• Aldosterone secretion independent of the renin-angiotensin system, usually caused by:
  • A unilateral aldosterone-producing adenoma, treated with unilateral adrenalectomy, or
  • Bilateral adrenal hyperplasia, treated with aldosterone antagonists
• Classically manifested by hypertension, hypokalemia, normal or mildly elevated sodium, and metabolic alkalosis
• System(s) affected: Endocrine/Metabolic
• Synonym(s): Conn syndrome; Hyperaldosteronism; Aldosteronoma

ALERT
Pregnancy Considerations

• Rare cause of hypertension (HTN) in pregnancy; can be associated with persistent HTN following delivery
• Increases in aldosterone production and plasma renin activity are physiologic during pregnancy.
• Treat HTN with agents safe during pregnancy; avoid spironolactone and ACE inhibitors.

Prevalence

• Uncommon in the general population
• 11.3% prevalence reported in a study of patients with resistant hypertension (1):
  • Resistant hypertension was defined as BP >140/90 mm Hg despite 3 antihypertensive agents, including a diuretic.
• 14% prevalence reported in a study of patients with both type 2 diabetes and resistant hypertension (2):
  • Resistant hypertension was defined as BP >140/90 mm Hg despite ≥3 antihypertensive agents.

Genetics Familial hyperaldosteronism is categorized as either glucocorticoid-remediable (autosomal dominant) or type II, and is a rare condition.

• Aldosterone secretion independent of renin-angiotensin stimulation
• Negative feedback loop suppresses renin.
• Increased aldosterone results in retention of sodium and excretion of potassium and hydrogen ions in the distal renal tubules.

• Unilateral aldosterone-producing adenomas (APA) are the most common cause of primary aldosteronism (∼85%).
• Idiopathic bilateral adrenal hyperplasia makes up the majority of the remainder of cases (∼10–40%).
• Bilateral aldosterone-producing adenomas are a less common cause (<5%)
• Less common causes include unilateral hyperplasia, aldosterone-producing adrenocortical carcinoma, aldosterone-producing ovarian tumor, or familial hyperaldosteronism, including glucocorticoid-remediable hyperaldosteronism.

Hypertension, especially treatment-resistant or severe

• Usually asymptomatic
• Can be associated with headaches, muscle weakness, fatigue, cramping, polyuria (hypokalemic nephropathy), nocturia, polydipsia, paresthesias, or tetany

• Hypertension
• Funduscopy: Benign or grade 1–2 hypertensive retinopathy
• Forceful and sustained apical impulse consistent with left ventricular hypertrophy or cardiac arrhythmias (complications of primary aldosteronism)
• Edema (uncommon)

Lab

• Patients should be screened for primary aldosteronism with laboratory testing if they are at higher risk (3)[C].
• Higher risk is variably defined as:
  • Hypertension (BP >140/90) resistant to treatment with 3 antihypertensive agents
  • Hypertension with hypokalemia
  • Hypertension in the presence of an adrenal incidentaloma
  • Hypertension that meets Joint National Commission (JNC) criteria as stage 2 (BP >160/100)

Initial Labs

• Serum aldosterone and plasma renin activity to determine the aldosterone-renin ratio (ARR) is recommended (3)[C], but no consensus cutoff value has been established at the time of this writing:
  • ARR values are affected by posture, time of day, and acute salt loading.
  • In one study, morning values obtained after 30 minutes in the seated position, in the absence of salt loading, suggest a cutoff value of ARR of 23.6 (using units of plasma aldosterone in ng/dL and plasma renin activitiy in ng/mL/hr), which conveys a sensitivity of 96.8 [95% CI 83.2–99.5], specificity of 94.1 [95% CI 71.2–99], and positive LR of 16.45) (4)[B].
  • It is suggested that the most sensitive testing is performed in the morning, after 2 hours of upright posture, and being seated for 5–15 minutes, on patients with unrestricted dietary salt intake before testing, and the most commonly used cutoff with this method is 30 (using units of plasma aldosterone in ng/dL and plasma renin activitiy in ng/mL/hr) (3)[C].
• Basic metabolic panel to determine serum sodium, potassium, chloride, and bicarbonate levels:
  • Sodium may be high-normal or elevated.
  • Hypokalemia, although “classic,” is present in a minority of patients:
    • Reported as low as 9–37% (5)
  • Chloride-resistant metabolic alkalosis
• Urine analysis may reveal dilute urine.
• Urine potassium may demonstrate inappropriate kaliuresis, usually >30 mmol/L.

