Chemistry, toxicology & urinalysis

Organ specific

Adrenal

Aldosterone



Last author update: 14 September 2023
Last staff update: 14 September 2023

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PubMed Search: Aldosterone

Junyan Shi, Ph.D.
Jieli (Shirley) Li, M.D., Ph.D.
Page views in 2023: 2,364
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Cite this page: Shi J, Li JS. Aldosterone. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/chemistryaldosterone.html. Accessed March 29th, 2024.
Definition / general
  • Aldosterone is a mineralocorticoid hormone derived from cholesterol in the zona glomerulosa (the outer layer) of the adrenal cortex
Essential features
  • Aldosterone helps control water and salt balance; production is controlled by the renin angiotensin aldosterone system (RAAS), adrenocorticotropic hormone (ACTH) and extracellular potassium concentration
  • Most patients with hyperaldosteronism present with normokalemic hypertension; hypoaldosteronism should be considered in any patient with persistent hyperkalemia
  • Adrenal adenoma and bilateral adrenal hyperplasia are the most common causes of hyperaldosteronism; causes of hypoaldosteronism include disorders that reduce aldosterone synthesis and cause aldosterone resistance
  • Screening test is a concurrent measurement of plasma renin, aldosterone and calculation of aldosterone to renin ratio (ARR); confirmatory testing and subtype classification should be followed with positive screening results
  • Many variables in preanalytical, analytical and postanalytical steps can affect plasma aldosterone and renin results; these factors should be considered when interpreting test results
Terminology
  • Steroid hormone
  • Mineralocorticoid hormone
ICD coding
  • ICD-10:
    • E26.01 - Conn syndrome
    • E26.02 - glucocorticoid remediable aldosteronism
    • E26.09 - other primary hyperaldosteronism
    • E26.9 - hyperaldosteronism, unspecified
  • ICD-11:
    • 5A72 - hyperaldosteronism
    • 5A73 - hypoaldosteronism
Diagrams / tables

Images hosted on other servers:
Aldosterone biosynthetic pathways

Aldosterone biosynthetic pathways

Pathophysiology
  • Aldosterone production is controlled by the RAAS in response to decreased renal perfusion and reduced tubular sodium content as well as increased ACTH and extracellular potassium concentration (Heart Fail Rev 2005;10:7)
  • RAAS involves multiple organ systems, including the kidney, liver, lung, vasculature, adrenal cortex and brain
  • Activation of juxtaglomerular (JG) cells causes the intracellular cleavage of prorenin to renin
  • Circulating renin cleaves angiotensin, primarily synthesized and secreted by the liver, to form inactive angiotensin I
    • Inactive angiotensin I is further cleaved to form active angiotensin II mediated by the angiotensin converting enzyme (ACE) expressed on plasma membranes of vascular endothelial cells in the lung (J Clin Pathol 1983;36:938)
  • Binding of angiotensin II to the angiotensin II type I receptor (AT1R) causes the aldosterone mediated effects of vasoconstriction and sodium and water reabsorption (Blood Press 2003;12:70)
  • Primary physiological function of aldosterone is to control the balance of water and salts in the kidney by sodium retention and potassium excretion
    • Second action of aldosterone is to promote the excretion of hydrogen ions while retaining bicarbonate
Clinical features

Causes of hyperaldosteronism (Jameson: Harrison's Endocrinology, 3rd Edition, 2013, Eur J Endocrinol 2019;180:R45)
Primary hyperaldosteronism (isolated excess production of aldosterone)
Bilateral (micronodular) adrenal hyperplasia 60%
Adrenal (Conn) adenoma 40%
Glucocorticoid remediable aldosteronism (ACTH driven) 1%
Secondary hyperaldosteronism (excessive activation of the RAAS)
Renin producing tumor
Renal artery stenosis
Edematous disorders (e.g., heart failure, cirrhosis with ascites, nephrotic syndrome)
Other rare causes (pseudoprimary aldosteronism due to exogenous aldosterone or enhanced mineralocorticoid activity)
Syndrome of apparent mineralocorticoid excess
Cushing syndrome
Glucocorticoid resistance
Adrenocortical carcinoma
Congenital adrenal hyperplasia
Progesterone induced hypertension
Liddle syndrome

  • Clinical manifestations of hyperaldosteronism
    • Primary and secondary hyperaldosteronism present similarly but can be differentiated by laboratory tests and diagnostic studies
    • Most patients present with normokalemic hypertension; hypokalemia can be only seen in the more severe cases (J Clin Endocrinol Metab 2016;101:1889)

