Is Adrenal Venous Sampling Necessary in All Patients with Hyperaldosteronism before Adrenalectomy?

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1 Is Adrenal Venous Sampling Necessary in All Patients with Hyperaldosteronism before Adrenalectomy? Rasa Zarnegar, MD, Alan I. Bloom, MD, James Lee, MD, Robert K. Kerlan, Jr, MD, Mark W. Wilson, MD, Jeanne M. Laberge, MD, Roy L. Gordon, MD, Electron Kebebew, MD, Orlo H. Clark, MD, and Quan-Yang Duh, MD PURPOSE: To evaluate whether selective rather than universal use of adrenal vein sampling (AVS) may be warranted in patients with hyperaldosteronism to characterize and lateralize disease before adrenalectomy. MATERIALS AND METHODS: Fifty-nine consecutive patients with biochemically diagnosed hyperaldosteronism underwent unilateral adrenalectomy at a single center during a 10-year period. In one group (n 30), adrenalectomy was based on computed tomography (CT) only; in another (n 29), it was based on CT and AVS. The indication for AVS was equivocal CT finding (n 26) or patient request (n 3). Outcome variables were postoperative serum potassium and aldosterone levels, number of hypertensive medications, and mean arterial blood pressure at 6 months. RESULTS: Preoperatively, both groups were matched for age, years of hypertension, mean arterial blood pressure, and number of hypertensive medications. Average tumor sizes were 2 cm (range, 1 3 cm) in the CT-only group and 1 cm (range, cm) in the CT/AVS group. Unilateral tumor was identified on CT in 30 patients (100%) in the CT-only group and in 17 patients (59%) in the CT/AVS group (P <.05). Postoperatively, aldosterone levels were lower in the CT-only group (6.3 ng/dl 5.9 vs 13.5 ng/dl 16; P <.05). Both groups had similar improvements in mean arterial blood pressure at 6 months (92 mm Hg 12 vs 96 mm Hg 9; P.14), reductions in number of hypertensive medications (to vs ; P.4), and improvements in hypokalemia (3.8 meq/l 0.5 vs 3.8 meq/l 0.5; P.5). CONCLUSIONS: The clinical impact of adrenalectomy was similar in both groups. CT can be used to reliably diagnose adenomas larger than 1.0 cm. AVS should be used when CT findings are equivocal or both adrenal glands are abnormal. J Vasc Interv Radiol 2008; 19:66 71 Abbreviations: A/C aldosterone/cortisol (ratio), AVS adrenal vein sampling, IVC inferior vena cava PRIMARY aldosteronism is one of the most common correctable causes of secondary hypertension and has an estimated prevalence that ranges widely from 1.4% to 10% in the hypertensive From the Departments of Surgery (R.Z., E.K., O.H.C., Q.Y.D.) and Interventional Radiology (A.I.B., M.W.W., J.M.L., R.G.), University of California San Francisco Medical Center, San Francisco, California; Department of Surgery (R.Z.), Weill Cornell Medical College; and Department of Surgery (J.L.), Columbia University Medical Center, New York, New York. Received May 14, 2007; final revision received August 10, 2007; accepted August 19, Address correspondence to Q.Y.D.; quan-yang.duh@med.va.gov Supported in part by the Friends of Endocrine Surgery, Mt. Zion Health Systems, The Jerold Heller Family Foundation, The Sanford and Helen Diller Foundation, and The Albert Clark Family Foundation. None of the authors have identified a conflict of interest. SIR, 2008 DOI: /j.jvir population (1 6). Patients with primary aldosteronism classically present with poorly controlled hypertension associated with hypokalemia (7). The appropriate treatment of primary aldosteronism depends on the correct differential diagnosis. Of the various subtypes of primary aldosteronism, an aldosterone-producing adenoma or bilateral adrenal hyperplasia, also known as idiopathic hyperaldosteronism, accounts for more than 95% of all cases. Primary adrenal hyperplasia, glucocorticoid-remediable aldosteronism, and adrenal carcinoma are uncommon causes of primary aldosteronism (8 12). Primary aldosteronism causes an excess of circulating plasma aldosterone that leads to adverse cardiovascular sequelae independent of the effects of blood pressure (13). Therefore, the goal of treatment is to normalize 66

