Selective Use of Adrenal Venous Sampling in theLateralization of Aldosterone-producingAdenomasYah Yuen Tan, MB, Jennifer B. Ogilvie, MD, Frederick Triponez, MD, Nadine R. Caron,

MD,1 Electron K. Kebebew, MD,1 Orlo H. Clark, MD, Quan-Yang Duh, MD

Department of Surgery, 4150 Clement Street, University of California San Francisco, San Francisco, California 94121, USA

Abstract

Introduction: It has been suggested that routine adrenal venous sampling (AVS) is necessary to

lateralize an aldosterone-producing adenoma in patients with primary hyperaldosteronism. How-

ever, the success rate of AVS is variable, with potential risks. We review our experience at

University of California San Francisco (UCSF), where AVS is used only selectively, to determine

outcomes with this approach.

Methods: All patients undergoing adrenalectomy for aldosteronoma at UCSF from January 1995

to October 2004 were included. Outcome after adrenalectomy was determined based on plasma

levels of aldosterone and potassium, rates of persistent hypertension, and reduced use of anti-

hypertensive medications.

Results: Altogether, 65 patients were included in the study, 52 (80%) of whom had their adrenal

tumors lateralized based on computed tomography scans, magnetic resonance imaging, or both.

The remaining 13 (20%) patients had doubtful localization of their lesions on imaging. We did not

routinely perform AVS in patients with definitive imaging findings. Thus, only 4 (8%) patients with

definitive imaging findings underwent AVS, and one was unsuccessful. Of the 13 patients with

doubtful lateralization on imaging, 8 underwent AVS. With this practice, biochemical cure rates

after adrenalectomy were up to 100%, and hypertension resolved or was improved in 85% of

patients.

Conclusions: AVS may be performed selectively only when preoperative imaging cannot defini-

tively lateralize the aldosteronoma. This practice in our center has resulted in high cure rates.

During the era of improved imaging resolution and experience, mandatory routine AVS is not

necessary to achieve high cure rates for aldosteronomas.

The major causes of primary hyperaldosteronism are

aldosterone-producing adenomas (APAs) (aldoste-

ronomas) and idiopathic hyperaldosteronism (IHA). Pre-

viously, up to 60% of primary hyperaldosteronism has been

attributed to APAs and 34% to IHA.1 However, with

increasing biochemical screening of hypertensive patients

for hyperaldosteronism, more patients are now being

diagnosed as having IHA and fewer as having an aldos-

teronoma.2,3 It is important to distinguish between these

two entities because aldosteronoma is treated surgically

whereas IHA is treated medically. Patients with aldoster-

onoma can be potentially cured of the secondary hyper-

tension by removing the hypersecreting adrenal tumor.

This work was presented at the meeting of the International Associ-ation of Endocrine Surgeons in Durban, South Africa, August 22, 2005.

Correspondence to: Quan-Yang Duh, MD, Surgical Service, VAMedical Center, 4150 Clement Street, San Francisco, CA 94121 , USA,e-mail: quan-yang.duh@med.va.gov

� 2006 by the Societe Internationale de Chirurgie World J Surg (2006) 30: 879–885

Published Online: 17 April 2006 DOI: 10.1007/s00268-005-0622-8

Because nonfunctioning adrenal cortical tumors are

commonly found as incidentalomas, they may lead to a

presumptuous erroneous diagnosis of aldosteronoma in

patients with IHA. Some endocrinologists and surgeons

have therefore advocated that adrenal venous sampling

(AVS) be performed routinely in patients suspected of

having an aldosteronoma to lateralize a hypersecreting

tumor definitively before adrenalectomy.4–6 It is argued

that this can avoid resecting a nonfunctioning adrenal

tumor, which cannot cure patients with IHA. On the other

hand, AVS is an invasive procedure with risks of failure

and complications, and its results are highly dependent

on the expertise of the radiologist.

We do not routinely perform venous sampling in pa-

tients with hyperaldosteronism who have a unilateral

adrenal tumor on imaging studies. We reviewed our re-

sults to determine whether selective use of AVS can

achieve a success rate similar to that seen with routine

use of venous sampling.

MATERIALS AND METHODS

At the University of California San Francisco (UCSF),

we maintain a prospective database of all patients

undergoing endocrine surgery. From this database we

identified all patients undergoing adrenalectomy for a

preoperative diagnosis of aldosteronoma. All adrenalec-

tomies for aldosteronomas were performed laparoscopi-

cally, with most being performed by a single endocrine

surgeon.

Data collected and analyzed were demographics, pre-

operative biochemical markers including serum levels of

potassium and the aldosterone/renin ratio (plasma aldo-

sterone level divided by plasma renin activity), imaging

modality and whether a definite unilateral adrenal mass

was seen, and whether venous sampling was performed,

if it was successful, and if the results affected patient

management. Adrenal venous sampling was performed

by interventional radiologists, usually without subjecting

the patient to adrenocorticotropin stimulation. Blood was

sampled from the adrenal veins, renal veins, and inferior

vena cava above and below the renal veins. The samples

were obtained to measure cortisol and aldosterone levels.

The adrenal vein sampling was considered unsuccessful

if the sample had only the low background serum level of

cortisol. Both adrenal veins must be catheterized suc-

cessfully for the procedure to be considered successful.

Only 1 of 12 venous samplings was unsuccessful in this

series.

