Share this article on:

Diagnosis and Management of Primary Aldosteronism

Thanavaro, Joanne L. DNP, ANP-BC, ACNP-BC, DCC

doi: 10.1097/01.NPR.0000394865.72672.2b
Feature: ENDOCRINOLOGY DISORDERS: CE Connection

Primary aldosteronism (PAL) is characterized by excessive production of aldosterone, which leads to hypernatremia, hypertension (HTN), hypokalemia, and alkalosis. Three crucial diagnostic steps include case detection, case confirmation, and subtype classification. Marked improvement or cure of HTN is achieved with appropriate treatment.

Primary aldosteronism is characterized by excessive production of aldosterone, which leads to hypernatremia, hypertension (HTN), hypokalemia, and alkalosis. The three crucial diagnostic steps are case detection, case confirmation, and subtype classification. Marked improvement or cure of HTN is achieved with appropriate treatment.

Joanne L. Thanavaro is a coordinator of the Adult Nurse Practitioner Program at St. Louis University School of Nursing, St. Louis, Missouri, Mo.

The author has disclosed that she has no financial relationship related to this article.

Figure

Figure

Primary aldosteronism (PAL) is a clinical disorder characterized by excessive production and release of aldosterone from the cortical zona glomerulosa of the adrenal gland.1–3 The high level of circulating aldosterone increases sodium reabsorption with potassium loss in the distal tubule, leading to mild hypernatremia, hypertension (HTN), severe hypokalemia, and alkalosis.1–3 Dr. Jerome Conn described the first case of PAL in a 34-year-old woman in 1955, hence, PAL is also known as Conn syndrome.1 Historically, PAL was believed to be a relatively rare cause of HTN, but recent studies demonstrate that PAL is much more prevalent than previously thought.2,4–6 PAL is responsible for 10% of all cases in hypertensive patients, and it is the most common form of secondary HTN.4,5,7 The prevalence of PAL increases with worsening severity of HTN.7–9 PAL is even more common in resistant HTN (BP above goal with three or more antihypertensive medications) with a reported prevalence of 20% to 23% in this group of patients.4,8 PAL is an important clinical disorder to recognize because marked improvement of symptoms and resolution of HTN can be achieved with correct diagnosis and appropriate treatment.4,6,10 Additionally, PAL can lead to significant vascular end-organ damage even with optimal BP control if hyperaldosteronism is not eliminated.11

Back to Top | Article Outline

Etiology

The most common types of PAL are idiopathic hyperaldosteronism (IHA) and aldosterone-producing adenoma (APA).12–14 Ectopic secreting aldosterone tumors and familial hyperaldosteronism (FH) are rare forms of PAL. Three types of FH (I-III) have been described and their diagnoses require evidence of hyperaldosteronism with genetic confirmation.3,15–17

Back to Top | Article Outline

Idiopathic hyperaldosteronism

Most hyperaldosteronism in newly diagnosed HTN is associated with IHA (57%).13,14 IHA is related to bilateral adrenal hyperplasia and enlarged adrenal glands may be smooth, micronodular, or macronodular in appearance.18,19 IHA is more responsive to angiotensin II and it is possible that some cases may be secondary to renin-angiotensin rather than a true PAL.18 Patients with IHA are generally older (over 40 years) and have only moderate HTN, hypokalemia, and serum aldosterone (SA) elevation.6,8,19–21 IHA generally does not respond to surgical correction and requires long-term medical treatment. Patients with IHA frequently respond to monotherapy with a mineralocorticoid receptor antagonist but some may require amiloride or other additional antihypertensive medications for optimal BP control.12 Angiotensin-converting enzyme (ACE) inhibitors may be more effective as added-on agents in these patients.