2 Volume 19 Number 1 Zarnegar et al 67 the patient s potassium level, blood pressure, and aldosterone level (14). A diagnosis of primary aldosteronism in a hypertensive patient leads to targeted therapy such as unilateral laparoscopic adrenalectomy for aldosterone-producing adenoma or medical therapy for idiopathic hyperaldosteronism (15). Most patients diagnosed with aldosterone-producing adenoma hope to have no further need for antihypertensive medication for blood pressure control after adrenalectomy. However, only 33% 35% no longer require these medications, even though most have improved control of hypertension (16,17). After the diagnosis of primary aldosteronism is established biochemically, cross-sectional imaging of the adrenal glands with computed tomography (CT) or magnetic resonance (MR) imaging is recommended to delineate the subtypes (18,19). Most CT and MR imaging studies have concentrated on establishing the diagnosis of an aldosterone-producing adenoma, with the diagnosis of idiopathic hyperaldosteronism being one of exclusion. However, there is a wide variation in the reported diagnostic performance of CT (sensitivity, 56% 100%) and MR imaging (sensitivity, 70% 100%) in the detection of aldosterone-producing adenomas (20,21). Studies that have directly compared CT with MR imaging in the detection of an aldosteroneproducing adenoma reported no significant difference in diagnostic performance between the two modalities (22). It has been suggested that the choice of preferred imaging modality be based on radiologist experience (22). The role of adrenal vein sampling (AVS) in the differentiation of aldosterone-producing adenoma and idiopathic hyperaldosteronism is controversial. AVS was initially described in the 1960s and appeared to be useful in the delineation of primary aldosteronism (23). The technique fell out of favor as a result of the technical difficulty of cannulating both adrenal veins but has recently reemerged as the gold standard in determining the etiology of hyperaldosteronism (24 26). However, the increasing spatial resolution of current CT imaging together with the invasiveness of AVS, with its risks of failure and complications, has led some authors to conclude that AVS is necessary only when cross-sectional imaging findings are equivocal (23,34). We hypothesized that, with the current routine use of CT, more selective use of AVS may be warranted. We therefore compared clinical outcomes between patients who underwent laparoscopic adrenalectomy for biochemically proven primary aldosteronism based on CT imaging of a unilateral tumor at least 1.0 cm in size versus patients who were treated based on the findings of CT and AVS. MATERIALS AND METHODS The criterion used to establish the diagnosis of primary aldosteronism was a history of persistent hypertension, with or without hypokalemia, with biochemical evidence of hyperaldosteronism. Biochemical evidence of hyperaldosteronism was defined by a ratio of plasma aldosterone to plasma renin activity of at least 20 with a plasma aldosterone concentration of at least 15 ng/dl, and suppressed plasma renin activity of less than 1 ng/ml per hour. At our institution, patients with aldosterone-producing adenomas were differentiated from those with idiopathic hyperaldosteronism based on identification of a unilateral unequivocal adrenal tumor at least 1.0 cm in size on CT. Patients were selected to undergo adrenal venous sampling for lateralization of the abnormal adrenal gland if (i) the tumor was smaller than 1.0 cm on CT, (ii) the contralateral adrenal gland was enlarged or equivocal, and (iii) by patient request. Study Groups This is a retrospective cohort study of patients with aldosterone-producing adenoma seen at a single tertiary referral center between January 1, 1996, and December 31, A computerized database was used to identify 110 patients with the diagnosis of primary adenoma who underwent adrenalectomy. The institutional review board approved the study, and informed consent was obtained from patients to be included. Patients lost to follow-up at 6 months after adrenalectomy (n 17) were excluded, as were those who declined to be in the study (n 5) and those who underwent CT or AVS at a referring institution (n 29). Of the 59 patients with adequate follow-up, 30 consecutive patients had surgery based on CT without AVS (CT-only group). This group was compared with 29 consecutive patients who also underwent AVS before adrenalectomy (AVS/CT group). Data Collection The following baseline variables were obtained by a review of the medical records: date of birth, date of operation, sex, size of tumor, number of antihypertensive medications, and years of hypertension