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The principal mineralocorticoid in man is aldosterone which is produced in the zona glomerulosa (outer zone) of the adrenal cortex and acts primarily at the renal distal convoluted tubule. However, extrarenal actions of aldosterone on cardiovascular tissues, the colon and salivary glands are also well established. Abnormal overproduction of aldosterone, due to either primary or secondary disorders, is prevalent in the general population, and is an important cause of morbidity and mortality. This chapter reviews the physiology of aldosterone action, as well as the clinical features, biochemical diagnosis, and treatment of hyperaldosteronism.

Aldosterone Secretogogues

Aldosterone synthesis is primarily regulated by the renin-angiotensin system. This system forms a volume-feedback loop whose level of activity can be suppressed or enhanced by sodium balance and/or circulating intravascular volume (Figure 1). Renin, an enzyme produced in the juxtaglomerular apparatus of the kidney, catalyzes the conversion of angiotensinogen (an inactive precursor peptide) to angiotensin I. Angiotensin I undergoes further enzymatic conversion by angiotensin- converting enzyme (ACE) to produce angiotensin II which acts via the angiotension (AT) AT2 receptor to stimulate the release of aldosterone from the zona glomerulosa of the adrenal gland. The renin-angiotensin II system is also locally expressed in the zona glomerulosa of the adrenal cortex and regulates aldosterone production in a paracrine fashion. Aldosterone production is positively and directly stimulated by potassium balance (Figure 1). Adrenocorticotropic hormone (ACTH) will also transiently stimulate aldosterone production but prolonged ACTH infusion over 24 hours leads to a return of aldosterone levels to baseline. Aldosterone production can also be modulated by additional factors including dopamine and atrial natriuretic peptide (ANP).

Figure 1. Renin-angiotensin-aldosterone and potassium-aldosterone negative-feedback loops. Aldosterone production is determined by input from each loop. (Redrawn from Williams GH, Dluhy RG. Disease of the adrenal cortex. In: Fauci AD, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998, with permission)

Volume-Feedback Loop

The action of angiotensin II on aldosterone secretion results in a negative-feedback relationship. For example, high sodium intake results in extracellular volume expansion and a decrease in aldosterone production by suppression of the renin-angiotensin system. This feedback loop functions to control two critical systems in the human body: 1) sodium homeostasis, and 2) regulation of arterial pressure (1, 2). The regulation of arterial pressure by the renin-angiotensin-aldosterone system (RAAS) is complex, resulting from direct and indirect actions of angiotensin II and aldosterone on 1) constriction of vascular smooth muscle; 2) release of norepinephrine from the peripheral sympathetic nerve endings and epinephrine from the adrenal medulla; 3) release of vasopressin; and 4) volume expansion. (3).

Aldosterone binds to the type I mineralocorticoid receptor located in the distal cortical collecting principal cells to increase the number of ‘open’ sodium channels, resulting in increased reabsorption of sodium. The resultant reabsorption of sodium produces a negative electrical gradient in the tubular lumen, resulting in potassium and hydrogen ion secretion to maintain electrical neutrality.

Angiotensin II and aldosterone may also exhibit direct toxic effects on the cardiovascular system (4), contributing to increased morbidity and mortality. These adverse effects, importantly, are direct actions of aldosterone and are additive to the elevation in arterial blood pressure (5-7). Cardiac left ventricular hypertrophy, and vascular remodeling of small resistance arteries disproportionate to the elevation of blood pressure have both been observed in patients and animal models treated with excessive doses of aldosterone. On histologic analysis, inflammation is often evident in the acute phases of excess aldosterone exposure. With more chronic exposure, however, evidence of fibrosis and more permanent damage is often confirmed. In support of this, recent randomized, controlled trials have demonstrated the benefit of mineralocorticoid blockade – first with spironolactone in patients with advanced heart failure, and second with eplerenone in patients with left ventricular dysfunction following myocardial infarction (8, 9)

EPIDEMIOLOGY OF ALDOSTERONE EXCESS

In 1954, Conn first reported the clinical syndrome of hypertension, hypokalemia, and metabolic alkalosis resulting from autonomous production of aldosterone due to an adrenal adenoma – a syndrome that continues to bear his name. Since that time, numerous studies have investigated the prevalence of primary aldosteronism and reported rates of between 0.05% - 14.4% among hypertensive individuals. Disparity in these percentages is probably due to the use of different hormone screening techniques, study design, and varying cohort populations (10-14). Initial studies diagnosed primarily patients with both hypertension and ‘spontaneous’ (not diuretic-induced) hypokalemia. Recently, however, milder, normokalemic forms of hyperaldosteronism are being diagnosed with increased frequency (15).