Back to Top | Article Outline

Aldosterone-producing adenoma

APA accounts for 66% of PAL in severe HTN.13,14 Most APAs are benign adenomas and adrenocortical cancer is rare.3 A large tumor size (over 2.5 cm) has a higher potential risk for malignancy and if not surgically removed, the adenoma should be monitored by radiographic imaging on a yearly basis.3 Patients with APA are usually younger (less than 40 years) and tend to have more severe HTN, lower serum potassium levels, and higher SA levels.6,8,20,21 Effective treatment of APAs is adrenalectomy with the goal of decreasing or eliminating potassium supplementation and antihypertensive medications.8 Some adenomas may be detected during imaging of nonadrenal related causes and they are referred to as incidentalomas.3 Less than 2% of these adenoma are secreting tumors.22

Back to Top | Article Outline

Familial hyperaldosteronism

Familial hyperaldosteronism I. FH I is associated with a hybrid (chimeric) gene as a result of crossover between two different genes: 11b hydroxylase (CYP 11B1) and aldosterone synthase (CYP 11B2) genes.3,16 Most affected individuals present with HTN in early life. Because this chimeric gene is expressed as adrenocortical hormone (ACTH) regulating aldosterone synthase instead of angiotensin II, type I FH is characterized by hyperaldosteronism and high levels of 18-hydroxycortisol and 18-oxocortisol.3,16,23 FH I responds to treatment with glucocorticoid and is, thus, referred to as glucocorticoid-remediable aldosteronism (GRA). A dexamethasone suppression test (DST) will demonstrate a marked and sustained suppression of plasma aldosterone (less than 4 ng/dL) and is the most reliable diagnostic test for FH I with over 90% sensitivity and specificity.3,23 A positive DST and the presence of a chimeric gene differentiate inherited from noninherited PAL.23

Familial hyperaldosteronism II. FH II includes IHA and APA, which is indistinguishable from sporadic forms of PAL except that at least two family members are affected by this autosomal dominant inheritance.16,17 FH II type PAL usually has HTN onset in adulthood: the diagnosis is based on the demonstration of a consistently high aldosterone renin ratio (ARR) and a positive confirmation test in at least two family members. A link between FH II and a locus on chromosome 7p22 has been demonstrated.24

Familial hyperaldosteronism III. A recently described new type of FH III is characterized by severe HTN in early childhood and is associated with marked hyperaldosteronism, hypokalemia, and significant end-organ damage.15 The adrenal glands in FH III are strikingly enlarged (3 to 6 times the normal weight) and demonstrate a diffuse hyperplasia of the zona fasciculata and atrophy of the zona glomerulosa.15,16 The production of several adrenal corticosteroids is also excessive (greater than or equal to 1,000 times of normal), 3 to 4 times more than sporadic PAL or FH II and 10 times more than FH I.16 FH III responds differently to DST with a paradoxical increase in aldosterone and a lack of suppression of cortisol levels, indicating defective regulation and inappropriate production.15 Patients with FH III are resistant to aggressive antihypertensive therapy including spironolactone and amiloride and frequently require bilateral adrenalectomy.16

Back to Top | Article Outline

Presentation

Severe or resistant HTN is often the only clinical presentation of PAL.2,25 Although hypokalemia is considered the hallmark of hyperaldosteronism, the majority of patients with PAL have normal serum potassium levels.2,5,7,26 Hypokalemia is believed to be a late manifestation of PAL and many patients with PAL may present with HTN well before they develop hypokalemia.5,7,25 Most symptoms of PAL are attributed to hypokalemia, which include muscle weakness, cramping, transient paralysis, palpitations, headache, or polyuria.1,27 Excessive aldosterone also deleteriously affects mineralocorticoid receptors that are present in the brain, myocardium, blood vessels, kidney, and colon.6,19 This is why PAL is associated with more vascular end-organ damage beyond the corresponding degree of HTN, including ischemic cardiac disease (16.3%), atrial fibrillation (7.1%), cerebrovascular events, metabolic syndrome, and renal dysfunction.6,28–30 PAL has also been shown to inappropriately increase left ventricular mass (LVM). 31 Although patients with hypokalemic PAL have a higher BP and suffer more from cardiovascular events than their normokalemic counterparts, both groups have a similar overall incidence of cerebrovascular disease.28

