Primary Hyperaldosteronism

Difficult Diagnoses

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Primary Hyperaldosteronism

Robert H. Noth, MD, * and Edward C. Biglieri, MDt

Primary hyperaldosteronism is the quintessential difficult diagnosis. A decade after it was first described in 1955, it was diagnosed only in those few research centers able to perform the then complicated renin and aldosterone assays and to conduct the meticulous clinical metabolic balance studies. ~1odern immunoassays, simplified diagnostic testing, and improved imaging techniqucs have diminished certain diagnostic barriers, but have introduced others. There remain uncertainties about the optimal methods of screening, diagnostic criteria, and differentiation of the growing number of etiological subgroups. Familiarity with the intricacies of the diagnostic process remains a challenge, particularly for those physicians who only infrequently manage such patients, but upon whom the primary responsibility of scrcening and diagnosis rests. SCREENING

The prevalence of primary hyperaldosteronism in the hypertensive population probably is fewer than 1 in 200, but is sufficiently common to be encountered occasionally in practice. Next to renovascular hypertension, it may be the most common surgically curable cause of hypertension. As many as 90 per cent of patients with aldosterone-producing adrenal adenomas can be cured surgically of both hypokalemia and hypertension. 2 Even patients with otherwise refractory, severe hypertension respond. 5 Patients with idiopathic hyperaldosteronism for whom surgery is not indicated are identified as candidates for spironolactone therapy. The rare patient with aldosterone-producing adrenal carcinoma will be identified. Finally, because most patients being evaluated for primary hyperaldosteronism are part of the broader spectrum of both primary and secondary *Associate Professor of Medicine, University ofCalifornia-Davis, Davis; Chief, Endocrinology and General Medicine, Veterans Administration Medical Center, Martinez, California tProfessor of Medicine, University of California-San Francisco; and Director, Clinical Study Center, San Francisco General Hospital, San Francisco, California

Medical Clinics of North America-Vo!' 72, No. 5, September 1988

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Table 1. Differential Diagnusis uf Hypertension and HypukaZemia Primary hyperaldosteronism Hyperdeoxycorticosteronism DOC-producing adrenal tumors Congenital adrenal hyperplasia ll-hydroxylase deficiency 17-hydroxylase deficiency Secondary hyperaldosteronism Antihypertensive therapy Ethanol abuse and withdrawal Coexistent sodium chloride deficiency or loss or hypovolemia Renovascular hypertension Malignant hypertension Pheochromocytoma Cushing's syn'drome Primary hyper-reninism Ectopic Renin-secreting renal tumor Exogenous mineralocorticoid High dose cortisol Fllldrocortisone 9-alpha-fluoroprednisolone Carbenoxolone Licorice Chewing tobacco Other endogenous mineralocorticoids lS-OH-DOC 19-Nor-DOC Abnormal steroid metabolites" Liddle's syndrome

hypermineralocorticoidism, other diagnoses of importance may be made (Table 1). Primary hyperaldosteronism is a laboratory diagnosis. Although in Conn's analysis of 145 of the first cases l5 most patients did have symptoms, including muscle weakness (73 per cent), polyuria (72 per cent), headache (51 per cent), paresthesias (24 per cent), intermittent paralysis (21 per cent), and tetany (21 per cent), these often were nonspecific. Furthermore, with earlier diagnosis, symptoms now are less common, Physical findings are even less helpful. Blood pressure ranges from normal 41 to severely elevated,8, 11 with no typical level. Absence of advanced hypertensive retinopathy despite severe hypertension is characteristic and may be a helpful clue. Nevertheless, malignant hypertension can occur. Orthostatic hypotension can occur but is not characteristic,9 nor is edema. Primary hyperaldosteronism has been associated with several other endocrine abnormalities, including acromegaly, 62 pheochromocytoma, 70 and primary hyperparathyroidism,19 The Significance of this is uncertain. Because the associations are infrequent, they are not of much help in screening for primary hyperaldosteronism. Serum Potassium Screening Serum potassium is the single most important screening test for primary aldosteronism. Its sensitivity is approximately 75 to 90 per cent in the

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hypertensive population.~· 7[ It should be obtained fasting without forearm exercise or prolonged venous stasis. [2 Although there is no important diurnal variation of serum potassium in patients with primary aldosteronism, ambulation for even 1 hour can raise serum potassium significantly. 01 Antihypertensive therapy can interfere and generally is stopped for 2 to 4 weeks before testing. Spironolactone, which can affect both plasma renin activity and aldosterone for months, is best avoided until a diagnosis is made. Spontaneous hypokalemia below 3.5 mEq per L usually is the criterion for further evaluation, but the sensitivity of the test may be increased if other criteria are used. These include severe hypokalemia, less than 3.0 mEq per L during therapy with usual doses of diuretics; failure to maintain normal serum potassium on diuretic therapy despite potassium supplementation; and the presence of refractory hypertension in the absence of other secondary causes, especially when end-organ damage is absent. [() Urinary potassium normally is conserved to less than 30 mEq per 24 hours when serum potassium is below 3.5 mEq per L, and the finding of higher values is confirmatory of mineralocorticoid excess. 3S Salt supplementation to increase sodium consumption to 200 to 250 mEq per day increases sensitivity substantially8 and may be useful in selected patients. Sodium intake should not be low during screening, for example below 100 mEq per L, because this may decrease renal potassium wasting sufficiently to normalize serum potassium. Although some investigators are not satisfied with the level of sensitivity afforded by serum potassium testing,8, 63 there probably is no other feasible approach at this time, given the large number of hypertensive patients. Serum potassium as a screening test also has been criticized for poor specificity, with the prevalence of spontaneous hypokalemia being as high as 5 per cent of referred hypertensives 63 and diuretic-induced hypokalemia as high as 20 to 60 per cent,23 at least before the modern emphasis on low dose diuretics. Evaluating only those with serum potassium below 3.2 mEq per L has been recommended as an optimal use of the test,25 and undoubtedly would decrease the number offalse positives. This also would result in unacceptable further losses in sensitivity, however. If diuretic-induced mild hypokalemia is evaluated only when not corrected by simple discontinuation of the diuretic while on a normal to high sodium diet, the number of further evaluations will be limited. , A second aspect of the specificity problem is the fact that there are many causes of hypertension and hypokalemia (see Table 1). This reflects the complex clinical reality, not any shortcoming of serum potassium as a screening test. Remarkably, the differentiation of primary aldosteronism from other causes of hypertension and hypokalemia usually is quite straightforward, despite the formidable differential. Most of the causes will be evident from a careful history and physical examination. Most of the remainder will be excluded readily by the initial hormonal profiling. The full differential diagnosis is considered in several recent broader reviews. 6, 7, 17,38. .J7, .J8 Plasma Renin Activity Other tests have been proposed for screening, but none is as simple as serum potassium. Plasma renin activity almost always is low in this