Secondary hyperaldosteronism is increasingly diagnosed with the assistance of improved radiological and hormonal testing. For example, it has been estimated that unilateral renal vascular disease is likely the underlying cause for approximately 1% of hypertensives, while bilateral renal parenchymal disease is the cause for 2-4% (16). As the elderly population is expected to increase over the upcoming decades, these percentages are likely to rise.

50 million people in the United States are currently estimated to be hypertensive. With conservative estimates, roughly 10% of individuals will have hypertension due to or associated with hyperaldosteronism. Awareness of this fact is crucial, as the large number of patients with these disorders is likely to effect the decision making of clinicians.

CLINICAL FEATURES OF HYPERALDOSTERONISM

The clinical features of hyperaldosteronism are non-specific and variable, often resulting in or associated with hypertension (Table 1). However, the most common finding remains renal potassium wasting, usually resulting in hypokalemia. The phenotype depends largely on the underlying cause and the degree of the aldosterone excess, as well as the presence of other comorbid illnesses. The classic features of moderate-to-severe hypertension, hypokalemia, and metabolic alkalosis are highly suggestive of a mineralocorticoid excess state (usually primary aldosteronism) and represent the consequences of excess aldosterone on the kidney and to a lesser extent, the cardiovascular system. In the majority of cases, however, only subtle clues of hyperaldosteronism exist such as the recent onset of refractory hypertension.

Primary Aldosteronism

Hypertension is common among patients with primary hyperaldosteronism, and may be severe or refractory to therapy. However, some patients have minimal blood pressure elevations and, as a result, hypertension is not a sine qua non for this disorder, and thus not required for the diagnosis (17). On the other hand, some subgroups of patients with secondary hyperaldosteronism are usually normotensive or have low blood pressure due to renal sodium wasting (see below).

Spontaneous hypokalemia in any patient (with or without concurrent hypertension) should warrant consideration of hyperaldosteronism as the etiology. Additionally, patients that develop severe hypokalemia after institution of a potassium-wasting diuretic (such as hydrochlorothiazide, furosemide) should be investigated. However, up to 20% of patients with confirmed primary hyperaldosteronism have normal serum potassium levels, probably reflecting a milder form of the hyperaldosteronism, and/or dietary sodium restriction resulting in decreased sodium delivery to the distant collecting system of the kidneys to allow for potassium ‘exchange.’

Primary hyperaldosteronism results in extracellular fluid volume expansion secondary to the effects of excess sodium reabsorption. However, after the retention of several liters of isotonic saline, an ‘escape’ from the renal sodium-retaining actions of aldosterone occurs. This is in part due to the release of atrial natriuretic peptide. Therefore, peripheral edema is rarely a feature of primary hyperaldosteronism if cardiac and renal functions are normal.

Metabolic alkalosis occurs secondary to renal tubule urinary hydrogen ion secretion. It is usually mild, causing no significant sequale and may go unnoticed. Hypomagnesemia and mild hypernatremia (likely secondary to resetting of the osmostat) can also be observed.

Rarely, patients experience neuromuscular symptoms, including paresthesias, or weakness, due to the electrolyte disturbances caused by the hyperaldosteronism. Nephrogenic diabetes insipidus, caused by renal tubule antidiuretic hormone resistance due to the hypokalemia, can cause nocturia and mild polyuria and polydipsia. In severe cases of hypokalemia, cardiac arrhythmias occur and can be life threatening.

