Guideline sources The following summarized guidelines for the evaluation and management of primary aldosteronism (PA) are prepared by our editorial team based on guidelines from the Canadian Urological Association (CUA 2023), the Japan Endocrine Society (JES 2022), the American Association of Endocrine Surgeons (AAES 2022), the Hypertension Canada Guidelines (Hypertension Canada 2020), the Italian Society of Arterial Hypertension (SIIA 2020), the Endocrine Society (ES 2016), and the European Society of Endocrinology (ESE/ENSAT 2016). 1 2 3 4 5 6 7 8 8 8 9 10 11 Definition Primary hyperaldosteronism is an endocrine disorder characterized by excessive secretion of aldosterone from the adrenal glands. 8 Epidemiology Hypersecretion of aldosterone may be due to neoplasia of the adrenal glands (adrenal adenoma or adrenocortical carcinoma), adrenal hyperplasia (typically bilateral), mutations in genes coding for enzymes involved in aldosterone synthesis (familial hyperaldosteronism), or may be https://web.pathway.md/diseases/reclNuP3UX5mGxVRk 1/10 6/29/23, 11:28 PM Primary aldosteronism Pathway idiopathic. Ectopic aldosterone-producing adenoma or carcinoma accounts for < 0.1% of cases. 8 Pathophysiology In patients with secondary hypertension, the prevalence of primary hyperaldosteronism is estimated at 5-20%. 9 Disease course Increased plasma aldosterone leads to the clinical manifestations of resistant hypertension and hypokalemia. Untreated disease may result in early cardiovascular complications and CKD. 8 Prognosis and risk of recurrence Patients with PA have an increased risk of cardiovascular morbidity (including myocardial infarction, stroke, and AF) as compared with patients with matched controls with essential hypertension. The 10-year survival of patients with hyperaldosteronism is similar to that of matched hypertensive controls. 10 11 Pathway Primary aldosteronism Diagnosis and management Guidelines 1. Screening and diagnosis Indications for testing, hypertension: As per Hypertension Canada 2020 guidelines, consider screening for hyperaldosteronism in hypertensive patients with any of the following: unexplained spontaneous hypokalemia (K < 3.5 mmol/L) marked diuretic-induced hypokalemia (K < 3.0 mmol/L) resistance to treatment with 3 drugs an incidental adrenal adenoma. C As per SIIA 2020 guidelines, test for PA in patients with any of the following: severe hypertension (stage 3, systolic BP 180 mmHg and/or diastolic BP 110 mmHg) resistant hypertension (BP values remaining above goal in spite of concurrent use of 3 antihypertensive agents of different classes, one of which is diuretic, if tolerated, and all agents are prescribed at maximum recommended or maximally tolerated antihypertensive doses) hypertension associated with (permanent or intermittent) spontaneous or diuretic-induced hypokalemia (serum potassium < 3.5 mmol/L in absence of other potential causes of hypokalemia (such as gastrointestinal disorders, abuse of licorice) https://web.pathway.md/diseases/reclNuP3UX5mGxVRk 2/10 6/29/23, 11:28 PM Primary aldosteronism Pathway normal potassium levels ( 3.5 to 5.0 mmol/L) associated with another of the above- mentioned indications for PA screening hypertension-mediated organ damage and cardiovascular or renal morbidity are more severe than expected from the level and duration of hypertension (hypertension-mediated organ damage such as microalbuminuria, renal disease, hypertensive retinopathy, LV hypertrophy and diastolic dysfunction) hypertension and sleep apnea hypertension and AF hypertension and a family history of early onset hypertension and/or cerebrovascular accident at a young age (< 40 years) and of first-degree relatives with PA. B As per SIIA 2020 guidelines, do not use potassium measurement as a screening test as hypokalemia is absent in the majority of patients with primary hyperaldosteronism. D As per ES 2016 guidelines, consider screening for primary hyperaldosteronism in patients with any of the following: sustained BP > 150/100 mmHg on 3 measurements obtained on different days hypertension resistant to 3 conventional antihypertensive drugs, including a diuretic hypertension requiring 4 antihypertensive drugs for adequate control 