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Departments of Endocrinology (E.A.E., T.G.Y., P.J.H.), Radiology (D.G.R.), and Cardiology (A.M.R.), Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand
Address all correspondence and requests for reprints to: Professor E. A. Espiner, Department of Endocrinology, Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand. E-mail: eric.espiner{at}chmeds.ac.nz.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Recently, several groups have reported on the relative discriminatory power of preoperative tests used in cases of PA to separate unilateral autonomous forms from bilateral disease. There is agreement that adrenal scanning techniques per se are often unreliable and may be misleading (4, 6). The bedside posture test, originally promoted as a means of separating aldosterone-producing adenomas (APA) from BAH (7), has received less attention in the wake of findings suggesting that a subset of APA (so-called angiotensin II-responsive adenomas) may respond to the postural stimulus in a manner simulating BAH (8). Although seen by some as of historical interest only (4), a recent report from the National Institutes of Health (NIH) on 48 patients with PA found that the posture test could identify as many as 30% with a unilateral source (9). The authors concluded that the posture test was an important step in the decision-making tree leading to surgical intervention. Whereas adrenal venous sampling has been increasingly advocated in this context, techniques and interpretation vary widely. For example, the criteria used to establish unilateral autonomy (dominance) differ in two recent reports (10, 11). Thus, in contrast to Doppman et al. (12), who emphasized the importance of identifying contralateral adrenal suppression in localizing the abnormal gland, Rossi et al. (10) reported no discriminating value from this analysis. Yet other reports (9, 13) have placed more emphasis on the differential aldosterone output from the two glands. Equally controversial has been the use of ACTH stimulation during adrenal venous sampling. Considered to be unnecessary by some authors (10, 11), a recent report clearly shows that defining contralateral suppression in patients with APA is facilitated by ACTH stimulation, without which some left-sided tumors would be overlooked (9). Despite its usefulness, successful sampling of both right and left adrenal veins remains technically demanding and has therefore been limited largely to major tertiary specialist units. Although found worthless in one study (10), little attention has been given to the diagnostic value of unilateral access, an important issue for those clinicians working in smaller centers where the expertise required for bilateral adrenal vein sampling may be limited.
Using the gold standards of the distinctive focal (unilateral) adrenal pathology, and the complete remission of aldosteronism postoperatively as final confirmation of the diagnosis, we now report the value of preoperative diagnostic testing in 41 patients with unequivocal PA, and contrast the findings with an additional eight patients with putative BAH. We hypothesized 1) that a single adrenal macroadenoma on computerized tomography (CT) scanning, a positive (4 h) posture test or suppressed contralateral aldosterone secretion [using the criteria proposed by Doppman et al. (12)] would all have high positive predictive value for the diagnosis of a unilateral autonomous lesion (UAL) responding to surgical intervention, and 2) that in patients with a positive posture test, sampling from either adrenal vein would accurately lateralize the lesion.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Patients
From 1975–2000, 49 hypertensive patients with unprovoked hypokalemia, inappropriately elevated urinary potassium excretion, and elevated plasma aldosterone (in the face of low plasma renin activity) were referred to the Christchurch Endocrine Unit for further testing. Definitive tests for the diagnosis of PA, including autonomy of aldosterone secretion during salt loading (14) and diagnostic subtyping were undertaken after cessation of spironolactone or amiloride for at least 6 wk, and other hypotensive drugs for at least 2 wk. Patients in whom cessation of therapy was considered unsafe received prazosin or doxazosin monotherapy for blood pressure control.
Adrenal CT imaging
Before 1982, CT scanning was unavailable. Thirty-two patients presenting after 1982 had adrenal imaging (5-mm sections) performed at Christchurch Hospital. For the purposes of this report, a positive CT result is defined by the presence of a single focal (usually hypodense) lesion of at least 10 mm in the presence of a normal surround and a normal contralateral gland.
Posture test
A 4-h postural stimulation test was performed in 42 of the 49 patients. Patients were admitted overnight for measurement of plasma aldosterone at 0800 h (overnight supine) and after 4 h (1200 h) of continued erect posture. Plasma cortisol was also measured at the same times in 38 of the 42 cases.