Secondary Hyperaldosteronism

Secondary causes of hyperaldosteronism have broader phenotypic variation. Renovascular etiologies, as well as coarctation of the aorta, almost always result in hypertension. In contrast, diuretic use (whether surreptitious or prescribed) can cause secondary hyperaldosteronism due to sodium and volume depletion. Rarely, renal “salt-wasting” syndromes such as Gitelman’s and Barrter’s syndromes, and pseudohypoaldosteronism Type I (due to resistance to the actions of aldosterone on the kidney) can result in mild hypotension due to renal sodium wasting. Similarly, illnesses such as congestive heart failure, nephrotic syndrome, and hepatic cirrhosis exhibit a reduction in the ‘effective’ circulating blood volume and are associated with hypotension, despite avid salt retention and total body sodium overload.

ETIOLOGIES OF HYPERMINERALOCORTICOIDISM

Mineralocorticoid-excess states (Table 2) comprise a group of disorders, logically separated into those mediated by the principle mineralocorticoid, aldosterone, and those caused by non-aldosterone etiologies. This chapter focuses on the former. Non-aldosterone mediated mineralocorticoid-excess states, including the syndrome of Apparent Mineralocorticoid Excess (AME) and Liddle’s Syndrome are discussed further in Chapter 26 (“Overview of Endocrine Hypertension”).

Primary Aldosteronism

Secondary Aldosteronism

Hyperaldosteronism can result from autonomous secretion of aldosterone from one or both adrenal glands (so-called primary aldosteronism). In this circumstance, plama renin activity (PRA) will be suppressed and the plasma aldosterone (PA/PRA) ratio will be elevated. In secondary hyperaldosteronism, excessive activation the renin-angiotensin is the initiating event. This initial distinction is of significant importance as the underlying causes and manifestations of excessive aldosterone production differ, thereby affecting subsequent testing and treatment. The diagnosis of primary aldosteronism is suspected when inappropriate hyperaldosteronism is noted in the setting of suppressed plasma renin activity; confirmation is by demonstration of autonomy of aldosteronism production in response to volume-expanding maneuvers (see Section VI below). Secondary aldosteronism is confirmed when plasma renin levels are normal or elevated in the setting of increased aldosterone secretion (Table 2)

A. PRIMARY ALDOSTERONISM

The five subtypes of primary hyperaldosteronism include: aldosterone-producing adenoma (APA), bilateral adrenal hyperplasia (BAH), glucocorticoid-remediable aldosteronism (GRA), unilateral adrenal hyperplasia (UAH), and adrenal carcinoma (Table 2). Formerly, it was thought that APA accounted for 65% of cases of primary aldosteronism, with BAH/UAH accounting for 30-40%, and GRA accounting for 1-3% (18). Recent studies, however, have suggested higher rates of BAH/UAH and GRA, likely due to improved detection of milder cases, a higher index of suspicion and improved screening tests (13, 19, 20). Definitive diagnosis of the cause for primary hyperaldosteronism can be a challenge in individual patients. Making the correct diagnosis, however, is of utmost importance since the treatments for each disorder are different.

APA tumors are often small, usually less than 2cm in diameter, and occur more commonly in women than in men (21). Histopathology of APA reveals ‘hybrid’ cells which have histological features of both zona glomerulosa and zona fasciculata cells. APA may be further subdivided into two subgroups: those responsive to angiotensin II (AII-R-APA), and those unresponsive to angiotensin II (AII-U-APA) (22). AII-R-APA tumors are composed predominantly of glomerulosa-like cells, whereas AII-U-APA tumors are composed predominantly of fasciculata-like cells. In AII-R-APA, aldosterone levels often increase in response to angiotension-stimulating maneuvers, such as assuming the upright posture, mimicking the response seen in BAH. This distinction is of importance as AII-R-APA tumors can be mistakenly diagnosed as BAH, for which the recommended treatment is medical as opposed to surgical management.

BAH probably represents a spectrum of disorders (23, 24). Although the etiology is idiopathic in the majority of cases, it has been suggested that BAH may result from enhanced responsiveness to angiotensin II. This is based on studies that have found an exaggerated aldosterone response to infused angiotensin II in BAH patients (25). Other possible etiologies, such as activating mutations of the aldosterone synthase gene or AT2 receptor, have yielded negative results. Histologic examination of the adrenal cortex reveals both hyperplasia and micronodular disease of the zona glomerulosa. As the extent of hyperaldosteronism is often milder in BAH compared to APA, the degree of hypokalemia and suppression of PRA is often less.