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 hypertension in a first-degree relative of a patient with primary hyperaldosteronism. B Indications for testing, tumor: As per JES 2022 guidelines, obtain dexamethasone (1 mg) suppression test to evaluate the presence of cortisol co-secretion in patients with adrenal tumors detected on CT. B As per SIIA 2020 guidelines, test for PA in patients with hypertension or hypokalemia associated with adrenal incidentaloma. B As per ENSAT/ESE 2016 guidelines, screen for PA with an aldosterone to renin ratio in patients with adrenal incidentaloma with concomitant hypertension or unexplained hypokalemia. A 2. Diagnostic investigations Plasma aldosterone-to-renin ratio: As per CUA 2023 guidelines, obtain aldosterone-to-renin ratio to evaluate for PA in patients with an adrenal incidentaloma and hypertension and/or hypokalemia. B As per CHEP 2020 guidelines: Obtain plasma aldosterone and plasma renin activity or plasma renin for the screening of hyperaldosteronism. Obtain plasma aldosterone and plasma renin activity or renin mass/concentration as follows: https://web.pathway.md/diseases/reclNuP3UX5mGxVRk 3/10 6/29/23, 11:28 PM Primary aldosteronism Pathway in the morning after the patient has been ambulatory (sitting, standing, or walking) for at least 2 hours patients seated for 5-15 minutes before the blood draw with corrected hypokalemia and liberalized sodium intake withdraw agents markedly affecting the results (aldosterone antagonists, potassium- sparing and -wasting diuretics) at least 4-6 weeks before testing repeat testing 2 weeks after withdrawing medications likely to interfere with test accuracy ( -blockers, centrally acting alpha-2 agonists, ARBs, ACEIs, directly acting renin inhibitors, and dihydropyridine CCBs), if the results are not diagnostic, and if hypertension can be controlled with medications less likely to affect testing (slow-release verapamil, diltiazem, hydralazine, prazosin, doxazosin, and terazosin) recognize that false positive results might occur with direct renin mass/concentration if the patient is a female using an oral contraceptives; discontinue oral contraceptives for 1 month before testing if possible, or alternately, measure plasma renin activity instead. As per ES 2016 guidelines, obtain plasma aldosterone-to-renin ratio to identify primary hyperaldosteronism in suspected patients. B Confirmatory testing: As per JES 2022 guidelines, obtain confirmatory tests to prove autonomous aldosterone hypersecretion and to exclude false-positive screening results. B Show 3 more As per CHEP 2020 guidelines, establish a diagnosis of autonomous hypersecretion of aldosterone if any of the following criteria is met (hold interfering drugs as outlined above): Situation Guidance Administer 2 L of normal saline IV over 4 hours with the patient in a recumbent position (contraindicated in the presence of severe, uncontrolled hypertension or congestive HF). Define PA as a postinfusion plasma aldosterone > 280 pmol/L. Recognize that PA is unlikely if < 140 pmol/L, and values in between are considered indeterminate. Saline loading tests Administer > 200 mmol/day of oral sodium (equivalent to > 5 g/day of sodium, > 12 g/day of sodium chloride, or > 2 teaspoon/day of salt) for 3 days. Define PA as a 24-hour urinary aldosterone > 33 nmol/day (measured from the morning of day 3 to the morning of day 4). Recognize that PA is unlikely if < 28 nmol/day > 1400 pmol/L/ng/mL/hour (or > 270 pmol/L/ng/L), with a plasma aldosterone > 440 pmol/L Plasma aldosterone to plasma renin ratio https://web.pathway.md/diseases/reclNuP3UX5mGxVRk 4/10 6/29/23, 11:28 PM Primary aldosteronism Pathway Administer 25-50 mg captopril PO after the patient has been sitting or standing for 1 hour. Measure renin and plasma aldosterone levels while seated at time 0 and 1-2 hours after ingestion. Recognize that PA is unlikely if plasma aldosterone is suppressed by > 30% after captopril ingestion. Recognize that plasma aldosterone level remains elevated in PA, while renin level remains suppressed. Captopril suppression test As per ES 2016 guidelines: Perform one or more confirmatory tests to definitively confirm or exclude the diagnosis in patients with a positive