Back to Top | Article Outline

Diagnosis

The diagnosis of hyperaldosteronism requires evidence of independent aldosterone hypersecretion and plasma renin suppression.6,32 The Endocrine Society has provided clinical practice guidelines for the diagnosis and treatment of PAL.2 There are three steps in making a complete diagnosis of hyperaldosteronism including case detection, case confirmation, and subtype classification (see Evaluation for PAL and Preparation for diagnostic procedures).2,6 The evaluation for PAL should be performed in patients with increased risk, including those with HTN and hypokalemia, Joint National Committee stage 2 HTN, resistant HTN, HTN at an early age (less than 20 years), HTN associated with stroke at a young age (less than 40 years), HTN with adrenal incidentaloma or HTN with PAL in first-degree relatives.2,5,6 Resistant HTN includes patients requiring three or more antihypertensive medications with poorly controlled BP.8 Genetic confirmation is also essential if the diagnosis of FH is suspected.2,3,5

Table

Table

Figure. Eva

Figure. Eva

Back to Top | Article Outline

Step I: Case detection

Case detection involves initial screening blood tests for SA, plasma renin activity (PRA) and SA/PRA ratio (ARR).2,3 Because SA and PRA may be influenced by an individual's posture and diurnal variation, the ARR should be measured in the midmorning, 2 to 4 hours after the patient has been up and ambulating.3 The presence of a high SA (greater than 16 ng/mL), low PRA (less than 0.5 ng/mL/hour) and very high ARR (greater than 50) is diagnostic for PAL.2,3,5 The diagnosis is probable if the ARR is greater than 25 without any other diagnostic criteria.5 Because ARR is now used as a screening test in hypertensive patients with hypokalemia as well as in those with severe HTN and normokalemia, the diagnosis of PAL has increased 10-fold.3

ARR has relatively poor predictive value with a high percentage of false-positive results because many factors such as medications, dietary sodium, and certain clinical conditions may alter SA and PRA (see Factors affecting ARR).8 These factors may decrease or increase these two biomarkers in the same direction (congruent), predominantly affecting PRA more than SA levels. Medications or conditions that decrease PRA more than SA will lead to false positive ARR; these include beta-blockers, central alpha2 agonists (clonidine or methyldopa), nonsteroidal anti-inflammatory drugs (NSAIDs), sodium loading, and advanced age. Those that increase the levels of PRA more than SA such as diuretics, sodium restriction, malignant HTN, and renovascular HTN will cause false-negative ARR.2,3

Some factors may affect SA and PRA in different directions (incongruent). Potassium loading and renal impairment cause false-positive ARR by relatively increasing SA and decreasing PRA, whereas ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, and hypokalemia lead to false-negative ARR. The influence of medications on the ARR varies with different agents. Significant false-negative results have been reported in patients taking amlodipine (1.8%) and irbesartan (23.5%), and these medications should be discontinued 2 to 4 weeks before screening tests are performed.2,3,33 Doxazosin, an alpha1-adrenergic antagonist, fosinopril, and atenolol do not affect the ratio enough to interfere with the diagnosis, and they may be used as substitution for other antihypertensive medications while patients are being evaluated for PAL.33

Table. Fac

Table. Fac

Back to Top | Article Outline

Step II: Case confirmation

The diagnosis of PAL needs to be confirmed by demonstrating autonomous aldosterone production independent of its normal regulator, angiotensin II.3 Four frequently used confirmation tests include the fludrocortisone suppression test (FST), the saline loading test (SLT), the oral sodium loading test (OSLT), and the captopril challenge test (CCT). Although most experts recommend SLT or OSLT, the FST with a high-salt diet is regarded as a more accurate and reliable test for a definitive diagnosis of PAL.