duration. Laboratory data collected included plasma levels of potassium and aldosterone, plasma renin activity, and aldosterone-to-renin activity ratio. Clinical outcome data included systolic and diastolic blood pressure together with the number of antihypertensive medications at the 6-month postoperative visit. Pathologic examination was not used to differentiate aldosterone-producing adenoma from idiopathic hyperaldosteronism because, with the advent of laparoscopic adrenalectomy, most specimens at our institution are morcellated or fragmented and removed in a piecemeal fashion, making pathologic confirmation of diagnosis difficult. Imaging All patients had undergone CT imaging at the University of California San Francisco in accordance with the adrenal protocol. CT imaging was performed with a LightSpeed 32- or 64-slice scanner (GE Medical Systems, Milwaukee, Wis). The adrenal protocol involves thin cuts ( mm) through the adrenal glands. The initial scan is not enhanced with contrast medium through the abdomen, and this is followed by an intravenous contrast medium enhanced scan with a 70-second delay. All results were reviewed and interpreted by experienced attending radiologists to determine tumor size, location, and presence of bilateral disease. If the contralateral adrenal gland was described as enlarged or equivocal, AVS was performed. AVS Procedures All AVS procedures were done by one of five interventional radiologists,

3 68 Adrenal Venous Sampling for Hyperaldosteronism before Adrenalectomy January 2008 JVIR each with more than 10 years of experience. The adrenal veins were catheterized sequentially via a right common femoral approach in all cases. Initially, a 5-F Cobra 2 catheter (Cook, Bloomington, Ind) with an added side hole near the tip was used to select either adrenal vein. A small amount of nonionic contrast medium was gently injected by hand to verify proper location of the catheter. Diagnostic adrenal venography was not performed. If the catheter configuration was unsuccessful, an alternative catheter was used, such as a 5-F Sos catheter (Cook) for the right adrenal vein or a 5-F Simmons 1 catheter (Cordis, Warren, NJ) for the left. In some instances, a high-flow coaxial microcatheter was helpful to recover samples. Immediately after samples were obtained, they were labeled and sent for aldosterone and cortisol determination. The catheter was then repositioned within the inferior vena cava (IVC), and supraadrenal and infraadrenal blood samples were drawn and sent for measurement of aldosterone and cortisol. Sampling was performed without the administration of cosyntropin (synthetic adrenocortical stimulating hormone). Sample Interpretation Successful adrenal vein catheterization was confirmed in all cases by laboratory analysis of the blood samples that showed a higher cortisol concentration in the adrenal vein compared with the IVC. To correct for asymmetric dilutional effects of caval effluent, the aldosterone/cortisol (A/C) ratios in the right and left adrenal veins were calculated. The differential between right and left A/C ratios determined lateralization of adrenal disease: an A/C ratio from a selectively sampled adrenal vein that was four or five times greater than the A/C ratio in the contralateral adrenal vein was considered diagnostic of unilateral disease. Nonlateralization was attributed to bilateral hyperplasia, which was treated medically. Statistical Methods Table 1 Comparison of Background Characteristics of Patients between Groups Student t tests, 2 tests, and Mann- Whitney U tests were used to compare the clinical presentation and outcomes of the two groups as appropriate. Statistical analysis was performed with use of commercially available Stata 9 SE software (Stata, College Station, Tex). RESULTS Variable During the study period, 30 consecutive patients who underwent only CT (ie, CT-only group) were compared with 29 consecutive patients who underwent CT and AVS (ie, CT/AVS group). The preoperative clinical characteristics of the two groups were similar in terms of age at operation, sex, duration of hypertension, number of preoperative antihypertensive medications, location of tumor, and clinical and laboratory findings. Preoperatively, the tumor size was significantly larger in the CT-only group than in the CT/AVS group (1.89 cm vs 1.10 cm; P.05). All 30 patients in the CT-only group had