aldosterone-to-renin ratio, instead of proceeding directly to subtype classification. B Consider avoiding further confirmatory testing in patients with spontaneous hypokalemia, plasma renin below detection levels, plus plasma aldosterone > 20 ng/dL (550 pmol/L). D Adrenal imaging: As per JES 2022 guidelines, consider obtaining CT or MRI as initial imaging for detecting adrenal adenomas in patients with hyperaldosteronism. B Show 3 more As per CHEP 2020 guidelines, consider obtaining CT or MRI to help localize the presence of adrenal lesions. Recognize that adrenal lesions/adenomas elicited by imaging may be nonfunctional. As per ES 2016 guidelines, obtain a CT of the adrenal glands as first-line diagnostic imaging in all patients with primary hyperaldosteronism, in order to exclude large masses that may represent adrenocortical carcinoma, and to assist the interventional radiologist and surgeon where anatomically appropriate. B Genetic testing: As per CHEP 2020 guidelines, consider obtaining selective genetic testing for corticosteroid- remediable aldosteronism in patients with confirmed primary hyperaldosteronism and either: a family history of primary hyperaldosteronism or stroke at 40 years of age onset of hypertension at 20 years of age and negative imaging. As per SIIA 2020 guidelines, consider obtaining genetic testing in patients diagnosed with primary hyperaldosteronism at a young age, with a family history of primary hyperaldosteronism and/or early cerebrovascular and cardiovascular events. B As per ES 2016 guidelines, consider genetic testing for familial hyperaldosteronism type 1 in patients with confirmed primary hyperaldosteronism and onset of disease at < 20 years of age, and in patients who have a family history of either primary hyperaldosteronism or stroke at a young age. C 3. Diagnostic procedures https://web.pathway.md/diseases/reclNuP3UX5mGxVRk 5/10 6/29/23, 11:28 PM Primary aldosteronism Pathway Adrenal venous sampling: As per CUA 2023 guidelines, perform adrenal vein sampling before offering adrenalectomy in patients with PA. B As per AAES 2022 guidelines: Consider deferring adrenal venous sampling in 35 years old patients with cross-sectional imaging demonstrating a unilateral adenoma and a normal contralateral gland because adrenalectomy directed by CT alone has a cure rate similar to adrenalectomy guided by adrenal venous sampling. C Consider performing adrenal venous sampling in all > 35 years old patients. C As per JES 2022 guidelines, obtain subtype testing to diagnose the unilateral subtype of PA. A Show 9 more As per CHEP 2020 guidelines, perform adrenal venous sampling (exclusively by experienced teams working in specialized centers) to assess for lateralization of aldosterone hypersecretion in patients with PA and a definite adrenal mass eligible for surgery. B Show 2 more As per ES 2016 guidelines, perform adrenal vein sampling to distinguish between unilateral and bilateral adrenal disease in patients in patients with primary hyperaldosteronism in whom surgery is feasible and desired. B 4. Medical management Mineralocorticoid receptor antagonists: As per JES 2022 guidelines, consider initiating pharmacotherapy taking into consideration other clinical features (gender, age, BMI, plasma aldosterone concentrations, aldosterone to renin ratio and results of confirmatory test) and bypassing adrenal venous sampling (after obtaining informed consent) in patients with normokalemia and no adrenal tumors on CT, as these patients are more likely to have bilateral disease. C Show 5 more As per CHEP 2020 guidelines: Initiate mineralocorticoid receptor antagonists (particularly spironolactone in low to moderate doses) in patients with bilateral disease (such as idiopathic/bilateral adrenal hyperplasia). Monitor potassium and creatinine, especially if combined with ARBs or ACEIs. Consider initiating mineralocorticoid receptor antagonists in patients ineligible for or refusing surgery (even with confirmed unilateral hypersecretion). Recognize that BP- lowering responses to other antihypertensive medications (such as ARBs, ACEIs, and CCBs) are often only modest to moderate. As per ES 2016 guidelines: Initiate a mineralocorticoid receptor antagonist in patients