Back to Top | Article Outline

Fludrocortisone suppression test

Fludrocortisone suppression is the standard test used to confirm the diagnosis of PAL. Fludrocortisone (Florinef) is given 0.1 mg every 6 hours orally together with high oral sodium of 200 mmol (6 g) per day for 4 days. Potassium supplement should be given to maintain a close to normal serum potassium level. Upright SA and PRA are obtained on day 4 of the test. SA greater than 6 ng/dL is indicative of failure to suppress the aldosterone production and is diagnostic of PAL; PRA should be suppressed to less than 1 ng/mL/hour.2,3 FST requires hospital admission because of hypokalemia associated with testing as well as the need for frequent blood samples to monitor serum potassium levels.3,34 This test is contraindicated in patients with severe HTN or heart failure (HF).3,34

Back to Top | Article Outline

Saline loading test

The SLT evaluates the suppression of aldosterone production by I.V. sodium loading and involves infusion of two liters of 0.9% saline I.V. over 4 hours while patients remain recumbent. SA, PRA and serum potassium are measured before and 4 hours after saline infusion. This test is diagnostic of PAL if SA is greater than 10 ng/dL, indicative of failure to suppress the aldosterone production. SLT is an easier test to perform and is a good alternative to the more complex FST and can be done in the outpatient settings.34 SLT is contraindicated in patients with severe HTN, chronic kidney failure, HF, cardiac dysrhythmias, or severe hypokalemia.2,3

Back to Top | Article Outline

Oral sodium loading test

This test is performed to evaluate the suppression of aldosterone by oral sodium loading. Twenty-four hour urinary aldosterone excretion 3 days after high salt intake (greater than 200 mmol/day) is measured. Urinary aldosterone levels greater than 12 mcg/24 hours indicate failure to suppress the aldosterone production by high salt intake and is diagnostic of PAL with over 90% sensitivity and specificity.35 Simultaneous urinary sodium and creatinine excretion should also be obtained to assure adequate high salt intake and urinary collection.

Back to Top | Article Outline

Captopril challenge test

The secretion of aldosterone in PAL is independent of angiotensin II and the CCT is performed with oral captopril administered to the patient in a sitting position. SA and PRA are measured at baseline and 1 hour after Captopril administration. The test is considered positive if SA remains greater than 12 ng/dL or ARR is greater than 26.32 This test has a higher sensitivity (100% versus 95.4%) and specificity (67% to 91% versus 28.3%) over the baseline screening tests, and is easier to perform than the SLT.

Back to Top | Article Outline

Step III: subtype classification

Differentiating IHA from APA is necessary to ensure appropriate patient management.13,14 Because IHA and APA cannot be reliably differentiated by clinical presentation or biochemical evaluation, radiographic imaging and adrenal vein sample (AVS) of aldosterone are used to determine the PAL subtypes as well as the evidence of unilateral or bilateral adrenal hypersecretion.3 These subtype classification procedures are final steps in the diagnosis and determination of treatment strategies for PAL and are especially critical if a surgical approach is contemplated.2,6

Back to Top | Article Outline

Radiographic imaging

Imaging of adrenal glands by computed tomography (CT) and magnetic resonance imaging (MRI) is frequently used to detect an adrenal mass in patients with positive screening and confirmation tests.2,6 The most common pathology of PAL is adrenal cortical hyperplasia; predominantly micro- or macronodular and infrequently diffused variety.3 APA is a solitary nodule of various sizes. Radiographic imaging techniques are increasingly used to diagnose APAs because they are less invasive, convenient, readily available and less expensive. The diagnostic performance of CT (sensitivity of 40% to 100%) and MRI (sensitivity of 70% to 100%) in detecting APA is variable.19,36–39 The yield for detecting APA less than 1 cm in diameter is even lower and has been reported to be around 25% in one study.3 In a recent comparative study, CT and MRI had similar sensitivity and specificities in detecting an APA, and the choice of imaging technique is dictated by the radiologist's experience.40

CT or MRI occasionally uncovers adrenal incidentalomas that are detected by these imaging procedures in about 2%.3,22 Not all adrenal masses discovered with CT or MRI in patients with PAL is a secreting tumor.3 Operative planning based on the radiographic imaging is inadequate because the cause of PAL is misdiagnosed in over one-third of patients, and could lead to inappropriate surgery.41–43 CT or MRI cannot differentiate a secreting from nonsecreting tumor but may be able to help separate a benign from a malignant nodule by demonstrating a low or high fat content in the tumor.19 A nodule with high fat content is more likely to be a benign adrenoma. Additionally, CT and MRI may be used as referent images to assist in locating adrenal veins during the AVS procedure.3