Unilateral adrenal hyperplasia (UAH), sometimes referred to as primary adrenal hyperplasia, shares many biochemical features of APA. This diagnosis if often made based on evidence of unilateral production of aldosterone, primarily adrenal vein sampling, and (see Diagnosis, Section VI) in the absence of a discrete radiographic mass. Similar to APA, however, the hypertension and biochemical abnormalities may be cured or ameliorated by unilateral adrenalectomy (26-28).

Glucocorticoid-remediable aldosteronism (also known as familial hyperaldosteronism type I) is an autosomal dominant disorder characterized by a chimeric duplication whereby the 5’-promotor region of the 11 B-hydroxylase gene (regulated by ACTH) is fused to the coding sequences of the aldosterone synthase gene (29). Aldosterone synthesis is therefore abnormally and solely regulated by ACTH. In general, this disorder should be considered in patients with early-onset hypertension in the setting of suppressed PRA. A strong family history of early cerebral hemorrhage (<35yr) should also raise suspicion for GRA. Screening of GRA pedigrees has revealed that most affected individuals are not hypokalemic (30, 31)

Adrenal carcinomas, an exceedingly rare cause of primary aldosteronism, are usually large (>5cm) at the time of diagnosis. At present, adrenal carcinoma cannot be differentiated from adrenal adenoma on the basis of fine needle aspiration biopsy, or core biopsy. Rather, the diagnosis is based upon evidence of extension of the tumor through the adrenal capsule or a high mitotic index on histologic examination.

Other mineralocorticoid-excess states with low plasma renin activity include congenital adrenal hyperplasia (CAH), the syndrome of apparent mineralocorticoid excess (AME), and Liddle’s syndrome. CAH, most often diagnosed in infancy, results from inherited defects in enzymes that regulate cortisol biosynthesis. As a result of ineffective glucocorticoid synthesis, excess mineralocorticoids (such as 11-deoxycorticosterone) and androgens are produced as a result of shunting of precursors into blocked and unblocked pathways, respectively. Sometimes there is marked virilization of the female infant in the most striking form of CAH. When adequately treated with glucocorticoids, however, abnormal mineralocorticoid production is reversed.

AME results from abnormal activation of the Type I mineralocorticoid receptor in the kidney by cortisol. This syndrome results from an acquired (licorice ingestion or chewing tobacco) or congenital deficiency of the renal isoform of the enzyme, 11 b-OH steroid dehydrogenase (11b-HSD), which normally metabolizes cortisol to the inactive compound cortisone (32, 33). As a result of 11b-HSD2 deficiency the Type I mineralocorticoid receptor is no longer ‘protected’ from activation by cortisol. Liddle’s Syndrome results from constitutive activation of the renal epithelial sodium channel (ENaC) as a result of activating mutations of ENaC. Since AME and Liddle’s syndromes result from intrinsic renal abnormalities leading to unregulated, excessive sodium reabsorption, the biochemical phenotype includes suppression of PRA, hypokalemia and undetectable levels of plasma aldosterone.

B. SECONDARY ALDOSTERONISM

Secondary hyperaldosteronism is the result of the hypersecretion of aldosterone as a consequence of increased activation of the renin-angiotensin system (RAS). The subgroups are best understood by contrasting etiologies that usually produce hypertension from those that do not (Table 2). The most common causes of secondary aldosteronism are medical illnesses that result from a reduction in perceived or ‘effective’ circulating blood volume, such as congestive heart failure and nephrotic syndrome. Secondary hyperaldosteronism in these disorders is the result of baroreceptor activation and thus a physiologic response to the decompensated state. Importantly, treatment and correction of the underlying medical illness results in reversal of the activated RAS.

Diuretic use can also cause secondary hyperaldosteronism. The findings can mimic those seen in renovascular hypertension, especially in a hypertensive patient. With chronic diuretic use, moderate to severe extracellular and intravascular volume depletion results in renal hypoperfusion, increased release of renin, and, subsequently, excessive aldosterone production. In rare occasions, surreptitious use of diuretics can produce misleading biochemical findings. A high degree of suspicion should be present in the appropriate setting, such as unexplained hypokalemia in a medical or paramedical worker.