Adrenal venous sampling (AVS)
Twenty-seven of the 49 patients had samples taken from the adrenal veins. AVS was performed in the morning during low-dose ACTH stimulation (1.25 µg synacthen/h) (15), which was commenced 30 min before femoral vein cannulation. Simultaneous samples of adrenal vein and peripheral (antecubital vein) blood were drawn for plasma aldosterone and cortisol measurement. Access to the adrenal veins was considered successful if the cortisol gradient (central to peripheral) exceeded 2.0. Before 1992, a central/peripheral aldosterone ratio more than 30 was accepted as evidence of an ipsilateral (autonomous) lesion, whereas ratios less than 2 were taken as evidence of contralateral suppression (i.e. sampling from the uninvolved gland) provided the cortisol central/peripheral ratio exceeded 10 (16). Subsequent to 1992, the criteria recommended by Doppman et al. (12), where all aldosterone measurements are normalized according to the cortisol concentration in the sample, have been used. For the purposes of the current study, adrenal vein analyses (all of which have been normalized for cortisol concentration) are reported as 1) lateralized ratio (aldosterone/cortisol ratio of the dominant adrenal vein divided by the aldosterone/cortisol ratio of the nondominant adrenal vein), 2) contralateral ratio (aldosterone/cortisol ratio of the non-dominant adrenal vein divided by the aldosterone/cortisol ratio in the matching antecubital vein) and 3) ipsilateral ratio (aldosterone/cortisol ratio of the dominant adrenal vein divided by the aldosterone/cortisol ratio in the matching antecubital vein).
Diagnosis
Of the 49 patients (45 Caucasian, four Polynesian), a solitary UAL was diagnosed in 41 (mean age 43.3 yr ± 1.5, 25 female) on the basis of preoperative testing (adrenal vein sampling, posture test, and adrenal imaging, Table 1
) and have proceeded to surgical exploration. An APA was confirmed and successfully lateralized in 40 of these 41 cases, all of whom had the typical golden-orange (focal) adrenocortical adenoma, also verified histologically. In the remaining case, generalized hyperplasia (without adenoma formation) was present in the excised (left) gland. In this case, because surgical biopsy of the contralateral (right) gland was normal, a diagnosis of primary (unilateral) adrenal hyperplasia was made. After surgery, aldosterone and renin levels were normalized and the patient has remained eukalemic. In eight patients (five female), mean age 52 ± 3.8 yr, BAH was diagnosed on the basis of findings from bilateral adrenal vein sampling (four patients, none of whom had surgery), adrenal histology (adrenalectomy in one, autopsy in another), and findings from adrenal vein sampling (two patients) and on clinical grounds (mild disease and enlarged nodular adrenals on CT scanning, two patients). A summary of the number of patients in whom the various diagnostic subtyping tests were undertaken, and listed according to final diagnosis, is shown in Table 1.
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Before 1983, plasma aldosterone was measured by RIA after paper chromatography (17). Subsequently, aldosterone was measured as reported by Lun et al. (18). Results from the two methods were in excellent agreement (18). Plasma cortisol was measured by ELISA (19) using a polyclonal antibody before 1992, after which a monoclonal antibody was used. Neither cortisol values nor reference ranges were altered by the change. Plasma renin activity (PRA) was measured as described previously (20) except that subsequent to 1992 the assay was converted to an antibody trapping method (21) to improve efficiency. Because of a systematic difference between the old and modified techniques (higher PRA values were found using the trapping technique when PRA was in the lower quintile), PRA values measured before 1992 have been adjusted using the formula y = 0.35 + 0.68x. This formula defines the relationship using the old (x) and modified (y) assays as determined by analyses on 91 plasma samples assayed concurrently by both techniques (r = 0.88). The normal range using the trapping assay (1000 h ambulant) is 0.5–3.0 µg/liter·h (0.4–2.3 nmol/liter·h), the lowest detectable level being 0.26 µg/liter·h.
The aldosterone renin ratio (ARR) (picograms per milliliter/micrograms per liter per hour) was measured in the ambulant state between 0800 and 1000 h when subjects were receiving a normal sodium intake. Some patients were receiving hypotensive drugs (but not spironolactone or amiloride) when assessed preoperatively. In contrast to the hypokalemia present preoperatively, all patients were eukalemic when the ARR was measured after successful surgery.