Back to Top | Article Outline

Adrenal vein sample

An adrenal vein sample of aldosterone is considered the gold standard for determining the cause of PAL even though it has a relatively low success rate because of the difficulty in placing catheters in the right locations.3,6,19,37,39 Studies have demonstrated that autonomous aldosterone production may be bilateral or even contralateral to the side of what appears to be a solitary adrenal nodule, or may be unilateral in patients with bilateral hyperplasia.3,44 Although adrenal CT and MRI may identify unilateral APA, patients will still need an AVS to assure that they have a unilateral form of PAL and not bilateral IHA in the presence of a nonsecreting APA.3,19,39 AVS procedure involves placing catheters in both adrenal veins and the distal inferior vena cava (IVC).3 Synthetic ACTH may be given to increase aldosterone secretion and the aldosterone to cortisone ratio (ACR) is used for the diagnosis to minimize the effect of stress-induced fluctuation of aldosterone release and venous dilution on the result of the test.2,3 Blood samples are obtained from both adrenal veins and IVC for the measurement of aldosterone and cortisone. An elevated ACR greater than 4 over the peripheral (IVC) ratio is indicative of increased aldosterone secretion.43

Back to Top | Article Outline

Treatment

The goal of treatment for PAL is focused on the normalization of circulating aldosterone or aldosterone receptor blockade to prevent the morbidity and mortality associated with HTN, hypokalemia and end-organ damage.6 Management strategies should take patient characteristics and desires into consideration. Treatment options and possible outcomes should be explored. Surgical treatment may not be appropriate for all patients with unilateral hypersecreting adrenal mass but may be reasonable for those with bilateral hypersecretion.6

Table

Table

Back to Top | Article Outline

Medical treatment

Medical treatment is recommended for patients with bilateral hypersecreting adrenal lesions or for those with unilateral lesion who are not optimal for or who do not want surgical treatment (see Pharmacotherapy for hyperaldosteronism).3,6 Medications that block aldosterone action are effective for the treatment of hypokalemia and HTN and these include nonselective (spironolactone [Aldactone]) and selective aldosterone receptor antagonists (eplerenone [Inspra]).3,6 Amiloride (Midamor) is not an aldosterone receptor antagonist and is not effective in controlling HTN in PAL but may be used for its potassium sparing property.3,6 Prior studies on the efficacy of spironolactone in treating resistant HTN have used 25 to 50 mg daily dosing, whereas true PAL may require larger daily doses up to 100 to 400 mg. The onset of action on BP may be slow.3,6 Measurements of PRA are not necessary but may be an indication that an optimal dose of the medication has been prescribed when it is no longer suppressed.3 Adverse reactions of Spironolactone include gynecomastia and impotence in men and menstrual dysfunction in women.6 Combined therapy with a small dose of spironolactone and amiloride may alleviate these undesirable consequences.3,6 Eplerenone has a better adverse reaction profile because it has substantially less binding affinity to androgen and progesterone receptors than spironolactone.45

Glucocorticosteroid is effective in the treatment of FH I (GRA). It is not necessary to completely suppress cortisol production in treating these patients.3 The lowest dose of glucocorticosteroid is recommended for patients with FH I (GRA) to control HTN and correct hypokalemia and to avoid adverse reactions.3 Aldosterone antagonists and amiloride may also be used to control HTN in these patients.3