unilateral tumors at least 1.0 cm in diameter, compared with only six of 29 patients (20.7%) in the CT/AVS group (P.05; Table 1). Among the patients in the CT/AVS group, nine of 29 (31.0%) had no tumor identified on CT, five (17.2%) had unilateral tumors smaller than 1.0 cm, 12 (41.4%) had tumors at least 1.0 cm in size, and three (10.3%) had bilateral tumors on CT. Six of the 12 patients (50.0%) who had tumors at least 1.0 cm CT Only (n 30) CT/AVS (n 29) P Value Mean age SD (y) Sex (%) Male Female Years of hypertension No. of antihypertensive medications Location (%) Right Left Size Resolution Unilateral (%) Clinical systolic blood pressure (mm Hg) Clinic diastolic blood pressure (mm Hg) Potassium (meq/l) Aldosterone (ng/dl)* 54.4 (14 140) 39.9 (17 139).85 Renin (ng/ml/h)* 0.25 ( ) 0.30 ( ).53 Aldosterone/renin ratio* 172 (11 720) 173 ( ).12 Note. Values presented as median and range where applicable. * Mann-Whitney U test. in size had equivocal findings in the contralateral adrenal gland. The sensitivity of CT for correct lateralization of adrenal tumors smaller than 1.0 cm was 67%, compared with 83% when combined with AVS. Five patients with unilateral tumors at least 1.0 cm in size on a cross-sectional view requested AVS before adrenalectomy. Two patients (6.9%) underwent repeat AVS as a result of inadequate cannulation of the right adrenal vein. When the outcomes for the two groups were compared 6 months postoperatively, systolic and diastolic blood pressure were similar in both groups, as were the number of antihypertensive medications and plasma aldosterone levels (Table 2). Serum potassium levels normalized in both groups at 1 month. After adrenalectomy, paired analysis showed that blood pressure and serum potassium and aldosterone improved significantly in both groups, and that the number of antihypertensive medications was reduced (Table 3). Subset analysis of the 29 patients who underwent AVS showed that 23 (79.3%) had improved blood pressure control together with a reduction in the number of hypertensive medications, four (13.8%) had improved blood pressure control with the same

4 Volume 19 Number 1 Zarnegar et al 69 Table 2 Postoperative Outcomes in Patients with Primary Aldosteronism Variable number of medications, and two (6.9%) had neither improvement in blood pressure control nor reduction in the number of medications. The adrenal vein to IVC cortisol ratio was at least 3 in seven of 29 patients (24.1%), at least 2 in 13 patients (44.8%), and at least 1 in 21 patients (72.4%). Eight patients had an adrenal vein to IVC cortisol ratio of less than 1 (27.6%). Of these, five had an abnormal CT finding that was used together with the AVS ratio to lateralize for CT Only (n 30) CT/AVS (n 29) P Value Blood pressure (mm Hg) Postoperative Systolic Diastolic At 1 month Systolic Diastolic At 6 months Systolic Diastolic Hypertensive medications Laboratory studies Postoperative Potassium (meq/l) Aldosterone (ng/dl)* 4.0 (1 17) 6.5 (2 39).12 At 1 month Potassium (meq/l) Aldosterone (ng/dl)* 7.0 (3 50) 9.2 (6 41.4).51 Potassium at 6 months Note. Values presented as means SD and medians with ranges where applicable. * Mann-Whitney U test. Table 3 Comparison of Clinical Parameters before and after Treatment Variable Before Operation After Operation CT only group (n 30) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Number of antihypertensive medications Plasma potassium (meq/l) Plasma aldosterone (ng/dl)* 54.4 (14 140) 4.0 (1 17) CT/AVS group (n 29) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Number of antihypertensive medications Plasma potassium (meq/l) Plasma aldosterone (ng/dl)* 39.9 (17 138) 6.5 (2 39) Note. All P values.001. Values presented as means SD and medians with ranges where applicable. * The Mann-Whitney U test was used when values were not normally distributed. surgery. Four of these five (80%) had improved blood pressure control and a reduction in number of antihypertensive medications postoperatively, whereas one had improved blood pressure control but still required the same number of antihypertensive medications. Of the three patients with normal CT findings, one had improved blood pressure control but still required the same number of antihypertensive medications after adrenalectomy and the remaining two patients had improved blood pressure control and a reduction in the number of antihypertensive medications. In