Data were analyzed by unpaired or paired t tests as appropriate for comparison between designated groups. P < 0.05 was considered a significant difference. Data are shown as mean ± SEM.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Mean age of the 49 patients (30 female) was 44 ± 2 yr. All were hypokalemic (mean plasma potassium 2.8 ± 0.06 mmol/liter) at the time of presentation with inappropriately increased urine potassium excretion (>30 mmol/24 h). Mean ARR was 633 ± 152 (n = 49), normal less than 223. Plasma potassium concentration at presentation was unrelated to hyperaldosteronism as reflected by 0800 h (overnight supine) plasma aldosterone level (r = -0.29; P = 0.1).
Response to unilateral adrenalectomy
In 41 patients with UAL (20 left sided), plasma aldosterone fell to a mean of 47 pg/ml ± 4 (130 ± 11 pmol/liter) within 5 d of unilateral adrenalectomy. In 24 of these patients, ARR was again measured within 3 months after surgery. Compared with preoperative values in these patients (mean 562 ± 111), ARR values (59 ± 7) were similar to those of healthy normotensive subjects (62 ± 6). Tumor diameter, measured at the time of sample preparation for histology, varied from 0.6–6.0 cm. Excluding one patient with a 6.0-cm diameter tumor, the mean tumor diameter was 1.7 cm ± 0.13. There was a significant (positive) correlation between tumor diameter and the preoperative 0800 h overnight supine plasma aldosterone (r = 0.44; P = 0.023).
Adrenal CT scanning
Adrenal CT scanning was undertaken in 26 of the 40 patients diagnosed with APA. In 16 of these (61%) CT correctly diagnosed a focal (single) adrenal adenoma with a normal contralateral gland. Excluding the one patient with the unusually large 6-cm diameter macroadenoma, mean tumor size (maximum diameter measured at the time of resection) in those with lesions visible on CT was 1.9 cm ± 0.2, range 1.2–3.5 cm. In the remaining 10 patients (39%) where CT was normal or equivocal, tumor size at surgery ranged from 0.6–1.5 cm (mean 1.2 ± 0.15).
CT was performed in six of the eight patients with putative BAH. Normal findings were reported in two, bilateral nodular enlargement in two, and single (isodense) nodules were reported in one adrenal in two patients. Because of tumor size (2-cm lesion and possible rapid enlargement), one of these latter patients underwent unilateral (left) adrenalectomy. However, at surgery no tumor was found and the pathology was that of diffuse generalized adrenal hyperplasia. This patient has remained hypertensive and hypokalemic post surgery.
Posture test
Thirty-five of the 41 patients with UAL, and seven of eight patients with BAH had posture tests performed. Plasma aldosterone responses are shown in Fig. 1 and in Table 2. The responses in patients with UAL have been divided into those where aldosterone decreased (positive posture test, n = 22) and those where aldosterone increased (negative posture test, n = 13). Plasma aldosterone in all seven patients with BAH increased during the upright posture test. In the single patient with primary unilateral adrenal hyperplasia, plasma aldosterone rose (150 supine, 341 pg/ml erect) despite a fall in plasma cortisol. Thus, all patients showing a positive posture test (fall in aldosterone) harbored an APA. Because no patient with BAH showed a fall, a positive posture test indicates 100% positive predictive value for APA. In the 38 patients where plasma cortisol was measured, levels fell in 75, 66, and 50% in posture-positive UAL, posture-negative UAL, and BAH, respectively, but differences in cortisol responses among the three groups were not significant (Table 2). Of note, eight of 12 patients with UAL and a negative posture test (rise in plasma aldosterone) showed a fall in plasma cortisol. These cases may be examples of angiotensin II-responsive lesions, and represent 35% of all UAL patients displaying a fall in plasma cortisol.