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syndrome, but also is low in 10 to 55 per cent of other hypertensives, depending on age,":)' .')6 sex, race, and methodology. Furthermore, plasma renin activity normally varies widely with posture and sodium intake, so random, uncontrolled, or uncorrected values are of limited value. The expense of any of the hormonal measurements is substantially more. Aldosterone Measurements Plasma or urinary aldosterone measurements similarly are difficult to interpret and require simultaneous determination of plasma renin activity to distinguish primary from secondary excess. Nevertheless, in one recent series, urinarv aldosterone excretion rate obtained on a 24-hour urine collection afte~' 3 days on a salt-supplemented diet was 96 per cent sensitive and 93 per cent specific in detecting patients with subsequently proven primary aldosteronism. 8 In other series not utilizing salt supplementation, and taking 20 f,Lg per 24 hours as the upper limit of normal, sensitivity ranged from 69 to 84 per cent. 48. 71 Correction for age and sodium intake using nomograms may improve sensitivity without increasing false positives. Hegsted and coworkers report that four of eight patients over 40 years of age with aldosterone-producing adenomas had normal aldosterone excretion rates before age correction, but all eight were abnormal when compared with age matched controls. 34 Measurement of urinary sodium and potassium on the same sample yields additional diagnostic data. Completeness of collection must be assessed by history and measurement of creatinine. Correctly done, urinary aldosterone remains one of the most useful tests in the diagnosis of this disorder. As a screening test applicable to all hypertensives, it clearly is substantially more involved and costly than serum potassium and is not applied routinely in most clinics. Aldosterone:plasma Renin Ratio Of the other diagnostic tests available, only the plasma aldosterone: plasma renin activity ratio is sufficiently convenient to be considered as a potential practical screening tool. Several recent reports indicate a sensitivity of as high as 90 to 100 per cent with acceptible specificity in high-risk groups, but more data are needed. 33. 45. 49 One inherent drawback of this test is the variability in methodology for plasma renin activity, which translates into variability in the absolute value of the ratio. Another is its expense, particularly when the prevalence of the condition is so low. Other diagnostic tests are even less convenient and more expensive. Although some investigators are dissatisfied with the level of sensitivity afforded by serum potassium testing, 8. 6.3 there probably is no feasible alternative approach at this time.

CONFIRMING THE DIAGNOSIS Confirmation of the diagnosis of primary hyperaldosteronism requires the repeated demonstration of multiple interrelated clinical and laboratory abnormalities. The key abnormalities are aldosterone values that are (1)

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higher than in normals or patients with essential hypertension and (2) fail to suppress normally. Because aldosterone secretion in primary aldosteronism can he episodic, no single value or single test result is pathognomonic. The diagnosis is not always difficult. It can bc cstablished with relatively few tests in the typical patient with an adenoma. In the hypertensive paticnt on no medications, demonstration of spontaneous hypokalemia, renal potassium wasting greater than 30 mEq per day, very low plasma renin activity, and confirmed simultaneously markedly elevated aldosterone in plasma and urine, there is only one diagnosis. At this point, one could proceed to localization tests, and if these are unequivocal, surgery. Often, however, values are marginally abnormal or inconsistent, and multiple tests are needed. Those currently in use include acute intravenous saline suppression, captopril administration, chronic oral sodium loading, integrated plasma aldosterone and plasma renin activity, combined sodium and exogenous mineralocorticoid suppression, and, finally, if these tests do not give an unequivocal answer, careful in-patient metabolic balance studies with multiple hormonal measurements. Saline Infusion Test The intravenous saline infusion test is an acute suppression test in which 1250 to 2000 ml of normal saline is infused over 4 hours. This ordinarily suppresses plasma renin activity and, secondarily, plasma aldosterone to less than 10 ng per dl in all normals and in most patients with secondary hyperaldosteronism. In one series of 51 patients with surgically proven primary hyperaldosteronism, every patient failed to suppress below 10 ng per dFl; that is, sensitivity was 100 per cent. On the other hand, Streeten and coworkers described an appreciable number of patients, 10 of 22, with subsequently proven or suspected primary hyperaldosteronism who nevertheless suppressed to less than 10 ng per dl. (i'l None of their eight patients with proven or suspected aldosterone-producing adenoma, however, suppressed. Holland and his coworkers report similar results, Cl6 and suggest that patients with plasma aldosterone values between 5 and 10 ng per dl following saline testing should undergo further testing. Arteaga and coworkers, using a lower volume (1250 ml) of saline infusion, reported plasma aldosterone values greater than 10 ng per dl in all 14 patients with aldosterone-producing adenomas, but in none of six patients with idiopathic hyperaldosteronism. 2 False positives are infrequent, usually are associated with increased plasma renin activity, and therefore are detected easily. In the previously quoted series, however, Streeten and coworkers reported 5 patients out of 789 who failed to suppress and who had low stimulated plasma renin activity, yet did not appear to have primary aldosteronism based on multiple other results. 63 This is approximately a 20 per cent false positive rate. It is not stated whether these were marginal values, or whether doing the test in the afternoon after a furosemide test and ambulation in the morning could have inHuenced the outcome. Because aldosterone is secreted episodically, however, it is unrealistic to expect any single sampling procedure to be entirely reliable. When 18hydroxycorticosterone (18-0HB) is measured, the test provides additional

