para>Increases in aldosterone production and plasma renin activity are physiologic during pregnancy, confirmation tests are not recommended, the diagnosis of PA during pregnancy relies on a repeatedly suppressed plasma renin level.
Avoid spironolactone and ACE inhibitors.
DIAGNOSIS
HISTORY
- Usually asymptomatic
- ROS: headaches, muscle weakness, fatigue, cramping, polyuria, polydipsia, paresthesia, or tetany (due to the hypokalemia)
- Family history of HTN, particularly early onset (<40 years old)
PHYSICAL EXAM
- HTN is key finding and is generally >160/100 mm Hg.
- Funduscopy: HTN retinopathy
- Displaced apical pulse due to LVH
DIFFERENTIAL DIAGNOSIS
- Diuretic use
- Essential HTN
- Renovascular HTN
- Pheochromocytoma
- Congenital adrenal hyperplasia
- Corticosteroid excess (exogenous or endogenous)
- Exogenous mineralocorticoid
- Bartter syndrome
- Licorice (glycyrrhizinic acid) ingestion
DIAGNOSTIC TESTS & INTERPRETATION
The Endocrine Society recommends screening in patients groups with high prevalence, including (1)[C]:
- HTN of >160/100 mm Hg
- Drug-resistant HTN (BP >140/90 mm Hg despite triple anti-HTN therapy)
- HTN with hypokalemia (spontaneous or diuretic-induced)
- HTN with adrenal incidentaloma
- HTN with FHx of early-onset (<40 years) HTN or CVA
- All hypertensive first-degree relatives of patients with primary aldosteronism
Initial Tests (lab, imaging)
Screening: Aldosterone-to-renin ratio (ARR) (1)[C]
- Liberalize sodium intake and correct hypokalemia.
- Collect metabolic panel (for sodium, potassium, bicarbonate, and creatinine), plasma renin activity (PRA), plasma aldosterone concentration (PAC).
- Collect sample in the morning, after an initial 2-hour ambulatory period and 5 to 15 minutes in a seated position.
- ARR cut offs 20 to 40, most commonly used >30 (PRA in ng/mL/hr and PAC in ng/dL)
- Analyze PAC, PRA, K+, and ARR together.
Is renin suppressed and aldosterone increased?
- PRA should be suppressed and PAC is increased (at least <1 ng/mL/hr and >10 to 15 ng/dL, respectively).
- Hypokalemia blunts aldosterone production.
- Most HTN meds affect the ARR.
- Withdraw for at least 4 weeks: spironolactone, eplerenone, amiloride, triamterene, potassium-wasting diuretics, and licorice products.
- If ARR is not diagnostic and HTN can be controlled on relatively noninterfering meds: Consider stopping β-blocker, clonidine, NSAIDs, ACE inhibitors, ARB, and dihydropyridine CCB-2 weeks prior to testing.
- Relatively noninterfering HTN meds: verapamil SR, hydralazine, prazosin, doxazosin, terazosin
- Basic metabolic panel to determine serum sodium, potassium, chloride, and bicarbonate levels
- Hypokalemia (may only be present in <37%)
- Hypernatremia and metabolic alkalosis
Follow-Up Tests & Special Considerations
Confirmation: Patients with a positive ARR should have confirmatory testing (1)[C].
- Is increased aldosterone production suppressible?
- Four confirmatory tests are available (1)[C],(3)[B].
- Oral sodium-loading test (OST)
- Increase sodium intake of >200 mmol/day (~6 g/day) 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 to 14 μg/24 hr) makes primary aldosteronism highly likely
- Note: Administer KCl supplementation to maintain normokalemia. High-performance liquid chromatography-tandem mass is spectrometry preferred over radioimmunoassay for urinary aldosterone measurements.
- Saline infusion test (SIT)
- Seated SIT (SSIT) testing may be more sensitive than recumbent SIT (RSIT), especially for posture-responsive forms; may represent a reliable, simpler, cheaper, and quicker alternative to fludrocortisone suppression testing
- Infuse 2 L of NS over 4 hours starting between 0800 and 0930 hours.
- PRA, PAC, cortisol, and potassium are drawn at time zero and after 4 hours.
- PAC <5 makes PA unlikely, 5 to 10 indeterminate, and >10 confirm PA.
- Notes and precautions: OST and SIT should not be performed in patients with severe uncontrolled HTN, renal insufficiency, cardiac insufficiency, cardiac arrhythmia, or severe hypokalemia.