Importantly, a distinction should be made between renal vascular disease, and renal vascular hypertension. While a large proportion of the adult population may have renal vascular disease (as evident by a 50% or greater decrease in renal artery luminal diameter), only a small portion of these patients experience critical renal hypoperfusion and ischemia. Therefore, documentation of both structural and functional abnormalities are required before any therapeutic intervention is entertained in such patients.

Renovascular hypertension remains the most common cause of secondary aldosteronism associated with hypertension, and is defined as hypertension associated with either unilateral or bilateral ischemia of the renal parenchyma. There are numerous causes of this disorder, though atherosclerosis of the renal arteries, and fibromuscular dysplasia are the most frequent (Table 3). In these disorders, decreased renal perfusion causes tissue hypoxia and perfusion pressure, thereby stimulating renin release from the juxtaglomerular cells and, as a result, excessive aldosterone release. Coarctation of the aorta can produce a similar pathophysiology due to renal hypoperfusion.

Although renal vascular hypertension can affect patients of all ages, it is commonly seen in older adults (>50 years) due to the increased prevalence of atherosclerosis in this population. When found in patients <50 years old, renal vascular hypertension is more common in women, usually as a result of fibromuscular dysplasia of one of both of the renal arteries.

In very rare cases, juxtaglomerular cell tumors of the kidney that hypersecrete renin have been described (34). Such patients often have severe hypertension, accompanied by elevated renin and aldosterone levels, hypokalemia, and a mass lesion in the kidney. Confirmation includes documentation of unilateral renin secretion in the absence of renal artery stenosis. While very rare, such cases are important to diagnose as surgical removal of the tumor can be curative.

DIAGNOSIS OF HYPERALDOSTERONISM

Secondary causes of hypertension (including hyperaldosteronism) should at least be considered initially in all hypertensive individuals. A thorough medical history and physical examination can greatly assist the clinician with decisions regarding which patients should be tested and what tests should be performed. Although the sensitivity of testing for hyperaldosteronism increases when limited to patients with moderate-to-severe hypertension, many patients with hyperaldosteronism have mild to moderate hypertension. The recent onset of refractory or accelerated hypertension, especially in a patient known to be previously normotensive, can be a valuable clinical clue. Therefore, the clinician must remain vigilant to the possibility of hyperaldosteronism, especially in the appropriate clinical setting.

Primary aldosteronism should be considered in all patients with a history of hypertension associated with ‘spontaneous’ hypokalemia. Suspicion is also warranted in patients with severe hypokalemia precipitated by diuretic therapy. Finally, all incidentally-discovered adrenal masses should prompt further investigation especially in a hypertensive patient. (35)

Secondary aldosteronism should be considered in patients with rapid acceleration of hypertension, or in hypertensive females less than 35 years of age. Other findings that suggest the possibility of renovascular hypertension include the presence of an abdominal bruit (systolic and diastolic components) on physical examination, decreased renal function, and poor blood pressure control on three drugs despite good compliance with medical therapy. In such settings, further evaluation is indicated (see: DIAGNOSIS OF SECONDARY ALDOSTERONISM below).

Diagnosis Of Primary Aldosteronism

Biochemical Screening

Evaluation for primary aldosteronism begins with hormonal screening, specifically determination of a random, simultaneous plasma aldosterone (PA) to plasma renin activity (PRA) ratio. In most studies, a ratio of plasma aldosterone (ng/dL) to plasma renin (ng/ml/h) of greater than 20:1 should raise suspicion for this disorder. A PA/PRA ratio < 20 is seen in normotensive or essential hypertensive subjects. A PA/PRA ratio of >30 (in the setting of a PA > 15 ng/dl) is 90% sensitive and 91% specific for the diagnosis of primary aldosteronism (36) while a ratio of 50 or greater is virtually diagnostic of this disorder (37, 38) (Figure 2).