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information that is helpful in subgrouping, as described later. When patients with recent myocardial infarction, stroke, or congestive heart failure are excluded, side efh~cts are infrequent (fewer than 0.5 per cent) and resolve rapidly with diuresis. (l3 Captopril Test The principle of the captopril test is similar, but angiotensin 11 levels are lowered by pharmacologic blockade of angiotensin-converting enzyme rather than by volume expansion. The advantage is less risk of volume overload, and this is the test of choice in patients with cardiac disease. Data are limited, however. Lyons and coworkers reported that 11 of 12 patients with primary hyperaldosteronism failed to suppress plasma aldosterone to less than 15 ng per dl 2 hours after an oral dose of 25 mg of captopril. 46 None of the seven patients with aldosterone-producing adenomas suppressed, but 9 of 10 patients with essential hypertension did. Similar results were reported by Naomi and coworkers,51 who also demonstrated that sodium intake did not influence the response in patients with primary aldosteronism. 52 Lyons and coworkers found better discrimination using the plasma aldosterone:plasma renin activity ratio after captopril. M uratani and coworkers performed captopril testing in 19 patients with primary hyperaldosteronism (17 patients with surgically confirmed adenoma, two with hyperplasia) and 72 patients with essential hypertension. 49 They found considerable overlap between the two groups, with the range after captopril in primary hyperaldosteronism being 8.9 to 123 ng per dl and in essential hypertension 1. 6 to 16.1 ng per dl. In their series, the best tests were basal plasma aldosterone and basal plasma aldosterone:plasma renin activity ratio after overnight recumbency on a 10 g per day salt diet. As with sodium loading, captopril suppression testing appears to be useful but not without occasional false positives and false negatives even with criteria that optimally minimize both. It offers an alternative to intravenous saline testing when the latter is contraindicated. Other Selected Tests The 24-hour integrated concentration of plasma aldosterone has been proposed by one group as an answer to the variability in plasma aldosterone levels. 76 Using a specialized continuous withdrawal technique, 11 of 12 patients with primary hyperaldosteronism were separated from 92 patients with essential hypertension without overlap. A 6-hour measurement may suffice,77 allowing outpatient testing. The advantage over carefully collected urinary aldosterone remains to be proven by direct comparison in larger series. In-hospital administration of deoxycorticosterone acetate or fludrocortisone for 3 days is a more prolonged form of volume-mediated suppression testing that can be used to provide additional evidence of nonsuppressibility of aldosterone if this is needed. 57 In addition to inconvenience there is increased risk of aggravating hypokalemia, however, so this test is reserved for research purposes or for those few patients with equivocal or inconsistent results on other testing. It has been used to identify a small subgroup of

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Table 2. Subtypes of Primary Hyperaldosteronism Aldosterone-producing adenoma (AP A) Primary adrenal hyperplasia (P AH) Aldosterone-producing renin responsive adenoma (AP-RA) Idiopathic hyperaldosteronism (IHA) Unilateral hyperplasia Glucocorticoid suppressible hyperaldosteronism (GSH) Aldosterone-producing carcinoma Indeterminate hyperaldosteronism (IndHA)

patients with marginally elevated plasma and urinary aldosterone but normal suppressibility. These patients have been classified as having "indeterminate" primary hyperaldosteronism (Table 2) because they differ from all other patients in this latter characteristic. Some investigators have argued that, in fact, idiopathic hyperaldosteronism and essential hypertension form extremes of a spectrum of abnormality in aldosterone secretion. Further analysis of data on blood pressure's relationship with electrolytes, exchangeable sodium, and potassium does not entirely support the existence of such a spectrum.42 In almost all cases, the distinction between primary hyperaldosteronism and essential hypertension can be made clearly based on different underlying pathophysiology.

DIFFERENTIATION OF SUBTYPES During the past decade, major advances have been made in the techniques of differentiation, including improvements in biochemical profiling, imaging, and adrenal vein sampling. The clinical applications of these advances and of the new knowledge of the pathophysiology of primary hyperaldosteronism are yet to be explored fully. One of the main challenges remains the differentiation between aldosterone-producing adenomas and idiopathic hyperaldosteronism caused by hyperplasia. These are the two most common subtypes, with adenomas being somewhat more common. Differentiation is important because surgery is not indicated for most cases of bilateral hyperplasia. Not only does bilateral adrenalectomy often fail to cure the hypertension, but it introduces a difficult-to-treat, potentially lethal new disease-primary hypoadrenalism. A recently described variant of idiopathic hyperaldosteronism, termed unilateral hyperplasia (see Table 2), shares the low surgical cure rate of the hypertension in bilateral hyperplasia, but shows misleading disparate results on adrenal vein aldosterone and cortisol testing, suggestive of a unilateral source of aldosterone. 22, 24 Surgical removal of the most involved adrenal gland does cure the hyperaldosteronism and hypokalemia without causing hypoadrenalism, so surgical removal probably is the treatment of choice, despite the histological finding of hyperplasia. Two other new, uncommon subtypes recently have been described. Like aldosterone-producing adenomas, these both are entirely curable surgically, but both share features with idiopathic hyperaldosteronism that might inappropriately exclude operative management. One of these, pri-

