Aldosteronism

Primary Authors: Straseski, Joely A., PhD, MS, MT(ASCP), DABCC. Young, Brittany, MD, PhD.

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)

Preparation

Attempt to correct hypokalemia
- Measure plasma potassium in blood collected slowly with syringe and needle (preferably not Vacutainer to minimize risk of spuriously raising potassium)
  - Avoid fist clenching – wait at least 5 seconds after tourniquet release to insert needle
  - Separate plasma from cells within 30 minutes of collection
- Target plasma potassium of 4 mmol/L
Encourage patient to liberalize (rather than restrict) sodium intake
Withdraw agents that markedly affect ARR for at least 4 weeks prior to testing
- Spironolactone, eplerenone, amiloride, triamterene
- Potassium-wasting diuretics
- Products derived from licorice root (eg, licorice, chewing tobacco)
If ARR testing is not diagnostic after withdrawing above agents and hypertension can be controlled with noninterfering medications, test again in 2 weeks after withdrawing other medications
- Beta blockers, methyldopa, clonidine, calcium channel blockers, ACE inhibitors, angiotensin receptor blockers

If necessary to maintain hypertension control, begin use of other antihypertensive medications that have lesser effects on the ARR

Medications with minimal effects on plasma aldosterone levels that can control hypertension during case finding and confirmatory testing for PA

Medications with Minimal Effects on Plasma Aldosterone Levels that Can Control Hypertension During Case Finding and Confirmatory Testing for PA*
	Verapamil slow-release	Hydralazine	Prazosin hydrochloride	Doxazosin mesylate	Terazosin hydrochloride
Class	Non-dihydropyridine slow-release antagonist calcium channel	Vasodilator	α-adrenergic blocker	α-adrenergic blocker	α-adrenergic blocker
Usual dose	90-120 mg	10-12.5 mg**	0.5-1 mg**	1-2 mg**	1-2 mg**
Frequency	2x daily	2x daily	2-3x daily	1x daily	1x daily
Comments	Use singly or in combination with other agents listed in table	Commence verapamil slow-release first to prevent reflex tachycardia Commencement at low doses reduces risk of side effects***	Monitor for postural hypotension
Adapted from Funder, Endocrine Society Guideline, 2016 Increasing as required **Side effects include headaches, flushing, and palpitations

Oral contraceptives and hormone replacement therapy may lower direct renin concentration (DRC) and cause false-positive ARR (plasma-renin activity [PRA] is unaffected)
- Recommend renin activity or aldosterone/renin activity ratio in these cases
- Do not withdraw oral contraceptives unless confident of alternative effect contraception

Conditions for blood collection
- Collect blood midmorning after patient has been sitting, standing, or walking for at least 2 hours and seated for 5-15 minutes
- Collect carefully and avoid stasis and hemolysis during collection
- Maintain sample at room temperature (not on ice) during transport to laboratory and prior to centrifugation and rapid freezing of plasma component pending assay
Collection and transport requirements
- Aldosterone and renin
  Refer to "Collection and transport requirements" section in Aldosterone-Renin Ratio ATI document
Factors affecting results
- Age
  >65 years of age – renin can be lowered more than aldosterone by age alone, leading to raised ARR
- Gender
  Premenstrual, ovulating females have higher ARR levels than age-matched men, especially during luteal phase of menstrual cycle
  False positive DRC can occur at this time; PRA is unaffected
- Time of day, recent diet, posture, length of time in posture
- Medications
- Method of blood collection
- Level of potassium
- Level of creatinine – renal failure can lead to false positive ARR

Interpreting ARR test results

Positive or equivocal – requires confirmation
Negative – primary aldosteronism unlikely

Factors that may lead to false-positive or false-negative ARR results (Funder, Endocrine Society Guideline, 2016)