Back to Top | Article Outline

Surgical treatment

Approximately one-third of all PAL patients has clear lateralization of aldosterone production and will benefit from unilateral adrenalectomy.3 Laparoscopic adrenectomy is the most suitable therapy for APA or unilateral adrenal hyperplasia.3,6 Chronic suppression of the renin-angiotensin axis may cause transient postoperative hypoaldosteronism and a liberal sodium diet should be allowed to prevent hyperkalemia after the surgery.6 An I.V. infusion of 0.9% sodium chloride every 8 to 12 hours may be necessary to avoid postoperative intravascular volume depletion.3 All antihypertensive medications, especially spironolactone and amiloride, should be withheld and other BP medications may be cautiously reinstituted as needed within a few days.3,46 The data on follow-up assessment of the remaining adrenal gland after surgery is scanty. Postoperative SA, PRA, and ARR are commonly repeated.3,46 Some authors recommended assessment of the autonomous function of the remaining adrenal gland by FST in 3 months.3 These authors also periodically obtained CT scan in their patients at 1 to 3 yearly intervals because they have observed that the remaining adrenal gland could slowly increase in size, become nodular or develop adenoma after surgery.3

Back to Top | Article Outline

Prognosis

Approximately 30% to 60% of APA patients are improved or have resolution of HTN and hypokalemia with normal SA and PRA after unilateral adrenectomy.3,12,47–49 HTN is normally resolved within 1 to 6 months and patients with persistent HTN are more likely to be older, require more than two antihypertensive drugs preoperatively, or have a longer duration of HTN or underlying renal dysfunction.49–52 The postoperative BP in those with persistent HTN is usually easier to control with fewer medications. The cardiovascular complications of patients who achieve optimal BP control with or without medications eventually decrease to the levels of those with essential HTN.49 Partial reversal of renal dysfunction, regression of LVM and improved diastolic left ventricular function have been demonstrated after successful treatment of PAL.53,54 It has been reported that adrenalectomy for APA is more cost-effective than long-term medical therapy.55

Back to Top | Article Outline

Implications for practice

PAL is more common than previously believed. The availability of screening blood test has increased the diagnosis of PAL in patients with severe or resistant HTN. Appropriate medical and surgical treatment has resulted in a complete cure or dramatic improvement in many patients with this disease. Strict adherence to diagnostic and treatment guidelines will facilitate effective patient management. NPs should familiarize themselves with these guidelines and determine when to refer patients to specialists or surgeons for definitive diagnostic procedures and treatment. Understanding these disease processes will help NPs develop diagnostic and treatment strategies and provide appropriate counseling to patients and their family members.