these patients, the side of adrenalectomy was determined by AVS A/C ratios alone. In total, three patients (5%) had no benefit from adrenalectomy (one in the CT-only group and two in the CT/ AVS group), whereas six patients (10%) had a partial response with improved blood pressure control or a reduction in medications (two in the CTonly group and four in the CT/AVS group). Of the three patients who continued to have poor blood pressure control and no reduction in antihypertensive medications, possible explanations include discordant CT and AVS findings (n 1), failed cannulation (n 1), and long-standing chronic hypertension (n 1). Of the six patients who exhibited a partial benefit from surgery, one had a reduction in the number of medications required for blood pressure control and five had better control of blood pressure with the same number of medications. Postoperative plasma aldosterone levels were in the normal range in five of six patients (one patient was not tested) and hypokalemia resolved within 1 month of surgery in all six patients. The average duration of hypertension in these six patients was 13.2 years (range, 6 20 y). Therefore, underlying essential hypertension seems a likely explanation for the partial response to surgery. DISCUSSION Primary aldosteronism secondary to an aldosterone-producing adenoma is a curable cause of secondary hypertension that leads to improved blood pressure control and prevention of further cardiac sequelae caused by hyperaldosteronism (27). Before a patient undergoes adrenalectomy, aldosterone-producing adenoma should be distinguished from idiopathic bilateral hyperplasia. The present study evaluates postoperative outcomes after 6 months of follow-up. The results suggest that, irrespective of age, patients with unilateral adrenal tumors that are at least 1.0 cm in diameter on CT do not need AVS before adrenalectomy. In 90% of patients with unilateral tumors at least 1.0 cm in size, regardless of the addi-

5 70 Adrenal Venous Sampling for Hyperaldosteronism before Adrenalectomy January 2008 JVIR tional information provided by AVS, blood pressure control improved and the number of antihypertensive medications was reduced. In another 6.7%, blood pressure control improved or the number of antihypertensive medications was reduced. Only one patient (3.3%) had neither improved blood pressure control nor reduction in number of antihypertensive medications. Our results may seem to differ from those of a recent publication by Young et al (26) that recommended AVS for patients at least 40 years of age with solitary unilateral adrenal tumors larger than 1.0 cm, but we used defined inclusion criteria together with resolution of CT scanning. In patients with unilateral tumors smaller than 1.0 cm on CT, AVS did provide important additional information to guide the lateralization of the aldosteroneproducing adenoma. In patients with bilateral adrenal tumors, patients with normal-appearing adrenal glands, and patients with equivocal findings in the adrenal glands on CT, lateralization by AVS led to improved blood pressure control and/or reduced antihypertensive medication requirements in 95.6% of patients after adrenalectomy. These results are consistent with previous reports that CT has a sensitivity of 58% 75% in the detection of adrenal adenomas (28,29) and high-resolution CT scanning may have a sensitivity approaching 80% 100% in distinguishing between aldosterone-producing adenoma and idiopathic hyperaldosteronism (30 32). However, recently, one group found a high degree of inaccuracy with CT and reported that AVS altered management in one third of cases, leading to the recommendation that AVS be used for routine management of primary aldosteronism (33). As a result, some authors regard AVS as a gold-standard method to differentiate these two conditions that should be used routinely before adrenalectomy (24 26). In our experience, AVS had to be repeated in 6.9% of patients as a result of inadequate sampling. This is consistent with previously published reports of a complication rate of 2.5% from the procedure, with the most important reported complications being groin hematoma and adrenal hemorrhage (26). At our institution, we perform preoperative AVS if CT indicates bilateral tumors, CT findings are equivocal (ie, no tumor identified), or rarely at patient request despite the presence of a unilateral