- Fludrocortisone suppression test (FST)
- May be the most reliable, but difficult to perform and expensive
- Fludrocortisone 0.1 mg q6h for 4 days
- KCl to maintain plasma K+ at 4.0 mmol/L (K+ measured QID)
- NaCl 1,800 mg TIDWM with unrestricted salt intake
- On day 4, PAC and PRA are measured at 10 am with patient seated; cortisol is drawn at 7 and 10 am.
- PAC >6 ng/dL confirms PA; however, PRA <1 ng/mL/hr and/or cortisol at 10 am < 7 am may indicate confounding ACTH effect.
- Captopril challenge test
- Patient receives captopril 25 to 50 mg PO after sitting or standing for at least 1 hour.
- Measure PRA, PAC, and cortisol at time zero and 1 to 2 hours after. Patient remains seated during the entire test.
- Aldosterone is normally suppressed by captopril.
- In patients with PA, PAC remains elevated and PRA remains suppressed.
- Note: substantial number of false-negative results
- Confirmed cases should undergo an adrenal CT scan to exclude ACC (1)[B].
- High-resolution CT scan with thin sections (2 to 3 mm) is preferred over MRI (1)[C].
- Overall accuracy of CT and MRI in detecting unilateral APA is poor (4)[B].
Diagnostic Procedures/Other
- Adrenal venous sampling (AVS) is the test of choice to differentiate unilateral (APA) from bilateral disease (BIH) in patients with established PA (1,5)[C],(6)[B].
- AVS should not be performed in patients at unacceptable high-surgical risk, or not desiring surgery, or with suspicion for ACC, or with proven/suspicious for FH syndromes (1,5)[C].
- Requires experienced multidisciplinary team with a standardized protocol (1,5)[C]
- In experienced centers, AVS has a low complication rate (<2.6%) (1,5)[C],(6)[B].
- ACTH stimulation may be the most accurate method for AVS lateralization (6)[B].
TREATMENT
- Treat HTN and electrolyte abnormalities, particularly hypokalemia, if present.
- Surgery is the definitive treatment for unilateral disease (7)[A].
- Medical management with aldosterone antagonists is the treatment of choice for bilateral hyperplasia. May be an alternative for patient not interested in surgery or poor surgical candidates (7)[A]
- For FH type I/GRA: Prefer long-acting glucocorticoids at the lowest effective dose (dexamethasone 0.25 to 0.5 mg/day or prednisone 2 to 3 mg/day) to normalize BP and potassium to aldosterone antagonists.
MEDICATION
First Line
- Aldosterone antagonist: spironolactone, or eplerenone as an alternative (1)[C]. Monitor potassium and creatinine frequently during the first 4 to 6 weeks of treatment.
- Dosage
- Spironolactone: Initial dose of 12.5 to 25 mg/day and titrated up to 50 to 400 mg/day as needed to achieve normokalemia without potassium supplements (1)[C].
- Eplerenone: less effective than spironolactone but less association with gynecomastia (3)[A]
- Initial dose of 25 mg twice daily and titrated to a maximum of 50 mg twice daily as needed for normokalemia and BP control
Second Line
- Other potassium-sparing diuretics: amiloride or triamterene
- Antihypertensive agents: calcium channel blocker, ACE inhibitor, ARB, β-blocker, or low-dose thiazide diuretic
- Contraindications: potassium-sparing agent and ACE inhibitors in renal failure, hyperkalemia, and pregnancy
- Precautions: Monitor serum potassium and creatinine closely after any adjustment in potassium replacement or potassium-sparing agent (monitor closely for 4 to 6 weeks).
- Significant possible interactions: lithium, NSAIDs with diuretics, digoxin, ACE inhibitors, ARB with spironolactone
ISSUES FOR REFERRAL
- Endocrinology for confirmatory testing in patients with a positive screening test
- Experienced interventional radiologist to perform AVS
- Experienced surgeon to perform unilateral laparoscopic or robotic adrenalectomy in patients with confirmed unilateral APA or hyperplasia
SURGERY/OTHER PROCEDURES
Surgical resection (laparoscopic or robotic adrenalectomy) is the treatment of choice for unilateral disease (APA or hyperplasia) (1)[C],(7)[B].