Back to Top | Article Outline

REFERENCES

1. Conn JW. Presidential address. Part I, Painting background. Part II, Primary aldosteronism, a new clinical syndrome. J Lab Clin Med. 1995;45:3–17.
2. 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.
3. Stowasser M, Gordon RD, Rutherford JC, Nikwan NZ, Daunt N, Slater GJ. Diagnosis and management of primary aldosteronism. J Renin Angiotensin Aldosterone Syst. 2001;2(3):156–169.
4. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the american heart association professional education committee of the Council for High Blood Pressure Research. Circulation. 2008;117(25):e510-e526.
5. Fardella CE, Mosso L, Gómez-Sánchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular Biology. J Clin Endocrinol Metab. 2000;85(5):1863–1867.
6. Young WF Jr. Minireview: Primary Aldosteronism—changing concepts in diagnosis and treatment. Endocrinology. 2003;144(6):2208–2213.
7. Mosso L, Carvajal C, González A, et al. Primary aldosteronism and hypertensive disease. Hypertension. 2003;42(2):161–165.
8. Calhoun DA. Is there an unrecognized epidemic of primary aldosteronism? (Con). Hypertension. 2007;50:454–458.
9. National Heart Lung and Blood Institute. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) .
10. Schirpenbach C, Reincke M. Primary aldosteronism: current knowledge and controversies in Conn's syndrome. Nat Clin Pract Endocrinol Metab. 2007;3(3):220–227.
11. Stowasser M, Sharman J, Leano R, et al. Evidence for abnormal left ventricular structure and function in normotensive individuals with familial hyperaldosteronism type I. J Clin Endocrinol Metab. 2005;90(9):5070–5076.
12. Karagiannis A, Tziomalos K, Kakafika AI, Athyros VG, Harsoulis F, Mikhailidis DP. Medical treatment as an alternative to adrenalectomy in patients with aldosterone-producing adenomas. Endocr Relat Cancer. 2008;15(3):693–700.
13. Gallay BJ, Ahmad S, Xu L, Toivola B, Davidson RC. Screening for primary aldosteronism without discontinuing hypertensive medications: plasma aldosterone-renin ratio. Am J Kidney Dis. 2001;37(4):699–705.
14. Rossi GP, Bernini G, Caliumi C, et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Col Cardiol. 2006;48(11):2293–2300.
15. Geller DS, Zhang JJ, Wisgerhof MV, Shackleton C, Kashgarian M, Lifton RP. A novel form of human Mendelian hypertension featuring non-glucocorticoid remediable aldosteronism. J Clin Endocrinol Metab. 2008;93(8):3117–3123.
16. Mulatero P. A new form of hereditary primary aldosteronism: familial hyperaldosteronism type III. J Clin Endocrinol Metab. 2008;93(8):2972–2974.
17. So A, Duffy DL, Gordon RD, et al. Familial hyperaldosteronism type II is linked to the chromosome 7p22 region but also shows predicted heterogeneity. J Hypertens. 2005;23(8):1477–1484.
18. Padfield PL. Primary aldosteronism, a common entity? The myth persists. J Hum Hypertens. 2002;16(3):159–162.
19. Patel SM, Lingam RK, Beaconsfield TI, Tran TL, Brown B. Role of Radiology in the management of primary aldosteronism. Radiographics. 2007;27(4):1145–1157.
20. Kaplan NM. The current epidemic of primary aldosteronism: Causes and consequences. J Hypertens. 2004;22(5):863- 869.
21. Kaplan NM. Is there an unrecognized epidemic of primary aldosteronism? Pro. Hypertension. 2007;50(3):447–453.
22. Barzon L, Sonino N, Fallo F, Palu G, Boscaro M. Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol. 2003;149(4):273–285.
23. Fardella CE, Pinto M, Mosso L, Gómez-Sánchez C, Jalil J, Montero J. Genetic study of patients with dexamethasone-suppressible aldosteronism without the chimeric CYP11B1/CYP11B2 Gene. J Clin Endocrino Metab. 2001;86(10):4805–4807.
24. Lafferty AR, Torpy DJ, Stowasser M et al. A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22). J Med Genet. 2000;37(11):831–835.
25. Calhoun DA. Aldosteronism and hypertension. Clin J Am Soc Nephrol. 2006;1:1039–1045.
26. Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004;89(3):1045–1050.
27. Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrino (Oxf). 2007;66(5):607–618.
28. Born-Frontsberg E, Reincke M, Rump LC, et al. Cardiovascular and cerebrovascular comorbidities of hypokalemic and normokalemic primary aldosteronism: Results of the German Conn's Registry. J Clin Endocrinol Metab. 2009;94(4):1125–1130.
29. Giacchetti G, Ronconi V, Turchi F, et al. Aldosterone as a key mediator of the cardiometabolic syndrome in primary aldosteronism: An observational study. J Hypertens. 2007;25(1):177–186.