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, 0800 h supine plasma aldosterone was significantly higher in those with a positive test (fall in aldosterone) when compared with those with a negative response (P = 0.025; Table 2). Although 0800 h supine aldosterone was lower in those with BAH when compared with patients with posture-negative UAL, the difference was not significant (P = 0.4). The incremental aldosterone response in BAH was significantly greater when compared with negative responders harboring UAL (P = 0.007). This was also true when the aldosterone increment in BAH was compared with that seen in angiotensin II responders (P = 0.005). Of the 11 patients with a positive posture test undergoing adrenal scanning, all but one (91%) had a single focal adrenal lesion. In the same time period, a positive adrenal scan was reported in five of 10 patients (50%) in whom the posture test was negative.
Adrenal vein sampling (AVS)
Mean peripheral plasma cortisol concentration (during ACTH stimulation) was 30 ± 1 µg/dl (837 ± 35 nmol/liter). Successful access and sampling was obtained from one or both adrenal veins in 27 of 29 patients in whom the procedure was attempted. In patients with UAL, the mean cortisol central/peripheral ratio when sampling from the left adrenal vein (n = 21) was 13.9 ± 2.5 and 18.5 ± 4 when sampling from the right (n = 12). In patients with BAH, the respective ratios were 10.3 ± 3.5 (n = 6) and 3.0 ± 0.7 (n = 4). In patients with a unilateral source, the mean aldosterone/cortisol ratio in the ipsilateral vein (11.8 ± 2.8, n = 17) did not differ from ratios found in either of the two adrenal veins in patients with BAH (10.1 ± 5.1, n = 6).
Results for 15 patients (11 UAL, four BAH) in whom bilateral access was obtained are shown in Fig. 2. In patients with a unilateral lesion, the lateralized ratio ranged from 3–38 (mean 12.7 ± 3.8), whereas in BAH values ranged from 2.3–4.6 (mean 3.1 ± 0.5, P = 0.15). In contrast, the contralateral ratio was significantly different in the two groups (P = 0.001). Mean contralateral ratio in those with a UAL was 0.54 ± 0.16 (range 0.1–1.4) vs. 3.0 ± 1 (range 1.2–5.1) in BAH. Nine of the 11 with a UAL had a contralateral ratio less than 1, whereas the ratio was above 1 in all patients with BAH.
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, together with normalized central/peripheral ratios in six patients with BAH (four bilateral access, two single vein access). Using the combined data, the mean contralateral ratio was 0.45 ± 0.09 in those with a UAL (n = 16), significantly lower (P < 0.001) than any central/peripheral ratio found in the six patients with BAH (mean 7.4 ± 3.1). In patients with UAL, there was a highly significant inverse correlation (Fig. 4) between the 0800 h (supine) plasma aldosterone level and the contralateral ratio (r = 0.79; n = 16; P < 0.001) but not with the lateralized ratio (r = 0.46; n = 11; P = 0.15) or with the ipsilateral ratio (r = 0.15; n = 17; P = 0.54). Suppression was not different in the setting of left (mean contralateral ratio 0.47 ± 0.2; n = 5) vs. right-sided lesions (contralateral ratio 0.44 ± 0.1, n = 11). In contrast to the contralateral ratio, mean ipsilateral ratio (5.3 ± 0.89; range 1.4–13.5; n = 17) in patients with a unilateral source was not significantly different (P = 0.36) from central/peripheral ratios (7.4 ± 3.1, range 1.05–20.8; n = 6) found in BAH patients (Fig. 3).
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. Of the 11 patients studied, ipsilateral ratios 
1.4 identified all UAL. When the uninvolved gland was sampled (contralateral ratios), the ratio was less than 1.4 with one exception (1.4). Thus using a cut off of 1.4, correct assignment could be made in 16 of 17 single vein samples in these posture positive patients.
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Predictive power of subtyping tests for diagnosis of UAL in the 49 cases is shown in Table 3. Provided the diagnosis of PA is secure, a fall in plasma aldosterone during the 4-h upright posture test and/or a contralateral ratio of less than 1, had 100% positive predictive value. The contralateral ratio had the lowest false-negative rate (high-negative predictive value). Where bilateral access was obtained, a combination of lateralized and contralateral ratios (i.e. lateralized/contralateral ratio more than 3) indicates 100% positive and 100% negative predictive values (Table 3).