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mary adrenal hyperplasia, resembles aldosterone-producing adenoma biochemically but, like idiopathic hyperaldosteronism, shows no localization by computerized tomography (CT) or by adrenal vein aldosterone testing. cl Surgical removal of 75 per cent of adrenal tissue results in apparent long term cure. This condition has been identified in 5 of 150 (3 per cent) patients with primary hyperaldostcronism evaluatcd by one of the authors (EGB). The other new subtype, aldosterone-producing (renin) responsive adenoma (AP-RA) biochemically resembles idiopathic hyperaldosteronism in some respects, but is unilateral by CT scanning and is cured by unilateral adrenalectomy. This lesion has been identified in 4 of 75 (5 per cent) of patients with primary hyperaldosteronism evaluated with full biochemical profiling (unpublished data, EGB). Cl(;a Less common forms of primary hyperaldosteronism are familial glucocorticoid suppressible hyperaldosteronism and isolated aldosterone secreting adrenal cortical carcinoma. Although the latter constitutes only a few percent of cases in most series, a number of recent reports documenting a dozen new cases indicate it is not a rare occurrence. I. 16. 1~. 27.59 It can be rccognized by its striking biochemical abnormalities, resembling aldosterone-producing adenoma, and the finding of a large adrenal mass and, sometimes, metastases on CT scanning. Clinical clues, again, are not very helpful. The clinical course of adenomatous disease tends to be more severe, with lower serum potassium, lower plasma renin activity, and higher aldosterone values, but there is much overlap with other groups. Carcinomas often produce profound hypokalemia. Familial incidence points to the glucocorticoid-suppressible variant, which follows an autosomal dominant form of inheritance. It generally is necessary, however, to rely on other preoperative evaluation using the techniques that we will discuss later. In most cases, accurate preoperative diagnosis is possible and surgical exploration of both adrcnals, unnecessary. One of the first biochemical tests used to differentiate between adenoma and hyperplasia was postural stimulation. plasma renin activity, aldosterone, and cortisol are determincd at 8:00 A. M. after at least 2 hours recumbency and again after 2 to 4 hours of quiet ambulation. In patients with adenomas, plasma renin activity remains suppressed and plasma aldosterone falls in response to decreasing ACTH. In patients with hyperplasia, plasma renin activity is not as suppressed, the hyperplastic tissue is responsive to small increases in plasma renin activity, and plasma aldosterone rises. Small series suggested the utility of this test, but a recent larger series showed only 20 of 33 patients with adenomas following the described pattern. H Furthermore, several patients with hyperplasia had the adenoma pattern. Additional testing therefore always is advisable. Another approach to demonstrating the relative independence of adenomas from regulation by angiotensin 11 is the spironolactone test, as recently described,39 but further data are needed. One of the most promising new biochemical parameters is 18-0IIB, now measured in a number of research centers. Although not a direct intermediate in the synthetic pathway to aldosterone, it isa marker of the activity of the final steps of aldosterone synthesis. It also is elevated

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markedly in most patients with adenomas, and normal in idiopathic hyperplasia. The reason for this difference is not known. Arteaga and colleagues compared basal 18-0HB levels in 14 patients with aldosterone-producing adenoma (APA) and six patients with idiopathic hyperaldosteronism (I HA) and found overlapping values in only two of the patients with APA. 2 By examining the changes in 18-0HB, plasma aldosterone, and plasma cortisol during saline infusion performed between 8:00 and 10:00 A.M., it was possible to select criteria that completely separated the 14 patients with adenomas from six with hyperplasia. In APA, plasma aldosterone declined more rapidly than 1S-OHB but in IHA, plasma aldosterone and 1S-OHB declined in parallel as renin values decreased. A ratio of 18-0HB to cortisol greater than 3.0 occurred in all patients with APA but in none of those with IHA. Kem and his associates recently reported values of 1S-OHB above 100 ng per dl in 22 of 23 patients with aldosterone-producing adenomas and none of nine patients with idiopathic adrenal hyperplasia. l2 18-Hydroxycorticosterone also is a marker for the subtype primary adrenal hyperplasia.';) These patients have 18-0HB levels comparable to patients with APA. In a patient with nonlateralization on CT or adrenal venous sampling, an elevated 1S-OHB level may be a valuable clue to surgical curability, to be confirmed by further diagnostic hormonal testing. 18-Hydroxycorticosterone is normal in patients with AP-RA, and this group of patients constitutes an exception to the close correlation between levels of 1S-OHB and the presence of surgical disease. Other potentially useful new biochemical parameters are urinary 18hydroxycortisol and 18-oxocortisol,26 hybrid molecules chemically related to both aldosterone and cortisol, which are increased in AP A and glucocorticoid suppressible hypoaldosteronism but not in IHA. Biochemical markers for IHA soon may be developed as a result of continuing research into the pathophysiology of the various subtypes of primary hyperaldosteronism. There long has been evidence of a non-ACTH pituitary regulator of aldosterone, and the suspicion that an excess of such a regulator causes idiopathic hyperaldosteronism. This theory recently received support by the serendipitous finding of nodular basophilic hyperplasia of the anterior and intermediate lobes of the pituitary at autopsy of a patient with idiopathic hyperaldosteronism diagnosed antemortem. 21 In the past decade, a number of new regulators of aldosterone have been identified and their role in the pathophysiology of this disorder explored. Carey and coworkers have described increased levels of the pituitary-derived aldosterone-stimulating factor in seven patients with hyperplasia but not in four patients with adenomas. 14 Similarly promising results have been described for plasma beta-endorphin 29 and plasma gammamelanotropin, a peptide derived from the NH 2 -tenninal region of proopiomelanocortin. 28 Not all investigators have found these differences, however. 32 Promising as these developments are, the number of patients is small, the assays are not generally available, and further investigation is needed." Another relevant area of current investigation is dopaminergic regulation of aldosterone secretion. In normal volunteers, dopamine has a tonic