30. Milliez P, Girerd X, Plouin PF, Blacher J, Safar, ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45(8):1243–1248.
31. Muiesan ML, Salvetti M, Paini A, et al. Inappropriate left ventricular mass in patients with primary aldosteronism. Hypertension. 2008;52(3):529–534.
32. Castro OL, Yu X, Kem DC. Diagnostic value of the post-captopril test in primary aldosteronism. Hypertension. 2002;39(4):935–938.
33. Mulatero P, Rabbia F, Milan A, et al. Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism. Hypertension. 2002;40(6):897–902.
34. Mulatero P, Milan A, Fallo F, et al. Comparison of confirmatory tests for the diagnosis of primary aldosteronism. J Clin Endocrinol Metab. 2006;91(7):2618–2623.
35. Young WF Jr. Primary aldosteronism: A common and curable form of hypertension. Cardiol Rev. 1999;7(4):207–214.
36. Espiner EA, Ross DG, Yandle TG, Richards AM, Hunt PJ. Predicting Surgically remedial primary aldosteronism: role of adrenal scanning, posture testing, and adrenal vein sampling. J Clin Endocrinol Metab. 2003;88(8):3637–3644.
37. Glodny B, Kuhle C, Cromme S, Brockmann J, Winde G. An assessment of diagnostic procedures preparatory to retroperitoneoscopic removal of adenoma in cases of primary hyperaldosteronism. Endocr J. 2000;47:657–665.
38. Lumachi F, Marzola MC, Zucchetta P, et al. Non-invasive adrenal imaging in primary aldosteronism: sensitivity and positive predictive value of radiocholesterol scintigraphy, CT scan and MRI. Nucl Med Commun. 2003;24(6):683–688.
39. Magill SB, Raff H, Shaker JL, et al. Comparison of adrenal vein sampling and computed tomography in the differentiation of primary aldosteronism. J Clin Endocrinol Metab. 2001;86(3):1066–1071.
40. Lingam RK, Sohaib SA, Rockall AG, et al. Diagnostic performance of CT versus MR in detecting aldosterone-producing adenoma in primary hyperaldosteronism (Conn's syndrome). Eur Radiol. 2004;14(10):1787–1792.
41. Kempers M J, 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):329–337.
42. Nwariaku FE, Miller BS, Auchus R, et al. Primary hyperaldosteronism: effect of adrenal vein sampling on surgical outcome. Arch Surg. 2006;141(5):497–502.
43. Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR, van Heerden JA. Role for adrenal venous sampling in primary aldosteronism. Surgery. 2004;136(6):1227–35.
44. McAlister FA, Lewanczuk RZ. Primary hyperaldosteronism and adrenal incidentaloma: an argument for physiological testing before adrenalectomy. Can J Surg. 1998;41(4):299–305.
45. de Gasparo M, Joss U, Ramjoué HP, et al. Three new epoxyspironolactone derivatives: characterization in vivo and in vitro. J Pharmacol Exp Ther. 1987;240(2):650–656.
46. Young WF Jr. Primary aldosteronism: management issues. Ann N Y Acad Sci. 2002; 970:61–76.
47. Plouin PF, Amar L, Chatellier G. Trends in the prevalence of primary aldosteronism, aldosterone-producing adenomas, and surgically correctable aldosterone-dependent hypertension. Nephrol Dial Transplant. 2004,19(4):774–777.
48. Sawka AM, Young WF, Thompson GB, et al. Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med. 2001;135(4):258–261.
49. Catena C, Colussi G, Nadalini E, et al.Cardiovascular outcomes in patients with Primary aldosteronism after treatment. Arch Intern Med. 2008;168(1):80–85.
50. Fukudome Y, Fujii K, Arima H, et al. Discriminating factors for recurrent hypertension in patients with primary aldosteronism after adrenalectomy. Hypertens Res. 2002;25(1):11–18.
51. Lumachi F, Ermani M, Basso SM, Armanini D, Iacobone M, Favia, G. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas: multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg. 2005;71(10):864–869.
52. Rossi H, Kim A, Prinz RA. Primary aldosteronism in the era of laparoscopic adrenalectomy. Am Surg. 2002;68(3):253–256.
53. Catena C, Colussi G, Lapenna R, et al. Long-term cardiac effects of adrenalectomy or mineralocorticoid antagonists in patients with primary aldosteronism. Hypertension. 2007;50(5):911–918.
54. Sechi LA, Novello M, Lapenna R, et al. C. Long-term renal outcomes in patients with primary aldosteronism. JAMA. 2006;295(22):2638–2645.
55. Sywak M, Pasieka JL. Long-term follow-up and cost benefit of adrenalectomy in patients with primary hyperaldosteronism. Br J Surg. 2002;89(12):1587–1593.
Keywords:

aldosterone-producing adenoma; hypertension; hypokalemia; idiopathic hyperaldosteronism; primary aldosteronism management

© 2011 Lippincott Williams & Wilkins, Inc.