ALERT
Check for increased serum aldosterone level AFTER potassium repletion, since the diagnosis may be missed otherwise. Lab results may be altered by malignant HTN or certain drugs, such as diuretics, ACE inhibitors, and aldosterone antagonists.

Follow-Up and Special Considerations

• Patients with a positive ARR screen should undergo confirmatory testing with one of the following (3)[C]:
  • Oral sodium loading test:
    • Sodium intake of >200 mmol/d (~6 g/d) for 3 days
    • 24-hour urine aldosterone is measured from the morning of day 3 to the morning of day 4
    • Elevated urinary aldosterone (>12 mcg/24 hr) makes primary aldosteronism highly likely
    • Notes and precautions: Patients should receive adequate slow-release KCl supplementation to maintain plasma potassium in the normal range. This test should not be performed in patients with severe uncontrolled HTN, renal insufficiency, cardiac insufficiency, cardiac arrhythmia, or severe hypokalemia. There are currently 2 methods available for measuring the urinary aldosterone, with the high performance liquid chromatography (HPLC)-tandem mass spectrometry preferred over the radioimmunoassay (RIA).
  • Saline infusion test
  • Fludrocortisone suppression test
  • Captopril or losartan challenge test
• Confirmed cases should then undergo CT scan and adrenal vein sampling (AVS) for subtype classification (3)[C].

ImagingInitial Imaging Approach Adrenal CT with fine cuts for subtype testing and to exclude large masses that may represent adrenocortical carcinoma (3)[C]

Diagnostic Procedures/Other Adrenal vein sampling should be performed to lateralize an aldosteronoma (6)[A],(7)[B]:

• Post–adrenocorticotrophic hormone (ACTH) stimulation values are the most accurate measurement for AVS lateralization (7)[B].

Pathological Findings

• Aldosteronoma usually solitary, benign
• Bilateral adrenal (zona glomerulosa) hyperplasia
• Aldosterone-producing adrenocortical carcinoma, rare

• Diuretic use
• Renovascular HTN
• Malignant HTN
• Pheochromocytoma
• Dexamethasone-suppressible hyperaldosteronism
• Congenital adrenal hyperplasia
• High-dose glucocorticoid therapy
• Exogenous mineralocorticoid
• Bartter syndrome
• Licorice (glycyrrhizinic acid) ingestion
• Edema secondary to other conditions (congestive heart failure [CHF], nephrotic syndrome, liver failure)

• Treat hypertension and electrolyte abnormalities, particularly hypokalemia, if present.
• Unilateral laparoscopic adrenalectomy is the definitive treatment for patients with documented unilateral APA or hyperplasia.
• Medical management with aldosterone antagonists is the treatment of choice for bilateral hyperplasia.

First Line Aldosterone antagonist: Spironolactone (Aldactone), or eplerenone (Inspra) as an alternative

Second Line

• Other potassium-sparing diuretics: Amiloride (Midamor) or triamterene (Dyrenium)
• Antihypertensive agents: Calcium channel antagonist, ACE inhibitor, angiotensin-II receptor antagonist, beta-blocker, or low-dose thiazide diuretic
• Contraindications: Potassium-sparing agent and ACE inhibitors in renal failure, hyperkalemia, and pregnancy
• Precautions: Monitor serum potassium closely after any adjustment in potassium replacement or potassium-sparing agent.
• Significant possible interactions: Lithium with diuretics, NSAIDs with diuretics, and ACE inhibitors with diuretics

Issue for Referral

• Endocrinology for confirmatory testing of a higher-risk hypertensive patient with elevated aldosterone, low renin, or an ARR suggestive of primary aldosteronism
• Interventional radiology to perform AVS
• General surgery to perform unilateral laparoscopic adrenalectomy in patients with confirmed unilateral APA or hyperplasia

The treatment of choice for patients with unilateral APA or hyperplasia is laparoscopic adrenalectomy.

Initial Stabilization Control of any HTN

Admission Criteria

• Hypertensive urgency/emergency
• Refractory HTN
• Severe hypokalemia
• Cardiovascular events

IV Fluids As needed

Nursing Careful monitoring of BP

Discharge Criteria When hemodynamically stable

Follow BP and potassium.