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inhibitory effect on aldosterone secretion." '54 Blockade of dopamine by the dopamine antagonist metoclopramide increases plasma aldosterone both in normals and in patients with primary aldosteronism. 2.3, :37 This effect was abolished by glucocorticoid pretreatment in five patients with glucocorticoid suppressible hyperaldosteronism, but not in patients with other forms of primary hyperaldosteronism. Results of administration of dopamine or dopamine agonists in primary hyperaldosteronism are conflicting. One group found that dopamine reduced the aldosterone and I8-0HB responses to angiotensin II infusion in patients with idiopathic hyperaldosteronism, but not in patients with adenomas.7.1 Another group, however, was unable to confirm this observation using the dopamine agonist bromocriptine. 72 Series have been small and more data are needed before clinical application can be made. Atrial natriuretic factor levels are increased in patients with APA and in a few with IHA, as might be expected,50. 54, 66, 74 but it seems unlikely that it will differentiate between AP A and IHA. In fact, the disadvantage of this marker is its nonspecificity, being elevated in a number of volume expanded states. Further data will be needed. Helpful though the biochemical markers are and promise to be, it essentially is always necessary to visualize the adrenals once the diagnosis of primary aldosteronism is made. This often serves both to confirm the biochemical findings and also to localize the source of aldosterone overproduction. In general, this means localization to one adrenal gland or both but, in rare instances, APAs have been localized to the kidnel·5 or the ovary. 20

LOCALIZATION Computerized tomography has proven highly useful in the process of localization. Because approximately I per cent of CT scans obtained for other reasons show incidental adrenal masses, most of which are not aldosteronomas, the CT cannot be relied on to make the initial diagnosis without definitive biochemical evidence. In fact, because the prevalence of adrenal masses at autopsy is over two-fold increased in hypertensives, one should be doubly cautious. Nevertheless, for localization, advantages include availability, noninvasiveness, and high resolution. In recent series, 48 to 80 per cent of adenomas have been visualized. 3 , 66, 74 Sensitivity is a problem because many of these tumors are under I cm in diameter and difficult to detect for this reason. When a definite abnormality is identified in one adrenal and the other adrenal gland is normal, however, there is a high likelihood of a unilateral adenoma. Hyperplastic glands usually appear normal, but there are reports of a small proportion showing bilateral abnormality. 3, 11, .30, 69 A negative scan is not particularly helpful because it may be caused by a small adenoma or hyperplasia. Magnetic resonance imaging may produce higher contrast between adrenal tissue and retroperitoneal fat,5k but more data are needed. Ultrasound detects some of the larger aldosteronomas,75 but probably is not sufficiently sensitive as a localization modality.

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Scintigraphic localization is based on the principle that cholesterol is taken up by tumors and hyperplasia but not by suppressed normal adrenal tissue. The radiolabeled cholesterol analog used in the United States is 131 1_ 6 beta-iodomethylnorcholesterol or NP-59. The unique advantage of scintigraphy is its dependence on function. It also is noninvasive. It has several disadvantages, however, including radiation exposure and inconvenience. It requires concurrent high dose iodide administration to protect the thyroid from taking up the radioiodine released from the metabolized cholesterol and, for optimum sensitivity, pretreatment with dexamethasone 4 mg daily for a week to suppress ACTH-dependent cholesterol uptake by the normal adrenal fasciculata. The dexamethasone also helps protect normal adrenal tissue from radiation exposure. Despite over a decade of use, this agent remains investigational, although possible to obtain. 30 Multiple imaging sessions over a 5-day period are required to assure an interpretable pattern and maximum sensitivity.:lo, .31 Enthusiasm for this technique has varied considerably, 30, 71 in part because many investigators failed to use or used inadequate amounts of glucocorticoid suppression,lo and in part because it may have difficulty in detecting small tumors. 71 In one series, scintigraphy detected only 6 of 13 adenomas, with an additional one lateralized incorrectly. 71 Another small series reports one false localization. 3.5 Nonetheless, the reported sensitivity of 96 per cent (48 of 50 adenomas) in a recent large, carefully done series suggests this technique warrants careful continued evaluation. It also has been successful in visualizing mineralocorticoid-producing adrenocortical carcinomas, including metastases. 50 It should be considered as an alternative to adrenal vein sampling in cases of equivocal or negative CT scan results. Adrenal vein hormonal sampling long has been considered the gold standard in localization testing but, in fact, is unnecessary in many cases where biochemical tests and noninvasive imaging techniques concur in identifying a unilateral adenoma. Therefore, it now should be considered a backup test when noninvasive testing is inconclusive or inconsistent. Performing the hormonal sampling both before and after intravenous infusion of cosyntropin undoubtedly has improved results over nonstimulated sampling. S.5. 71 This method overcomes the uncertainties caused by episodic secretion of cortisol. Because adrenal vein cortisol serves as a marker of adrenal venous effluent, it is critical that it be stimulated continuously. Furthermore, responsiveness of aldosterone secretion to ACTH can be demonstrated directly, and may serve as a marker of adenomatous tissue. Conversely, lack of significant aldosterone response can be used as an indicator of normal suppressed tissue:"·5 Alternatively, adrenal vein epinephrine may be used as a marker of adrenal vein blood. 43 Although adrenal venography now rarely is done because of a risk of intra-adrenal hemorrhage, small volume injections of contrast to localize the catheter have been utilized. These can be misinterpreted, however, and do not directly assess dilution factors. Perhaps the major shortcoming of adrenal vein sampling is the failure over 15 per cent of the time to sample the right adrenal effluent successfully. Furthermore, there always is risk of a complication of the often