Figure 2. Diagnosis of APA

To optimize the initial screening evaluation for primary aldosteronism, drugs that alter aldosterone or renin secretion should be avoided if possible. Hypokalemia should also be corrected as it directly inhibits aldosterone release. Beta-blockers, spironolactone and eplerenone should be withdrawn for 2-4 weeks before testing, as these agents alter plasma aldosterone and renin levels. Specifically, beta-blockers lower PRA secretion and often produce a false positive PA/PRA ratio in patients with essential hypertension. Spironolactone and eplerenone inhibit the actions of aldosterone on the mineralocorticoid receptor, thereby increasing serum concentrations of PRA. However, if the screening test is performed while on Ace Inhibitors (ACEI), angiotensin receptor blocker (ARB), calcium channel antagonists, or alpha-blocker therapies, and aldosterone levels remain frankly elevated in the setting of suppressed renin activity, the likelihood of primary aldosteronism remains high. For example, ACEI should normally increase PRA levels and decrease aldosterone secretion, while alpha blockers and calcium channel antagonists have neutral actions on the renin-angiotensin-aldosterone system.

Confirming the Diagnosis

If the PAC/PRA ratio is abnormal, but not considered to be diagnostic of primary aldosteronism (>70, if PAC is measured in ng/dL and PRA in ng/mL per hour), confirmation of the autonomous aldosterone secretion is necessary. Methods to demonstrate autonomy of aldosterone production focus on volume-expanding maneuvers and include the saline suppression test and the oral salt loading test. A third test is the fludrocortisone suppression test (Figure 2).

Acute intravascular volume expansion with isotonic saline normally suppresses the RAS. For the saline suppression test, 2-3 liters of isotonic saline are infused (500cc/h) over 4-6 hours. This test should not be performed in patients with compromised cardiac function due to the risk of pulmonary edema. In normal subjects, PA levels normally decrease below 166pmol/l (6ng/dl) at the end of the saline infusion while levels greater than 277 pmol/l (10ng/dl) are diagnostic of autonomous aldosterone production. Values between 166 - 277 pmol/l (6-10 ng/dl) are considered indeterminate but are highly suspicious for this disorder.

Oral salt loading for 3 days results in extra and intravascular volume expansion and RAAS suppression in normal individuals. In the oral salt-loading test, patients are instructed to eat a high (200mmol) sodium diet for 3 days, or take two 1-gm NaCl tablets (100 mmol) with each meal for 3 days. On the third day of the high-sodium diet, a 24-hour urine collection for aldosterone excretion, creatinine, and sodium is collected. Aldosterone excretion greater than 39 nmol/d (14 ug/d), in the presence of a urinary sodium excretion greater than 200 mmol per 24 hour, is 96% sensitive and 93% specific for the diagnosis of primary hyperaldosteronism. Compared to the intravenous infusion saline test, oral salt loading is easier for both the patient and clinician, as it can be performed on an outpatient basis. However, blood pressure and potassium levels should be monitored during the testing to avoid acceleration of blood pressure or the precipitation of severe hypokalemia.

Etiologic Diagnosis

Once the biochemical diagnosis of primary hyperaldosteronism has been confirmed, further testing is required to determine the etiology of this disorder. Distinguishing between APA, BAH, and less common forms of primary hyperaldosteronism, such as GRA, is important. For example, resection of APA cures hypertension in 30-69% of patients and invariably reverses hypokalemia. In contrast, bilateral adrenalectomy in BAH cures hypertension in only 19% of patients. Hence, surgical therapy of APA, and medical therapy of BAH is usually recommended.

Biochemical characteristics can assist with diagnosis of the various causes of primary hyperaldosteronism. Young age (<50 years old), severe hypokalemia (<3.0 mmol/L), high plasma aldosterone concentrations (>700pmol/l or 25ng/dl), and high urinary aldosterone concentrations (>30ug/24hr) favor the diagnosis of APA versus BAH. However, while sensitive, these findings lack specificity, and therefore cannot be relied on a as means to determine the underlying etiology in individual patients. (39).

18-hydroxy-corticosterone (18-OH-B), a steroid intermediate in the aldosterone biosynthetic pathway, has been used to assist in the differentiation of APA form BAH. Levels of 18-OH-B greater than 100ng/dl are suggestive of APA, while measurements less than 100ng/dl support the diagnosis of BAH (sensitivity 82%) (18). Due to overlap, most clinicians have abandoned the measurement of this compound.