Factors That May Lead to False-positive or False-negative ARR Results*
Factor	Effect on aldosterone plasma levels	Effect on renin levels	Effect on ARR
Medications**
ACE inhibitors	↓	↑ ↑	↓ (false negative)
Angiotensin II type 1 receptor blockers	↓	↑ ↑	↓ (false negative)
Potassium-sparing diuretics	↑	↑ ↑	↓ (false negative)
Ca²⁺ blockers (dihydropyridine)	→ ↓	↑
Potassium-wasting diuretics	→ ↑	↑ ↑
Central alpha-2 agonists (eg, clonidine, α-methyldopa)	↓	↓ ↓	↑ (false positive)
Nonsteroidal anti-inflammatory drugs	↓	↓ ↓
β-Adrenergic blockers	↓	↓ ↓
Renin inhibitors	↓	↓ ↑	↑ (false positive); ↓ (false negative)
Potassium status
Hypokalemia	↓	→ ↑	↓ (false negative)
Potassium loading	↑	→ ↓	↑
Dietary sodium
Sodium loaded	↓	↓ ↓	↑ (false positive)
Sodium restricted	↑	↑ ↑	↑ (false negative)
Age
>65	↓	↓ ↓	↑ (false positive)
Premenopausal females***
Compared with males	→ ↑	↓	↑ (false positive)
Other conditions
Malignant hypertension	↑	↑ ↑	↓ (false negative)
Pregnancy
Renovascular hypertension
Pseudohypoaldosteronism type 2	→	↓	↑ (false positive)
Renal impairment	→	↓	↑ (false positive)
Adapted from Funder, Endocrine Society Guideline, 2016 Renin inhibitors lower PRA but raise DRC. This would be expected to result in false-positive ARR levels for renin measured as PRA and false negatives for renin measured at DRC. **In premenopausal, ovulating women, plasma aldosterone levels measured during the menses or the proliferative phase of the menstrual cycle are similar to those of men but rise briskly in the luteal phase. Because renin levels are lower, the ARR is higher than in men for all phases of the cycle, but especially during the luteal phase during which aldosterone rises to a greater extent than renin. False positives can occur during the luteal phase, but only if renin is measured as DRC and not PRA. In preliminary studies, some investigations have found false positives on the current cutoffs for women in the luteal phase. Accordingly, it would seem sensible to screen women at the follicular phase, if practicable.

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 concentration 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

Confirmatory testing, localization studies, and molecular testing (Funder, Endocrine Society Guideline, 2016)
- If confirmatory test for hyperaldosteronism is positive
  All patients with PA should undergo adrenal CT as initial study in subtype testing to exclude large masses that may represent adrenocortical carcinoma
  Lacks sensitivity, specificity
  
  Most useful to rule out adrenocortical cancer
  
  MRI has no advantage over CT in subtype evaluation of PA
  More expensive
  
  Less spatial resolution than CT
- Localization studies
  AVS
  Should be performed in all patients considering surgery
  
  Gold standard to distinguish unilateral (APA or UAH) from bilateral (IHA) disease
- Molecular testing
  Test for familial hyperaldosteronism type 1 (FH-I)
  Patients with onset of confirmed PA earlier than 20 years of age and in those who have a family history of PA or stroke at a young age (<40 years)
  
  Test for germline mutations in KCNJ5 causing familial hyperaldosteronism type 3 (FH-III)

Indications for Testing

Refer to Screening section

Laboratory Testing

Refer to Key Points section

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 (Chao, 2013)
  Normal, micronodularity, or bilateral masses on imaging
  Refer to bilateral adrenal vein sampling (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 distinguish unilateral (APA or UAH) from bilateral (IAH) disease
- 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

Read more about Hyperaldosteronism Testing Algorithm

Endocrine Society Clinical Practice Guidelines (Funder, 2016) recommends case detection of primary aldosteronism (PA) in 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
- ATP1A1, ATP2B3, CACNA1D
  - 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
  - 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
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

Recommended Use

Screen and diagnose hyperaldosteronism

Refer to Key Points section for patient preparation information, a complete list of agents that can affect the ARR, and alternative medications

Follow-up

Positive/equivocal results require confirmation

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

Recommended Use

Screen and diagnose hyperaldosteronism

Refer to Key Points section for patient preparation information, a complete list of agents that can affect the ARR, and alternative medications

Follow-up

Positive/equivocal results require confirmation

Aldosterone, Serum 0070015
Method: Quantitative Chemiluminescent Immunoassay

Recommended Use

The combined aldosterone/renin tests are preferred when screening for hyperaldosteronism; refer to aldosterone/renin activity ratio test or the aldosterone and renin, direct with ratio tests

Refer to Key Points section for patient preparation information, a complete list of agents that can affect the ARR, and alternative medications

Aldosterone, Urine 0070480
Method: Quantitative Chemiluminescent Immunoassay

Recommended Use

Screen and diagnose hyperaldosteronism

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