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protracted procedure. In one author's (RHN) experience as an observer of over 100 cases of renal vein renin sampling, a procedure technically similar to adrenal vein sampling, complications have included two cases of deep vein thrombophlebitis, one case of serious retroperitoneal hemorrhage, and one case of a broken catheter necessitating surgical retrieval. It probably is best undertaken by an individual with experience in this type of procedure. Therefore, although sometimes needed and often definitive, adrenal vein sampling is not the initial test of choice, nor is it a panacea.

SUMMARY Primary hyperaldosteronism is a challenging diagnosis because of its low incidence and variable pathophysiology. Serum potassium, properly done, is the routine screening test, but is not without its limitations. Confirmation of the diagnosis requires demonstration of abnormally high and nonsuppressible values for aldosterone in plasma and urine and low plasma renin activity. Sophisticated biochemical profiling and localization procedures often are required to identify those subtypes that will benefit from surgical management, including aldosterone-producing adenomas, primary adrenal hyperplasia, unilateral hyperplasia, and aldosterone-producing renin responsive adenomas. Glucocorticoid-suppressible hyperaldosteronism and isolated aldosterone-producing adrenal carcinoma are rare additional subtypes to be identified. Differentiation among these subtypes is a developing process that can be expected to continue to improve with new techniques and new understanding of underlying pathophysiology. REFERENCES 1. Arteaga E, Biglieri EG, Kater CE, et al: Aldosterone-producing adrenocortical carcinoma. Ann Intern Med 101:316, 1984 2. Arteaga E, Klein R, Biglieri EG: Use of the saline infusion test to diagnose the cause of primary aldosteronism. Am J Med 79:722, 1985 3. Balkin PW, Hollifield JW, Winn SD, et al: Primary aldosteronism: Computerized tomography in preoperative evaluation. South Med J 78:1071, 1985 4. Banks W A, Kastin AJ, Biglieri EG, et al: Primary adrenal hyperplasia: A new subset of primary hyperaldosteronism. J Clin Endocrinol Metab 58:783, 1984 5. Biglieri EG: The pituitary and idiopathic hyperaldosteronism. N Engl J Med 311:120, 1984 6. Biglieri EG, Kater CE, Arteaga EA: Mineralocorticoid hypertension due to hyperaldosteronism and hyperdeoxycorticosteronism. J Hypertension 4(Suppl 5):S61, 1986 7. Biglieri EG, Baxter JD: The endocrinology of hypertension. In Felig P, Baxter JD, Frohman L, et al (eds): Endocrinology and Metabolism. Edition 2. New York, McGrawHill, 1987 8. Bravo EL, Tarazi RC, Dustan HP, et al: The changing clinical spectrum of primary aldosteronism. Am J Med 74:641, 1983 9. Bravo EL, Tarazi RC, Dustan HP, et al: The sympathetic nervous sytem and hypertension in primary aldosteronism. Hypertension 7:90, 1985 10. Bravo EL: Secondary hypertension: A streamlined approach to diagnosis. Postgrad Med 80: 139, 1986 11. Bravo EL, Fouad-Tarazi F'.1, Tarazi RC, et al: Clinical implications of primary aldosteronism with resistant hypertension. Hypertension 11(Suppl 1):1-207, 1988