with primary hyperaldosteronism due to bilateral adrenal disease. B Consider using spironolactone as the primary agent, with eplerenone as an alternative. C https://web.pathway.md/diseases/reclNuP3UX5mGxVRk 6/10 6/29/23, 11:28 PM Primary aldosteronism Pathway Conventional antihypertensives: as per JES 2022 guidelines, consider initiating antihypertensive agents, including mineralocorticoid receptor antagonists, in patients with a positive PA screening test rejecting confirmatory tests. C Show 2 more Corticosteroids: administer the lowest effective dose of corticosteroids required to lower ACTH and thus normalize BP and potassium levels as first-line treatment in patients with corticosteroid-remediable aldosteronism. B 5. Perioperative care Preoperative medical therapy: As per JES 2022 guidelines: Initiate appropriate treatment for the complications before unilateral adrenalectomy to reduce the risks during general anesthesia and adrenalectomy, as the prevalence of resistant hypertension, hypokalemia and cardiovascular complications is higher in patients with unilateral PA than in patients with bilateral PA and essential hypertension. B Initiate mineralocorticoid receptor antagonists as first-line therapy to control hypertension and hypokalemia before adrenalectomy. B As per SIIA 2020 guidelines, correct obesity and hypokalemia in preparation for elective surgery. B Postoperative monitoring: As per JES 2022 guidelines, obtain careful monitoring and manage serum potassium concentrations and renal function since hyperkalemia and decreased eGFR are frequently observed early after adrenalectomy. B As per SIIA 2020 guidelines, measure potassium shortly after surgery as transient postoperative hyperkalemia and increased serum creatinine may follow adrenalectomy in some patients. B Postoperative corticosteroid replacement therapy: initiate corticosteroid replacement therapy after adrenalectomy in patients with unilateral PA co-secreting cortisol. B 6. Surgical interventions Indications for adrenalectomy: As per CUA 2023 guidelines, perform adrenalectomy, with a minimally invasive technique when feasible, in patients with a unilateral aldosterone-secreting adrenal mass. E As per AAES 2022 guidelines: Perform laparoscopic adrenalectomy in patients with unilateral primary hyperaldosteronism because they are more likely to use fewer medications with lower defined daily doses to achieve normalization of BP and potassium levels and have lower risks of new-onset AF, CKD, stroke, and all-cause mortality. Perform laparoscopic adrenalectomy for primary hyperaldosteronism due to unilateral disease to improve the quality of life and reduce healthcare-related costs. B https://web.pathway.md/diseases/reclNuP3UX5mGxVRk 7/10 6/29/23, 11:28 PM Primary aldosteronism Pathway Perform adrenalectomy preferentially by a high-volume adrenal surgeon to optimize outcomes, including lower rates of morbidity and mortality. B As per JES 2022 guidelines, recognize that adrenalectomy of the affected side in PA is highly effective for normalizing the plasma aldosterone concentrations, cure/improvement of hypertension and improvement/prevention of target organ damage. A Show 3 more As per CHEP 2020 guidelines, consider performing ipsilateral adrenalectomy in patients with unilateral aldosterone-secreting diseases, such as aldosterone-producing adenoma. Follow patients closely after surgery, as a significant proportion may remain hypertensive despite resection of the causative lesion. As per ES 2016 guidelines: Perform ipsilateral laparoscopic adrenalectomy for patients with documented unilateral primary hyperaldosteronism, such as aldosterone-producing adenoma or unilateral adrenal hyperplasia. B Administer medical therapy, including a mineralocorticoid antagonist, in patients who are unable or unwilling to undergo surgery. B 7. Specific circumstances Pregnant patients: as per JES 2022 guidelines, initiate antihypertensives approved for pregnancy (alpha-methyldopa, hydralazine, labetalol, and nifedipine only after 20 weeks of pregnancy) for the treatment of hypertension in pregnant patients. B Show 2 more 8. Follow-up and surveillance Follow-up: As per JES 2022 guidelines, recognize that the cure rate of