Causes of hypoaldosteronism (adapted from UpToDate: Etiology, Diagnosis, and Treatment of Hypoaldosteronism [Accessed 8 August 2023], StatPearls: Hypoaldosteronism [Accessed 8 August 2023])
Reduced aldosterone production
Hyporeninemic hypoaldosteronism Kidney disease, most often diabetic nephropathy Most common acquired causes
Nonsteroidal anti-inflammatory drugs
Calcineurin inhibitors
Angiotensin inhibitors (ACE inhibitors, angiotensin II receptor blockers and direct renin inhibitors)
Chronic heparin therapy
Primary adrenal insufficiency Infrequent causes
Severe illness
Inherited disorders Congenital hypoaldosteronism (21 hydroxylase deficiency and isolated hypoaldosteronism)
Pseudohypoaldosteronism type 2 (Gordon syndrome)
Aldosterone resistance
Inhibition of the epithelial sodium channel Potassium sparing diuretics
Antibiotics (trimethoprim and pentamidine)
Voltage defects Markedly reduced distal sodium delivery
Acquired or congenital defects in sodium reabsorption by the distal tubule principal cells (obstructive uropathy), systemic lupus erythematosus (SLE) and sickle cell disease
Inherited disorders Pseudohypoaldosteronism type 1

  • Clinical manifestations of hypoaldosteronism
    • Persistent hyperkalemia with no obvious cause
    • Mild metabolic acidosis with a normal anion gap
Test indications
  • Hyperaldosteronism (J Clin Endocrinol Metab 2016;101:1889)
    • Resistant hypertension; blood pressure remains above 140/90 mm Hg on concurrent use of 3 antihypertensive agents (1 agent should be a diuretic) of different classes taken at maximally tolerated doses
    • Controlled BP (< 140/90 mm Hg) on 4 or more antihypertensive drugs
    • Hypertension and spontaneous or diuretic induced hypokalemia
    • Hypertension and adrenal incidentaloma
    • Hypertension and sleep apnea
    • Hypertension and a family history of early onset hypertension or cerebrovascular accident at a young age (< 40 years)
    • Hypertensive first degree relatives of patients with primary aldosteronism
  • Hypoaldosteronism (UpToDate: Etiology, Diagnosis, and Treatment of Hypoaldosteronism [Accessed 8 August 2023], StatPearls: Hypoaldosteronism [Accessed 8 August 2023])
    • Patients on medications that can impair aldosterone release (see Clinical features)
    • Critically ill patients, patients with diabetes or nephropathies from various causes, patients with sickle cell disease or HIV infection
  • Patients who undergo adrenalectomy for Conn syndrome (Surgery 2018;163:183)
Laboratory
  • Hyperaldosteronism (J Clin Endocrinol Metab 2016;101:1889)
    • Screening test of hyperaldosteronism is concurrent measurement of plasma renin activity (PRA) or direct renin concentration (DRC) and aldosterone concentration (PAC) and calculation of aldosterone to renin ratio (ARR)
    • Confirmatory testing with a positive ARR screening result includes saline infusion, oral sodium loading, fludrocortisone suppression and captopril challenge
      • For oral sodium loading, aldosterone is measured in the 24 hour urine collection
    • Adrenal CT and adrenal vein sampling (AVS) are used for subtype classification of confirmed hyperaldosteronism
    • AVS should be performed to lateralize adrenal mass when surgical treatment is feasible, with or without cosyntropin stimulation
      • Cortisol corrected aldosterone ratio of high side to low side > 4:1 indicates unilateral aldosterone production
      • Ratio of < 3:1 suggests bilateral aldosterone production (Surgery 2004;136:1227)
  • Hypoaldosteronism
    • PRA or PAC, PAC and serum cortisol can be used to differentiate different causes of hypoaldosteronism

Differential diagnosis of hyper or hypoaldosteronism based on laboratory tests (Endotext: Hyperaldosteronism [Accessed 8 August 2023], UpToDate: Etiology, Diagnosis, and Treatment of Hypoaldosteronism [Accessed 8 August 2023])
Disease Laboratory test
PAC PRA or PRC ARR Serum cortisol
Primary hyperaldosteronism x
Pseudoprimary hyperaldosteronism / x
Secondary hyperaldosteronism x
Hyporeninemic hypoaldosteronism /
Primary adrenal insufficiency /
Congenital adrenal hyperplasia /
* Symbols: ↑ = increase; ↓ = decrease; → = normal; x = not used; / = variable

  • Preanalytical requirements (J Clin Endocrinol Metab 2016;101:1889)
    • Normalize serum potassium
    • Unrestricted dietary salt intake
    • Withdraw interfering medications that markedly or moderately affect the ARR if possible or commence medications that minimally affect the ARR
    • Collect blood samples midmorning after the patient has been up (sitting, standing or walking) for a minimum of 2 hours and then seated for 5 - 15 min prior to collection
    • For either renin mass or activity, it is recommended that samples are collected and processed at room temperature (not chilled), followed by rapid freezing of separated plasma at -20 °C to prevent cryoactivation
      • Cryoactivation may result in a false elevation of renin mass or activity

