Aldosteronism

Key Points

Measuring Aldosterone-to-Renin Ratio (ARR)

Suggested approach from the Endocrine Society (Funder, 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^a

  	Verapamil Slow-Release	Hydralazine	Prazosin Hydrochloride	Doxazosin Mesylate	Terazosin Hydrochloride
  Class	Nondihydropyridine slow-release antagonist calcium channel	Vasodilator	α-adrenergic blocker	α-adrenergic blocker	α-adrenergic blocker
  Usual dose	90-120 mg	10-12.5 mgb	0.5-1 mgb	1-2 mgb	1-2 mgb
  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 effectsc	Monitor for postural hypotension	Monitor for postural hypotension	Monitor for postural hypotension
  aAdapted from Funder, Endocrine Society Guideline, 2016 bIncreasing as required cSide 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
  • If measuring renin activity, collect midmorning after patient has been out of bed ≥2 hours and after patient has been seated 5-15 minutes.
  • If measuring direct renin, collect midmorning (7-10am) after patient has been out of bed ≥30 minutes; if taking an upright sample, patient should be seated for 5-15 minutes; if taking a supine sample, patient should be in the supine position for ≥30 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 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^a

    Factor	Effect on Aldosterone Plasma Levels	Effect on Renin Levels	Effect on ARR
    Medicationsb
    ACE inhibitors	↓	↑ ↑	↓ (false negative)
    Angiotensin II type 1 receptor blockers	↓	↑ ↑	↓ (false negative)
    Potassium-sparing diuretics	↑	↑ ↑	↓ (false negative)
    Ca2+ blockers (dihydropyridine)	→ ↓	↑	↓ (false negative)
    Potassium-wasting diuretics	→ ↑	↑ ↑	↓ (false negative)
    Central alpha-2 agonists (eg, clonidine, α-methyldopa)	↓	↓ ↓	↑ (false positive)
    Nonsteroidal anti-inflammatory drugs	↓	↓ ↓	↑ (false positive)
    β-Adrenergic blockers	↓	↓ ↓	↑ (false positive)
    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 femalesc
    Compared with males	→ ↑	↓	↑ (false positive)
    Other conditions
    Malignant hypertension	↑	↑ ↑	↓ (false negative)
    Pregnancy	↑	↑ ↑	↓ (false negative)
    Renovascular hypertension	↑	↑ ↑	↓ (false negative)
    Pseudohypoaldosteronism type 2	→	↓	↑ (false positive)
    Renal impairment	→	↓	↑ (false positive)
    aAdapted from Funder, Endocrine Society Guideline, 2016 bRenin 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. cIn 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

Subtype Differentiation

Diagnosis

Indications for Testing

Refer to Screening.

Laboratory Testing

Refer to Key Points.

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

Screening

• 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

Background

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)
• 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