Adrenal computed tomography (CT) scanning with thin-slice (3mm), spiral technique is the best radiographic procedure to anatomically diagnose a solitary adrenal mass, and, if found, lends support to the diagnosis of APA. If an adrenal tumor is imaged in a patient with biochemical features of primary aldosteronism (especially a PA/PRA ratio >70), and the contralateral adrenal gland is anatomically normal, no further evaluation is usually needed and laporoscopic adrenalectomy is recommended (Figure 2). Unfortunately, even when biochemical features suggestive of APA are present, only one-third to one-half of patients have positive CT findings for a solitary APA. Alternatively, it is not uncommon for both adrenal glands to be anatomically abnormal in patients with primary aldosteronism. In addition, it is emphasized that a radiographic abnormality does not correlate with a functional equivalent. For example, non-functioning adrenal ‘incidentalomas’ can co-exist with an APA in the ipsilateral or contralateral adrenal gland, and data suggest that, if relied on solely, adrenal anatomy may wrongly predict lateralization in a significant proportion of patients (40).

Adrenal vein sampling is the ‘gold standard’ to diagnose unilateral versus bilateral aldosterone hypersecretion. In this protocol, simultaneous right and left adrenal vein samples, as well as a sample from the inferior vena cava (IVC) are collected for aldosterone and cortisol levels, and a cortisol/aldosterone ratio is calculated. This test is also usually performed under continuous adrenocorticotropin (ACTH) stimulation to exaggerate side-to-side differences, though not all investigators favor this approach (15). The subsequent ratio is termed the “cortisol-corrected” aldosterone ratio and is more sensitive than aldosterone measurements alone, eliminating dilutional influences. When the side-to-side “cortisol-corrected” aldosterone ratios are compared, a ratio of >4.0 strongly favors the diagnosis of APA, while a value of <3.0 suggests BAH. Using these criteria, positive and negative predictive values of over 90% are obtained (39).

Importantly, however, adrenal vein sampling is not needed in all patients. Data suggest that patients with a high probability of APA by biochemical criteria, and a >1cm unilateral adrenal nodule (with an anatomically normal contralateral gland) should be considered for unilateral adrenalectomy, especially if less than 40 years old (41). In cases of inconclusive data or equivocal radiographic features, however, we recommend adrenal vein sampling (performed by an experienced angiographer) to provide an accurate diagnosis.

Diagnosis Of Secondary Aldosteronism

When there is clinical suspicion for renovascular hypertension, and initial screening has revealed a normal or elevated plasma renin activity, further testing for renovascular hypertension should be pursued. Importantly, the diagnosis of renovascular hypertension requires two criteria: 1) the identification of a significant arterial obstruction (structural abnormality), and 2) evidence of excess renin secretion by the affected kidney (functional abnormality) (42). Structural abnormalities can be detected by a variety of imaging techniques including computed tomography (CT) scanning, duplex ultrasonography, magnetic resonance/ angiography, or conventional angiography. Choosing among the various options is largely dependent on availability of the technology, cost of the examination, and physician experience in performing and interpreting the results.

Functional testing can be performed with the captopril renogram or bilateral renal vein renin sampling In the former test, captopril (an ACEI) is given 30 minutes prior to the renogram. Maintenance of glomerular filtration and renal blood flow in normal subjects is highly dependent on actions of angiotensin II primarily at the efferent but also the afferent glomerular arterioles. A reduction in angiotensin II action (caused by captopril) results primarily in relaxation of the efferent arteriole. If the afferent blood flow, however, is fixed by the presence of an arterial stenosis, maintenance of glomerulus filtration is dependent on enhanced angiotensin-mediated efferent arteriolar tone. Thus, delayed excretion of the isotopic tracer is exaggerated by captopril on the affected side, providing functional evidence of renal artery narrowing.

The definitive test for a correctable unilateral renal vascular lesion is the combination of bilateral renal vein renin sampling and renal angiography . Bilateral renal vein renin sampling provides important information for predicting whether therapeutic angioplasty will modify the hypertension. Venous concentrations of renin from the ischemic kidney that are at least 1.5 times greater than that from the contralateral kidney correctly predict a pathophysiologically functional lesion in over 80% of subjects. Some administer captopril before renal vein renin sampling to augment renin release from the stenotic side. Agents, such as B-blockers, should be discontinued prior to the procedure to avoid falsely lowering PRA values.