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
- Hypertensive urgency/emergency
- Refractory HTN
- Severe hypokalemia
- Cardiovascular events
- Control of HTN
Nursing
Careful monitoring of BP and telemetry (for arrhythmia with hypokalemia)
Discharge Criteria
When hemodynamically stable and normokalemic
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
- Potassium supplements, anti-HTN therapy, and spironolactone may need to be stopped/decreased after surgery.
- High-sodium diet may be needed to avoid the hyperkalemia that can develop from hypoaldosteronism due to chronic contralateral adrenal gland suppression during the 1st few weeks postop.
- BP usually normalizes in 1 to 6 months after unilateral adrenalectomy for APA.
Patient Monitoring
- Check BP.
- Check serum potassium.
- PAC and PRA should be checked early after surgery (postop day 1) to assess biochemical response.
DIET
Low sodium, high potassium
PATIENT EDUCATION
- HTN management
- Medication management
- Diet
PROGNOSIS
- Chronic therapy with spironolactone can be limited by gynecomastia (dose-related), decreased libido, and impotence in men along with menstrual abnormalities in women, consider eplerenone in these cases.
- HTN is reduced in nearly all patients who undergo treatment (1).
- To better predict resolution of HTN after adrenalectomy, use the Aldosteronoma Resolution Score (ARS).
- BMI <25 kg/m2 (1 point)
- Female sex (1 point)
- Duration of preop HTN <6 years (1 point)
- <2 preop anti HTN meds (2 points)
- 27.6% of ARS of 0 to 1 had cure of HTN, whereas 75% of ARS 4 to 5 had complete resolution of HTN. This scoring system does not account for hypokalemia.
- Earlier intervention is linked with decreased risk of cardiovascular and renal disease, and treatment is associated with halting or reversal of end-organ damage.
COMPLICATIONS
Increased prevalence of cardiovascular events (including ventricular hypertrophy, atrial fibrillation, stroke) in untreated primary aldosteronism compared to patients with essential HTN
REFERENCES
11 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):3266-3281.22 Funder JW. Genetics of primary aldosteronism. Front Horm Res. 2014;43:70-78.33 Stowasser M. Update in primary aldosteronism. J Clin Endocrinol Metab. 2015;100(1):1-10.44 Lim V, Guo Q, Grant CS, et al. Accuracy of adrenal imaging and adrenal venous sampling in predicting surgical cure of primary aldosteronism. J Clin Endocrinol Metab. 2014;99(8):2712-2719.55 Rossi GP, Auchus RJ, Brown M, et al. An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism. Hypertension. 2014;63(1):151-160.66 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):384-390.77 Muth A, Ragnarsson O, Johannsson G, et al. Systematic review of surgery and outcomes in patients with primary aldosteronism. Br J Surg. 2015;102(4):307-317.
ADDITIONAL READING
- Galati SJ. Primary aldosteronism: challenges in diagnosis and management. Endocrinol Metab Clin North Am. 2015;44(2):355-369.
- Pizzolo F, Zorzi F, Chiecchi L, et al. NT-proBNP, a useful tool in hypertensive patients undergoing a diagnostic evaluation for primary aldosteronism. Endocrine. 2014;45(3):479-486.
CODES
ICD10
- E26.09 Other primary hyperaldosteronism
- E26.01 Conn's syndrome
- E26.81 Bartter's syndrome
- E26.02 Glucocorticoid-remediable aldosteronism
ICD9
- 255.10 Hyperaldosteronism, unspecified
- 255.12 Conn's syndrome
- 255.13 Bartter's syndrome
- 255.11 Glucocorticoid-remediable aldosteronism
SNOMED
- Primary hyperaldosteronism (disorder)
- Glucocorticoid-responsive primary aldosteronism (disorder)
- Bartter syndrome (disorder)
CLINICAL PEARLS
- Primary aldosteronism is currently the most common cause of secondary HTN.
- Newer evidence suggests a prevalence of up to 13% of patients with HTN and up to 23% in those with refractory HTN.
- Patients at increased risk for primary aldosteronism include those with HTN plus hypokalemia, HTN plus adrenal incidentaloma, drug-resistant HTN, or HTN >160/100 mm Hg.
- Patients at increased risk should have testing with serum aldosterone and PRA, and the ARR should be calculated.
- Confirmed cases should undergo high-resolution CT scan to exclude ACC.
- If surgery is desired and patient is not a poor surgical candidate, AVS should be performed to exclude BIH.
- Unilateral adrenalectomy is the treatment of choice for unilateral APA or hyperplasia and spironolactone for the treatment of bilateral hyperplasia.