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1.4 in posture positive patients, n = 9), 39 of the 41 patients with UAL were correctly identified. In the remaining two patients (who only had CT scanning performed), imaging showed focal lesions <1 cm, both confirmed at surgery. |
Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We evaluated the predictive power of three preoperative procedures to identify the lesion and compared the findings to those in a further eight patients with putative BAH. The value of adrenal CT scanning in subtyping has been seriously questioned in several recent reports (6, 9, 11). In the present study, a single focal macroadenoma (10 mm) was correctly identified in only 61% of patients with surgically confirmed APA. This sensitivity is similar to that reported by others (6, 9). Not surprisingly, mean tumor diameter was smaller (1.2 cm compared with 1.9 cm in CT positive patients) in those with negative CT scans, yet eight of these 10 subjects with negative CT scans were found to have a single macroadenoma at surgery. Although CT scanning cannot reliably discriminate BAH from APA (11, 12), and has low sensitivity for APA, in our study the finding of a single focal macroadenoma on CT had high positive predictive value. Thus, we would agree with others (9) that in this circumstance patients with a positive posture test (predictive value 100%, see below) can be referred for unilateral adrenalectomy without need for AVS. However, the fact that some patients with BAH may exhibit single (focal) adrenal lesions (9) means that a positive adrenal CT alone should not be an indication for surgery even in patients with unequivocal PA.
The plasma aldosterone response to upright posture, either 2 or 4 h as originally proposed (7) has been used to separate APA from BAH where plasma aldosterone rarely, if ever, falls during the test. However, the sensitivity of the test is limited as significant numbers of patients with verified UAL have a negative test (4, 8). Recently the group at NIH has reviewed its experience of the (abbreviated, 2 h) posture test (9), concluding that an APA was accurately predicted by the finding of a positive test (i.e. fall in plasma aldosterone or 18 hydroxy corticosterone). However, only in a minority (30% of patients with APA) was the test positive, and in only 50% of all subjects did a diurnal fall in plasma cortisol occur. In the current study of 35 patients with UAL (34 with APA) using a 4-h period of ambulation, the percentage of those with APA showing a fall in aldosterone (65%) or in plasma cortisol (70%) was much higher and similar to that observed by Feltynowski (22), who also used a 4-h test. Once again, a fall in aldosterone (positive test) was highly specific for APA. Because no patient with putative BAH showed a fall in plasma aldosterone, the positive predictive value of a positive test in our series was 100%. To our knowledge, the current report of postural responses in 42 patients with PA (35 with UAL, seven with BAH) is one of the largest series employing the 4-h test. Despite claims to the contrary (23, 24), the current findings suggest that there is a higher yield of positive results in APA when the extended (4 h) test is used, provided every care is taken to reduce external stressors or comorbidities such as postural hypotension.
Despite increasing emphasis on the value of AVS in defining the surgically remedial lesion (4, 12, 13), both the test procedure itself and methods used to analyze results vary across referral centers. Three recent reports (9, 10, 11) highlight this lack of consensus. In a recent Italian study of 104 patients (10), analysis of AVS (done without ACTH stimulation, and using a very low central/peripheral cortisol ratio of 1.1 to confirm access) showed that a lateralized ratio of at least 2 was most discriminating for the diagnosis of a UAL. In contrast, the contralateral ratio, which reflects aldosterone suppression in the uninvolved gland and emphasized by Doppman and others as the crucial parameter (25), provided no useful information. Furthermore, these authors reported no accurate diagnosis could be obtained if only one adrenal vein was accessed. In two recent studies from large U.S. referral centers, ACTH stimulation (50 µg/h) was used in one study (11), and in the second study results were given both before and after exogenous ACTH stimulation. In both reports, a lateralized ratio of at least 4 and a contralateral ratio of 1 or less were used to define a UAL. However, in the NIH study (9), misinterpretation occurred in the absence of ACTH stimulation, e.g. contralateral suppression went undetected in the setting of a left-sided UAL. Further, these authors showed that separation of BAH from APA was less satisfactory pre-ACTH compared with results post-ACTH (9). Young et al. (13) using ACTH infusions of 50 µg/h, report similar satisfactory separation of UAL from BAH when the lateralized ratio exceeded 4–5, and when the contralateral ratio was less than 1, though it is to be noted that four of 14 patients diagnosed as BAH also had a suppressed ratio on one side.