Medications that markedly affect the ARR (withdraw for at least 4 weeks) Spironolactone, eplerenone, amiloride and triamterene
Potassium wasting diuretics
Products are derived from licorice root
Medications that moderately affect the ARR (withdraw for at least 2 weeks) Beta adrenergic blockers, central alpha 2 agonists (e.g., clonidine, alpha methyldopa) and nonsteroidal anti-inflammatory drugs
Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors and dihydropyridine calcium channel antagonists
Medications that minimally affect ARR Verapamil slow release, hydralazine, prazosin, doxazosin, terazosin

  • Analytical limitations (Clin Biochem 2015;48:377)
    • DRC assay crossreactivity with prorenin is most significant in the low renin state
    • Lack of assay standardization is a common problem with both CLIA and LC MS / MS assay for aldosterone and renin measurement
  • Postanalytical considerations
    • PRA: reporting units of ng/mL/h is most commonly used
    • Plasma aldosterone concentration (PAC): reporting patient posture and providing posture specific (supine and upright) reference intervals
    • ARR cutoff values depend on assay and reporting units; numbers with asterisks indicate the most commonly adopted cutoff values (J Clin Endocrinol Metab 2016;101:1889)

PRA, ng/mL/h PRA, pmol/L/min DRC, mU/L DRC, ng/L
PAC (as ng/dL) 20 1.6 2.4 3.8
30* 2.5 3.7 5.7
403.14.97.7
PAC (as pmol/L) 750* 60 91 144
1000 80 122 192

  • Comparison studies of platforms or methodologies
    • Methodology to measure aldosterone and renin assay
      • Assays have evolved from radioimmunoassay (RIA) and chemiluminescent immunoassay (CLIA) to liquid chromatography tandem mass spectrometry (LC MS / MS) assay
      • CLIA is commonly used on automated instruments; the results from RIA and CLIA are shown to be comparable (J Hypertens 2016;34:920, Prague Med Rep. 2021;122:80)
      • LC MS / MS method is available in large reference laboratories
        • Aldosterone was substantially lower by LC MS / MS than immunoassay, presumably due to antibody crossreactivity with structurally similar metabolites in immunoassay but other contributing factors may also play a role (J Endocr Soc 2022;6:bvac049)
      • Clinicians should be aware of assay characteristics
        • As the current diagnostic cutoffs are from previous studies based on RIA and CLIA, there is a need to update clinical guidelines to reflect the differences between CLIA and modern LC MS / MS assays
  • Different renin assays (PRA versus DRC)
    • PRA assay measures the concentration of angiotensin I produced
    • DRC assay directly measures renin mass (concentration)
    • For most patients, both assays give comparable information; however, renin activity and mass assays may give conflicting results in patients taking direct renin inhibitors and in patients with significantly high renin activity, high estrogen states (e.g., pregnancy) or congestive heart failure (Pract Lab Med 2021;25:e00229)
Board review style question #1
Which of the following is commonly associated with hyperaldosteronism?

  1. Adrenal nodules
  2. Easily managed hypertension
  3. High plasma potassium
  4. Hypertension after 50 years of age
  5. Increased plasma sodium
Board review style answer #1
A. Adrenal nodules. Bilateral (micronodular) adrenal hyperplasia is the most common cause of hyperaldosteronism. Answer B is incorrect because resistant hypertension is presented in hyperaldosteronism. Answer D is incorrect because early onset hypertension before 40 years old is a clinical indication of hyperaldosteronism. Answer C is incorrect because most patients with hyperaldosteronism present with normokalemic hypertension. Answer E is incorrect because plasma sodium tends to be normal due to the concurrent fluid retention.

Comment Here

Reference: Aldosterone
Board review style question #2
Which of the following factors can cause misinterpretation of aldosterone, renin or the aldosterone to renin ratio (ARR)?

  1. Interferences with the testing methods
  2. Patients without restriction on dietary salt intake
  3. Sample collected and processed at room temperature, followed by rapid freezing
  4. Upright position during blood collection
  5. Use of selective serotonin reuptake inhibitors (SSRIs) prior to testing
Board review style answer #2
A. Interferences with the testing methods. Assay specific interferences can cause erroneous results. Answer E is incorrect because SSRIs can affect metanephrines but are not known to affect aldosterone or renin. Answer B is incorrect because the endocrinology practice guideline does not recommend dietary salt restriction. Sodium restriction can significantly raise plasma renin activity (PRA), normalize the ARR and could cause falsely negative screening results (J Clin Endocrinol Metab 2016;101:3989). Answer D is incorrect because samples should be collected after the patient has been up (sitting, standing or walking) for a minimum of 2 hours. Answer C is incorrect because the sample should be collected and processed at room temperature and separated plasma should be rapidly frozen to prevent cryoactivation and false elevation of renin.

Comment Here

Reference: Aldosterone
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