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12. Brown JJ, Chinn HH, Davics DL, ct a1: Falsely high plasma potassium values in patients with hyperaldosteronism. Br 1\1ed J 2: 18, 1970 1:3. Carey HM, Thorner 'VI 0, Ortt EM: Dopaminergic inhibition of me to clop rami de-induced aldosterone secretion in man. J Clin Invest 66: 10, 1980 14. Carey HM, Sen S, Dolan L'vl, et a1: Idiopathic hyperaldosteronism: A possible role for aldosterone-stimulating factor. N Engl J Med 311:94, 1984 15. Conn JW, Knopf HF, r-.:esbit HM: Clinical characteristics of primary aldosteronism from an analysis of 145 cases. Am J Surg 107:159, 1964 16. Cugini P, Lucia P, Murano G, et al: Pure primary hyperaldosteronism due to adrenal cortical carcinoma. Am J Med 77:A51, 1984 17. Drury PL: Disorders of mineralocorticoid activity. Clin Endocrinol Metab 14:175, 1985 18. Farge D, Chatellier G, Pagny J-Y, et al: Isolated clinical syndrome of primary aldosteronism in four patients with adrenocortical carcinoma. Am J Med 83:635, 1987 19. Ferriss JB, Brown JJ, Cumming AM'V!, et al: Primary hyperparathyroidism associated with primary hyperaldosteronism. Acta Endocrinol 103:365, 1983 20. Flanagan MJ, McDonald JH: Heterotopic adrenocortical adenoma producing primary aldosteronism. J Urol 98:133, 1967 21. Franco-Saenz H, Mulrow PJ, Kim K: Idiopathic aldosteronism: A possible disease of the intermediate lobe of the pituitary. JAMA 251:2555, 1984 22. Ganguly A, Zager PG, Luetscher JA: Primary aldosteronism due to unilateral adrenal hyperplasia. J Clin Endocrinol Metab 51:1190, 1980 23. Ganguly A, Pratl JH, Weinberger 'VIH, et al: Differing effects of metoclopramide and adrenocorticotropin on plasma aldosterone levels in glucocorticoid-suppressible hyperaldosteronism and other flmns of hyperaldosteronism. J Clin Endocrinol Metab 57:388, 1983 24. Ganguly A, Yum M;>,!, Pratt JH, et al: Unilateral hypersecretion of aldosterone associated with adrenal hyperplasia as a cause of primary aldosteronism. Clin Exp HypertensTheory and Practice A5:163.5, 1983 25. Goldenbcrg K, Snyder DK: Screening fClr primary aldosteronism: Hypokalemia in hypertensive patients. J Gen Intern 'VIed 1:368, 1986 26. Gomez-Sanchez CE, Montgomery 'vI, Ganguly A, et al: Elevated urinary excretion of 18oxocortisol in glucocorticoid-suppressible aldosteronism. J Clin Endocrinol Metab 59: 1022, 1984 27. Greathouse DJ, McDermotl MT, Kidd GS, et al: Pure primary hyperaldosteronism due to adrenal cortical carcinoma. Am J Med 76:1132, 1984 28. Griffing GT, Berelowitz B, Hudson M, et al: Plasma immunoreactive gamma melanotropin in patients with idiopathic hyperaldosteronism, aldosterone-producing adenomas, and essential hypertension. J Clin Invest 76:16,3, 1985 29. Griffing GT, I\lcIntosh T, Berelowitz B, et a1: Plasma beta-endorphin levels in primary aldosteronism. J Clin Endocrinol Metab 60:315, 1985 30. Gross MD, Shapiro B, Grekin HJ, et al: Scintigraphic localization of adrenal lesions in primary aldosteronism. Am J .Vled 77:839, 1984 31. Gross 'VID, Shapiro B, Freitas JE: Limited significance of asymmetric adrenal visualization on dexamethasone-suppression Scintigraphy. J l\iucl Med 26:43, 1985 32. Gullner H-G, Nicholson WE, Gill JR Jr, et al: Plasma immunoreactive pro-opiolipomeIanocortin-derived peptides in patients with primary hyperaldosteronism, idiopathic hyperaldosteronism with bilateral adrenal hyperplasia, and dexamethasone-suppressible hyperaldosteronism. J Clin Endocrinol Metab 56:853, 1983 33. Hamlet SM, Tunny TJ, \Voodland E, et al: Is aldosterone:renin ratio useful to screen a hypertensive population for primary aldosteronism r Clin Exp Pharmacol Physiol 12:249, 1985 34. Hegstad H, Brown HD, Jiang N-S, et al: Aging and aldosterone. Am J Med 74:442, 1983 3.5. Hietakorpi S, Korhonen T, Aro A, et a1: The value of scintigraphy and computed tomography for the differential diagnosis of primarv hyperaldosteronism. Acta Endocrinol (Copenhagen) 113:118, 1986 36. Holland BO, Brown H, Kuhnert LV, et al: Further evaluation of saline infusion for the diagnosis of primary aldosteronism. Hypertension 6:717, 1984 36a. Irony I, Biglieri EG: !\;ew types of primary aldosteronism. Clin Hes 36:123A, 1988 37. Jungmann E, AlthofI P-Il, Rosak C, et al: Endogenous dopaminergic inhibition of

1130

38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64.

ROBERT

H.

l\"OTH A:-.1D EDWAHD

G.

