study in subtype testing

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

Epidemiology

  • Prevalence – >5% and possibly >10% of hypertensive patients (Funder, Endocrine Society Guideline, 2016)
  • 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 (refer to Genetics section)
  • Ectopic aldosterone-producing adenoma or carcinoma

Genetics

  • Three forms of familial hyperaldosteronism (FH)
    • FHI autosomal dominant (AD)
      • Unequal recombination between CYP11B1 and CYP11B2
      • Glucocorticoid-remediable aldosteronism (GRA)
    • FHII AD
      • Associated with region chromosome 7p22
      • Familial occurrence of adenoma or hyperplasia
      • Not glucocorticoid remediable
    • FHIII
      • KCNJ5 mutation
      • Severe hypertension and massive adrenal hyperplasia
  • Mutations in sporadic aldosterone-producing adenomas (Funder, Endocrine Society Guideline, 2016) 
    • KCNJ5
      • Tends to be female and younger
      • Higher in Japanese
      • More severe primary aldosteronism
    • ATP1A1ATP2B3CACNA1D
      • These mutations tend to be more common in males

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/Quantitative Enzyme-Linked Immunosorbent Assay

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

Guidelines

Funder JW, Carey RM, Mantero F, Murad H, Reincke M, Shibata H, Stowasser M, Young WF. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016; 101(5): 1889-916. 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, Lenders JW, van Outheusden L, van der Wilt GJ, Kool LJ, Hermus AR, 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: February 2017