Patient Monitoring

• BP checks
• Serum potassium check
• 24-hour urine aldosterone following surgery

Low-sodium, high-potassium

• HTN management
• Medication management

• Hypertension and hypokalemia can usually be controlled by doses of 25–100 mg spironolactone q8h:
  • Chronic therapy in men may be limited by side effects of gynecomastia, decreased libido, and impotence.
• Surgical adrenalectomy resulted in hypertension cure or improvement in 77% of patients with unilateral adenoma (8).
• There is no further increased risk of complications of primary aldosteronism (see below) after treatment with either surgery or medical management (9,10).

• Increased prevalence of cardiovascular events in untreated primary aldosteronism compared with essential hypertension (35% vs. 11%, OR 4.61) (10)[B]
• Increased glomerular filtration rate (GFR) (likely due to hyperfiltration) and albuminuria in untreated primary aldosteronism compared with essential hypertension (9)
• Left ventricular hypertrophy
• Cardiac arrhythmias if hypokalemia is severe

• Willatt JM, Francis IR. Radiologic evaluation of incidentally discovered adrenal masses. Am Fam Physician. 2010;81(11):1361–6.
• Wu VC, Chang HW, Liu KL, et al. Primary aldosteronism: Diagnostic accuracy of the losartan and captopril tests. Am J Hypertens. 2009;22(8):821–7.

Algorithm: Aldosteronism

255.10 Hyperaldosteronism, unspecified

• E26.09 Other primary hyperaldosteronism
• E26.01 Conn's syndrome
• E26.02 Glucocorticoid-remediable aldosteronism

190507007 Primary hyperaldosteronism (disorder)

• Primary aldosteronism is the most common cause of secondary hypertension.
• Patients at increased risk for primary aldosteronism include those with: HTN plus hypokalemia, HTN plus adrenal incidentaloma, drug-resistant HTN, or JNC VII stage 2 HTN.
• Patients at increased risk should have testing with serum aldosterone and plasma renin activity, and the ARR should be calculated.
• Suggestive ARR values (in general, at least 20–30 in conventional units) should be referred for confirmatory testing.
• Confirmed primary aldosteronism warrants an adrenal CT and AVS for lateralization.
• Unilateral adrenalectomy is the treatment of choice for unilateral APA or hyperplasia; spironolactone for the treatment of bilateral hyperplasia.

Amara Lai, MD
Jeffrey D. Wolfrey, MD

1. Douma S, Petidis K, Doumas M, et al. Prevalence of primary hyperaldosteronism in resistant hypertension: A retrospective observational study. Lancet. 2008;371:1921–6.  [PMID:18539224]
2. Umpierrez GE, Cantey P, Smiley D, et al. Primary aldosteronism in diabetic subjects with resistant hypertension. Diabetes Care. 2007;30(7):1699.  [PMID:17429062]
3. Funder JW, Carey RM, Fardella C, et al. 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.  [PMID:18552288]
4. Tiu SC, Choi CH, Shek CC, et al. The use of aldosterone-renin ratio as a diagnostic test for primary hyperaldosteronism and its test characteristics under different conditions of blood sampling. J Clin Endorinol Metab. 2005;90(1):72–8.
5. Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from 5 continents. J Clin Endocrinol Metab. 2004;89:1045–50.  [PMID:15001583]
6. Kempers, Lenders JW, van Outheusden L, et al. Systematic review: Diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism. Ann Intern Med. 2009;151(5):329–37.  [PMID:19721021]
7. Mathur A, Kemp CD, Dutta U, et al. Consequences of adrenal venous sampling in primary hyperaldosteronism and predictors of unilateral adrenal disease. J Am Coll Surg. 2010;211(3):384–90.  [PMID:20800196]
8. Letavernier E, Peyrard S, Amar L, et al. Blood pressure outcome of adrenalectomy in patients with primary hyperaldosteronism with or without unilateral adenoma. J Hypertens. 2008;26(9):1816–23.  [PMID:18698217]
9. Sechi LA, Novello M, Lapenna R, et al. Long-term renal outcomes in patients with primary aldosteronism. JAMA. 2006;295(22):2638–45.  [PMID:16772627]
10. Catena C, Colussi G, Nadalini E, et al. Cardiovascular outcomes in patients with primary aldosteronism after treatment. Arch Intern Med. 2008;168(1):80–5.  [PMID:18195199]

© Wolters Kluwer Health Lippincott Williams & Wilkins