TREATMENT OF HYPERALDOSTERONISM

Primary Aldosteronism

Treatment for primary aldosteronism is dependent on the underlying etiology. Surgery is most often the treatment of choice for APA, and is often performed with laporoscopic techniques, thereby reducing patient recovery time and hospital cost. Resection of APA may cure or ameliorates hypertension in APA patients and invariably reverses the hypokalemia. Data suggests, however, that full resolution of hypertension after adrenalectomy for primary aldosteronism may be more closely associated with a lack of family history of hypertension and the preoperative use of two or fewer antihypertensive agents. In one recent analysis, only one-third of patients returned to a normotensive state postoperatively (43). Caution should be exercised in the perioperative (44) and postoperative management of APA patients since suppression of aldosterone secretion in the contralateral adrenal gland is expected, thus resulting in a transient hyporeninemic hypoaldosterone state. As a result, some patients exhibit post-operative salt wasting, mild hyperkalemia, and are at increased risk of dehydration if sodium restricted. For patients who are not operative candidates, medical management of hyperaldosteronism should be pursued (45), as described below for BAH.

BAH is best treated medically with the use of a mineralocorticoid receptor antagonist, eplerenone or spironolactone (46, 47). Spironolactone dosages required are between 50mg and 400mg per day, usually administered twice daily. While effective for controlling blood pressure and hypokalemia, the use of spironolactone is limited by side effects (usually at doses >100mg/day), especially in males. Gynecomastia and erectile dysfunction often occur during long-term treatment in males due to the anti-androgenic actions of spironolactone. In women, spironolactone may lead to menstrual dysfunction, primarily intermenstrual bleeding. Fatigue and gastrointestinal intolerance are other common side effects. Epleronone has similar antagonistic actions at the type I renal mineralocorticoid receptor, but has no anti-androgen activity since it does not bind to androgen or progesterone receptors. Compared to spironolactone, uncertainties in dosing and increased cost are considerations in decisions to use eplerenone to treat patients with primary aldosteronism. When blood pressure is not controlled with spironolactone/eplerenone, or side-effects limit usefulness, the addition of additional antihypertensive therapies may be required. Other potassium-sparing diuretics, such as triamterene or amiloride have been used, but usually are not as effective as spironolactone (48). The dihydropyridine calcium channel antagonists have also been shown to effectively reduce blood pressure and may even reduce aldosterone secretion. Use of these agents as combination therapy is reasonable when blood pressure is not controlled with spironolactone alone. Dietary sodium restriction (<100mmol/day), regular aerobic exercise, and maintenance of ideal body weight contribute to the success of pharmacologic treatment for hypertension in BAH.

Glucocorticoid-remediable aldosteronism (GRA) can be successfully treated with low doses of glucocorticoids such as dexamethasone. By inhibition of the release of ACTH, the abnormal autonomous production of aldosterone can be suppressed. The mineralocorticoid receptor antagonist, eplerenone and spironolactone, or the sodium epithelial channel antagonist, amiloride, are also effective treatments of hypertension in GRA and are alternatives to glucocorticoid suppression. Direct genetic screening for the presence of the gene duplication in GRA is possible and can diagnose affected at-risk individuals in GRA kindreds. An international registry is now available for glucocorticoid-remediable aldosteronism, and can accessed online at: http://www.brighamandwomens.org/gra/introduction.asp.

Secondary Aldosteronism

Renal angioplasty is the optimal treatment for renal artery stenosis. In certain instances, such as disease effecting the ostium of the renal artery, angioplasty and stent placement appears to improve outcome over angioplasty alone. In general, angioplasty should be performed by an experienced interventional angiographer, as successful outcomes are more frequent. Surgery for repair of renal vascular hypertension is usually reserved for patients with prior unsuccessful angioplasties who remain hypertensive but are good surgical candidates.

Medical therapy may be indicated in patients whom have failed angioplasty or are unsuitable candidates for interventional procedures. Given the pathophysiology of RVH, ACEI or angiotensin-II blockers are the agents of first choice. However, caution must be taken given the propensity of these agents to worsen renal hypoxia and reduce glomerular filtration in the affected kidney. ACEI and angiotensin II blockers are of particular concern in patients who have bilateral renal artery stenosis where these agents may precipitate renal failure.