hypertension by adrenalectomy in patients with unilateral PA is affected by the following factors: number of antihypertensive medications before surgery duration of hypertension gender BMI age renal function. B Show 3 more As per CHEP 2020 guidelines, recognize that PA is associated with a relative hyperfiltration injury to the kidney in excess of that seen in essential hypertension, and treatment of PA (with either surgery or medical therapy) may unmask significant underlying renal disease with an increase in creatinine and decrease in eGFR. Obtain close monitoring of renal function after treatment. https://web.pathway.md/diseases/reclNuP3UX5mGxVRk 8/10 6/29/23, 11:28 PM Primary aldosteronism Pathway Clinical findings Symptoms Past medical history Dysuria Adrenal adenoma Fatigue Obstructive sleep apnea Headache Resistant hypertension Muscle cramps Lab findings Thirst Urinary frequency Metabolic alkalosis aldosterone to renin ratio ratio Vital signs serum aldosterone Hypertension serum plasma renin activity serum potassium ECG findings Imaging findings AF Adrenal cortex hyperplasia Diagnostic procedures Adrenal mass captopril challenge test fludrocortisone suppression test oral salt loading test overnight dexamethasone- captopril-valsartan test saline infusion test Likelihood Ratios Pertinent positives The following findings increase the probability of primary aldosteronism in adults. 11 Finding LR+ Value Increased aldosterone to renin ratio ratio (> 13.1 ng/mL/h) 8.68 Decreased serum plasma renin activity* 8.2 Increased serum aldosterone* 4.2 obtained in the early morning, in recumbent position obtained in early afternoon, after 4 hours of ambulation Pertinent negatives The following findings decrease the probability of primary aldosteronism in adults. 11 Finding LR- Value serum plasma renin activity not decreased* 0.1 aldosterone to renin ratio ratio not increased ( 13.1 ng/mL/h) 0.32 https://web.pathway.md/diseases/reclNuP3UX5mGxVRk 9/10 6/29/23, 11:28 PM Primary aldosteronism Pathway serum aldosterone not increased* 0.32 obtained in the early morning, in recumbent position obtained in early afternoon, after 4 hours of ambulation References 1. Funder JW, Carey RM, Mantero F et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016 May;101 5 1889 916. Open 2. Doreen M Rabi, Kerry A McBrien, Ruth Sapir-Pichhadze et al. Hypertension Canada's 2020 Comprehensive Guidelines for the Prevention, Diagnosis, Risk Assessment, and Treatment of Hypertension in Adults and Children. Can J Cardiol. 2020 May;36 5 596 624. Open 3. Mitsuhide Naruse, Takuyuki Katabami, Hirotaka Shibata et al. Japan Endocrine Society clinical practice guideline for the diagnosis and management of primary aldosteronism 2021. Endocr J. 2022 Apr 12. Open 4. Gian Paolo Rossi, Valeria Bisogni, Alessandra Violet Bacca et al. The 2020 Italian Society of Arterial Hypertension SIIA practical guidelines for the management of primary aldosteronism. Int J Cardiol Hypertens. 2020 Apr 15;5 100029. Open 5. Neal E Rowe, Ravi M Kumar, Nicola Schieda et al. Canadian Urological Association guideline: Diagnosis, management, and followup of the incidentally discovered adrenal mass. Can Urol Assoc J. 2023 Feb;17 2 12 24. Open 6. Linwah Yip, Quan-Yang Duh, Heather Wachtel et al. American Association of Endocrine Surgeons Guidelines for Adrenalectomy: Executive Summary. JAMA Surg. 2022 Aug 17. Open 7. Fassnacht M, Arlt W, Bancos I et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016 Aug;175 2 G1 G34. Open 8. Kline GA, Prebtani APH, Leung AA et al. Primary aldosteronism: a common cause of resistant hypertension. CMAJ. 2017 Jun 5;189 22 E773 E778. Open 9. Fagugli RM, Taglioni C. Changes in the perceived epidemiology of primary hyperaldosteronism. Int J Hypertens. 2011;2011 162804. Open 10. Milliez P, Girerd X, Plouin PF et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005 Apr 19;45 8 1243 8. Open 11. Reincke M, Fischer E, Gerum S et al. Observational study mortality in treated primary aldosteronism: the German Conn's registry. Hypertension. 2012 Sep;60 3 618 24. Open 12. 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 Endocrinol Metab. 2005 Jan;90 1 72 8. Open https://web.pathway.md/diseases/reclNuP3UX5mGxVRk 10/10