tumor larger than 1 cm in diameter. We have previously shown that this selective approach results in good biochemical and clinical outcomes (34), but the follow-up period was too short to assess whether blood pressure stabilized. This new data based on longer follow-up suggests that, with the selective use of AVS, 84.7% of patients have improved blood pressure control and a reduction in number of antihypertensive medications, 10.2% of patients have improved blood pressure control or a reduction in number of antihypertensive medications, and only 5.1% of patients have neither improved blood pressure control nor reduction in number of hypertensive medications. Seven of 29 patients referred for selective catheterization had an adrenal vein cortisol to IVC cortisol ratio greater than 3 (24.1%). Even though this ratio was not achieved in 22 of 29 patients, interpretable data from 20 patients allowed determination of the subtype of primary aldosteronism and facilitated accurate lateralization of surgically correctable disease. Therefore, 93% of patients who underwent AVS in our study had correct differentiation of hyperaldosteronism. Other groups have reported successful bilateral AVS rates of 75% 100% (20,26,32, 35). The discrepancy between our rate of successful cannulation and those of previous reports may be a result of the routine use of adrenocorticotropic hormone stimulation before sampling in other centers. Carr et al (35) showed that, without adrenocorticotropic hormone stimulation, an adrenal vein to IVC cortisol ratio greater than 3 is achieved in only 18.2% of patients, and lateralization based on the A/C ratio provided contradictory or confounding information in 27% of patients. The right adrenal vein may be especially difficult to catheterize because it enters the IVC at an acute angle. The associated failure rate for successful catheterization of this vessel has been reported to be 26% (26). It has been suggested that, in patients with aldosterone-producing adenoma or primary adrenal hyperplasia, the A/C ratio for the nondominant adrenal gland is less than the corresponding ratio for the peripheral vein (20,30). Our results partly agree with this finding. We found that contralateral adrenal vein A/C ratios were less than the ratios in the IVC in 20 of 29 patients with aldosterone-producing adenoma (69.0%). However, the nondominant adrenal vein A/C ratios cannot be relied on to predict a unilateral source of excess aldosterone. Of the 29 AVS procedures performed, five of six patients (83%) with partial or no improvement in blood pressure control or number of antihypertensive medications had a nondominant A/C ratio that was less than the ratio in the IVC. Also, eight of 23 patients with improved blood pressure control and reduction in number of antihypertensive medications did not have a nondominant A/C ratio that was less than the ratio in the IVC. There are several limitations to this study. First, because of the low prevalence of primary aldosteronism, the number of patients undergoing adrenalectomy for primary aldosteronism in a single institution like ours is small, which limited our ability to test for significant differences between subgroups of patients. A larger multicenter study would provide the necessary statistical power to differentiate between subsets of patients with tumors that are at least 1.0 cm in size, smaller than 1.0 cm, or bilateral. Another limitation is the low adrenal vein to IVC cortisol ratio. Only 24.1% of patients who underwent AVS had an adrenal vein to IVC cortisol ratio of at least 3. The reason for this may be that cosyntropin (an adrenocorticotropic hormone analogue) stimulation was not used routinely at our institution during the study period. We are presently initiating an investigation of the outcome of AVS with cosyntropin stimulation. In conclusion, our study provides evidence that CT alone can reliably lateralize an aldosterone-producing adenoma at least 1.0 cm in diameter and, when used as a guide for adrenalectomy, is associated with excellent clinical outcomes. We believe that AVS may be used selectively for patients with bilateral tumors or tumors smaller than 1.0 cm or for equivocal CT studies, and that the clinical benefit of adrenalectomy is similar in this group of patients. The aldosterone ratio in the two adrenal veins can be

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