Using lower (more physiological) ACTH stimulation (1.25 µg/h), our data in subjects where bilateral adrenal vein access was proven show similar findings, although the contralateral ratio provided better separation than the lateralized ratio. Nine of 11 subjects with UAL had contralateral ratios less than 1, whereas the ratio exceeded 1 in all four patients with BAH. The two UAL exceptions (contralateral ratios 1.4 and 1.08) had lateralized ratios of 5.1 and 10.2, respectively. Though numbers are small, it seems likely that combining these ratios (e.g. lateralized/contralateral) will further improve discrimination in difficult cases and should improve predictive value. The value of the contralateral ratio is further shown in our study in circumstances where only one adrenal vein is accessed. Thus, in five of 11 with proven APA, the lesion was accurately predicted by the finding of a very low contralateral ratio. The range of central/peripheral ratios encountered in our patients with putative BAH overlapped those drawn from the side of the lesion (ipsilateral ratio) in patients with UAL. Thus, when a single adrenal vein is accessed and happens to be the vein draining the lesion, the analysis cannot alone discriminate UAL from BAH. However, provided the posture test is positive, the finding of an ipsilateral ratio >1.4 in our experience will accurately localize the side of the lesion. This finding now requires confirmation in larger, prospective studies. Overall, our data are consistent with the views of Doppman et al. (12, 25) who emphasized the need to identify the suppressed (contralateral) gland rather than the gland overproducing aldosterone. Consonant with this view is our finding that the degree of contralateral suppression, but not ipsilateral aldosterone hypersecretion, is highly correlated with severity as indicated by 0800 h basal (supine) plasma aldosterone level. Clearly, bilateral access should be the aim of AVS, but outside a few special referral centers, this is often not achieved. Our data show that provided AVS is done carefully using ACTH infusions in patients with verified PA, the finding of a low contralateral ratio (<1), even when only single vein access is proven, has very high predictive and localizing value for UAL. To clarify and emphasize this point, we suggest that authors in future report actual data based upon results of central/peripheral ratio (always corrected for concurrent cortisol concentration) rather than listing aldosterone/cortisol ratio in adrenal vein and peripheral blood individually.
Based on an unselected series of 49 patients with unequivocal PA, our experience indicates that patients with a positive posture test and a single focal adrenal macroadenoma on CT scanning can proceed to surgery without further testing. The relatively high percentage (65%) of subjects with positive 4-h posture tests, plus the high concordance of positive adrenal scans in patients with a positive posture test (91% in the current study, 83% in the NIH study) (9) support this approach in the routine assessment of PA. However, because a single adrenal macroadenoma or nodule may also occur in the setting of BAH, CT appearances alone are insufficient to recommend surgery. In the setting of a positive CT adrenal scan, a positive posture test allows direct referral for surgery. However, if the CT is negative or equivocal (i.e. absence of a single focal adenoma), AVS is required both for definitive diagnosis and localization. AVS is also required in CT positive, posture negative patients. The finding of a suppressed contralateral ratio (i.e. <1) with proven access (either single or bilateral), accurately predicts a UAL and remission after surgery. When the posture test is positive, single vein access showing a central/peripheral ratio of at least 1.4 strongly suggests an ipsilateral lesion. However, subjects with negative posture tests in whom only one adrenal vein is accessed will require retesting for definitive diagnosis. This approach to preoperative testing is shown diagrammatically in Fig. 6 and makes it clear that posture tests are not required if unequivocal positive findings are obtained from adrenal vein sampling but can materially assist interpretation and final diagnosis when data from AVS is equivocal.
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Acknowledgments |
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Footnotes |
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Abbreviations: APA, Aldosterone-producing adenoma; ARR, aldosterone renin ratio; AVS, adrenal venous sampling; BAH, bilateral adrenal hyperplasia; CT, computerized tomography; PA, primary aldosteronism; PRA, plasma renin activity; UAL, unilateral autonomous lesion.
Received December 27, 2002.
Accepted May 5, 2003.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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