BICLIERI

aldosterone and prolactin secretion is apparently not increased in primary aldosteronism. Honn >"1etab Res 18: 138, 1986 Kaplan :'\IM: Clinical Hypertension. Baltimore, Williams & Wilkins, 1986, p 407 Kater CE, Biglieri EG, Schambelan M, et al: Studies of impaired aldosterone response to spironolactone-induced renin and potassium elevations in adenomatous but not hyperplastic primary aldosteronism. Hypertension 5(Suppl V):V-115, 1983 Kem DC, Tang K, Hanson CS, et al: The prediction of anatomical morphology of primary aldosteronism using serum 18-hydroxycorticosterone levels. J Clin Endocrinol Metab 60:67, 1985 Kono T, Ikeda F, Oseko F, et al: Normotensive primary aldosteronism: Report of a case. J Clin Endocrinol ~1etab 52:1009, 1981 Lasaridis A, Brown H, Davies DL, et al: Arterial blood pressure and plasma and body electrolytes in idiopathic hyperaldosteronism: A comparison with primary hyperaldosteronism (Conn's syndrome) and essential hypertension. J Hypertension 2:329, 1984 Levinson PD, Zadik Z, Hamilton BPM, et al: Adrenal vein epinephrine levels: A useful aid in venous sampling for primary aldosteronism. Ann Intern Med 97:690, 1982 Lim RC, Nakayama DK, Biglieri EG, et al: Primary aldosteronism: Changing concepts in diagnosis and management. Am J Surg 152: 116. 1986 Lins P-W, Adamson U: Plasma aldosterone-plasma renin activity ratio: A simple test to identify patients with primary aldosteronism. Acta Endocrinol (Copenhagen) 113:564, 1986 Lyons DF, Kem DC, Brown RD, et al: Single dose captopril as a diagnostic test for primary aldosteronism. J Clin Endocrinol Metab 57:892, 1983 Mantero F: Exogenous mineralocorticoid-like disorders. Clin Endocrinol Metab 10:465, 1981 Melby JC: Diagnosis and treatment of primary aldosteronism and isolated hypoaldosteronism. Clin Endocrinol Metab 14:977, 1985 Muratani H, Abe I, Tomita Y, et al: Is single oral administration of captopril beneficial in screening for primary aldosteronism? Am Heart J 112:361, 1986 Nakamura T, Ichikawa S, Sakamaki T, et al: Role of atrial natriuretic peptide in mineralocorticoid escape phenomenon in patients with primary aldosteronism (42568). Proc Soc Exp BioI Med 185:448, 1987 Naomi S, Iwaoka T, U meda T, et al: Clinical evaluation of the captopril screening test for primary aldosteronism. J pn Heart J 26:549, 1985 Naomi S, Umeda T, Iwaoka T, et al: Effects of sodium intake on the captopril test for primary aldosteronism. Jpn Heart J 28:357, 1987 Noth RH, Lassman N, Tan SY, et al: Age and the renin-aldosterone system. Arch Intern Med 137:1414, 1977 Noth RH, McCallum RW, Contino C, et al: Tonic dopaminergic suppression of plasma aldosterone. J Clin Endocrinol Metab 51:64, 1980 :'\loth RH, Glaser SL, Palmaz JC: Cosyntropin stimulation in adrenal vein testing for aldosteronoma. West J Med 142:92, 1985 Noth RH, Mazzaferri EL: Age and the endocrine system. Clin Geriatr Med 1:223, 1985 Rodriguez JA, Lopez JM, Biglieri EG: DOCA test for aldosteronism: Its usefulness and implications. Hypertension 3(Suppl II):II-102, 1981 Roberts L Jr, Dunnick NR, Thompson WM, et al: Primary aldosteronism due to bilateral nodular hyperplasia: CT demonstration. J Comp Assist Tomogr 9:1125, 1985 Scott HW Jr, Sussman CR, Page DL, et al: Primary hyperaldosteronism caused by adrenocortical carcinoma. World J Surg 10:646, 1986 Shenker Y, Gross MD, Grekin RI. et al: The scintigraphic localization of mineralocorticoidproducing adrenocortical carcinoma. J Endocrinol Invest 9:115, 1986 Sonkodi S, Nicholls MG, Cumming AMM, et al: Effects of change in body posture on plasma and serum electrolytes in normal subjects and in primary aldosteronism. Clin EndocrinoI14:613, 1981 Strauch G, Vallotton MB, Touitou Y, et al: The renin-angiotensin-aldosterone system in normotensive and hypertensive patients with acromegaly. :'\I Engl J Med 287:795, 1972 Streeten DHP, Tomycz N, Anderson GH: Reliability of screening methods for the diagnosis of primary aldosteronism. Am J Med 67:403, 1979 Sugawara A, Nakao K, Kono T, et al: Atrial natriuretic factor in essential hypertension and adrenal disorders. Hypertension l1(Suppl 1):1-212, 1988

PRI\IARY HYPERALDOSTERON1S\1

1131

65. Todesco S, Terribile V, Borsatti A, et al: Primary aldosteronism due to a malignant ovarian tumor. J Clin Endocrinol Metab 41:809, 1975 66. Tunny TJ, Higgins BA, Gordon HD: Plasma levels of atrial natriuretic peptide in man in primary aldosteronism, in Gordon's syndrome and in Bartter's syndrome. Clin Exp Pharmacol Physiol 13:341, 1986 67. Ulick S, Levine LS, Gunczler P, et al: A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. J Clin Endocrinol Metab 49:757, 1979 68. Velchik MG, Kressel HY, Noel AW, et al: Primary aldosteronism: CT, MHI, scintigraphic correlation. Invest Radiol 20:237, 1985 69. Vetter H, Fischer M, Galanski M, et al: Primary aldosteronism: Diagnosis and noninvasive lateralization procedures. Cardiology 72(Suppl 1):57, 1985 70. Wajiki M, Ogawa A, Fukui J, et al: Coexistence of aldosteronoma and pheochromocytoma in an adrenal gland. J Surg Oncol 28:75, 1985 71. Weinberger MH, Grim CE, Hollifield JW, et al: Primary aldosteronism: Diagnosis, localization, and treatment. Ann Intern Med 90:.386, 1979 72. Wisgerhof M, Mellinger HC: Effect of bromocriptine treatment on the aldosterone response to angiotensin II and adrenocorticotropin in idiopathic hyperaldosteronism. J Clin Endocrinol Metab 61:192, 1985 73. Witzgall H, Lorenz H, Werder KV, et al: Dopamine reduces aldosterone and 18hydroxycorticosterone response to angiotensin II in patients with essential low-renin hypertension and idiopathic hyperaldosteronism. Clin Sci 68:291, 1985 74. Yamaji T, Ishibashi M, Sekihara H, et al: Plasma levels of atrial natriuretic peptide in primary aldosteronism and essential hypertension. J Clin Endocrinol Metab 63:815, 1986 75. Yamakita N, Yasuda K, Goshima E, et al: Comparative assessment of ultrasonography and computed tomography in adrenal disorders. Ultrasound Med BioI 12:23, 1986 76. Zadik Z, Levin P, Kowarski A: The diagnostic value of the 24 hour integrated concentration of plasma aldosterone. Clin Exp Theory Practice A7:1233, 1985 77. Zadik Z, Levin PA, Hamilton BP, et al: Detection of primary aldosteronism by the 6 hour integrated aldosterone:renin ratio. Hypertension 8:285, 1986 Medical Service Veterans Administration Medical Center 150 ~1uir Hoad Martinez, CA 94553