The general protocol for the diagnostic workup for pa-

tients suspected of having an APA is shown in Figure 1.

As a general rule, AVS was not routinely performed if the

surgeon was confident that the preoperative scan had

accurately lateralized the functioning adrenal tumor.

To determine if the patient was cured of hyperaldos-

teronism after adrenalectomy, we followed the biochem-

ical and clinical markers. Postoperative plasma

aldosterone and potassium levels were used as bio-

chemical indicators of cure, whereas the resolution of

hypertension, reduced use of antihypertensive medica-

tions, or both were used as clinical indicators. These

markers were evaluated at the first follow-up visit, usually

2 to 4 weeks after adrenalectomy. Because this was a

retrospective study, the postoperative biochemical and

clinical markers could not be obtained for some patients.

The cure rates were calculated using only patients from

whom we had the data.

The patients were divided into two groups based on

whether the preoperative imaging scan definitively later-

alized the adrenal mass. Definitive lateralization of the

adrenal tumor was defined as the presence of a definite

mass in the adrenal gland on a preoperative computed

tomography (CT) scan or magnetic resonance imaging

(MRI) scan with a normal contralateral gland. All other

patients were considered to have doubtful lateralization of

the tumor. They included patients in whom both adrenal

glands were normal, both were abnormal, or when only

prominent adrenal limbs were seen.

These two groups of patients were further subdivided

as to whether venous sampling was performed. The

biochemical and clinical cure rates for each subgroup of

patients were then analyzed and compared.

RESULTS

A total of 91 consecutive patients underwent adrenal-

ectomy for preoperative diagnosis of aldosteronoma from

January 1995 to October 2004 at UCSF. Among them, 26

patients were excluded because of insufficient clinical

information available from the medical records for anal-

ysis, almost all of whom had undergone adrenalectomy

prior to the year 2000.

Of the 65 patients included in the study, there were 39

men and 26 women, a ratio of 1.5:1.0. The median age

was 56.0 years (range 20–74 years) (Table 1). Among

the 65 patients, 28 (43%) had uncontrolled hypertension

despite multiple antihypertensive medications, and 52

(80%) had hypokalemia at presentation. The median

serum aldosterone level was 35.3 ng/dl (9–650 ng/dl),

880 Tan et al.: Adrenal Venous Sampling

and 90% (45/50) of the patients had an aldosterone/renin

ratio higher than 30.

Of the 65 patients, 58 (89%) had had a CT scan of the

adrenals first, and 7 patients (11%) had had an MRI first.

Three patients (5%) had undergone both MRI and CT,

and one patient had had an iodocholesterol scan. A total

of 56 patients (86%) had a definite unilateral adrenal

mass on imaging; 7 patients (11%) had only a unilateral

adrenal prominence, and 2 (3%) patients had normal

adrenal glands seen by CT scanning. The mean size of

the adrenal mass seen on preoperative CT scans or MRI

was 1.60 cm (0.4–3.8 cm).

Most (91%) of the contralateral adrenal glands were

reported as normal on preoperative imaging. Five pa-

tients had a prominent contralateral adrenal gland; three

were in patients with a definite adrenal mass on the

opposite side (eventually the operated side), and two had

prominent adrenal glands bilaterally. One patient had

bilateral adrenal masses measuring 1.8 and 1.2 cm,

respectively. Overall, based on the preoperative imaging

scans, 52 (80%) patients had definitive lateralization of

the adrenal tumor, and 13 (20%) had doubtful lateraliza-

tion after imaging.

Adrenal venous sampling was performed in 12 (18%)

patients, 8 of whom had doubtful lateralization on pre-

operative imaging (Fig. 2). The remaining four patients

had venous sampling despite having had definitive lat-

eralization of the adrenal mass preoperatively. One pro-

cedure was deemed unsuccessful owing to failed

catheterization of the right adrenal vein. The remaining 11

procedures successfully lateralized the hypersecreting

adrenal gland.

Cure rates were assessed based on biochemical and

clinical parameters as described above. Among the 52

patients with definitive lateralization, 4 patients underwent

adrenal venous sampling, with one procedure unsuc-

cessful. For theis group of 49 patients without lateraliza-

tion by AVS, overall biochemical cure rates based on the

Figure 1. Diagnostic workup of patientssuspected of having an aldosteronoma.

Tan et al.: Adrenal Venous Sampling 881

plasma aldosterone and potassium levels were 87% and

100%, respectively (Table 2). Altogether, 46% of patients

had normalized blood pressure, and an additional 39%

had their antihypertensive medications reduced. Hence

overall improvement in blood pressure control was

achieved in 85% of patients. Only three patients with

definitive lateralization of imaging scans underwent suc-

cessful AVS. Of these three patients, two had normalized

blood pressure; the remaining patient also achieved

blood pressure control with fewer medications. All three

had normal potassium and aldosterone levels after the

adrenalectomy.

Among the 13 patients with doubtful lateralization on

CT/MRI, 8 underwent successful AVS; and in this group

of 8 patients, the biochemical cure rates were 84%

(aldosterone) and 88% (potassium) (Table 3). Clinically,

29% had normalized blood pressure after adrenalectomy,

and an additional 57% had improved blood pressure

control with fewer medications. Of the five patients with

doubtful lateralization based on imaging who did not un-

dergo venous sampling, all were cured of hypokalemia,

but all had persistent hypertension; only one of the five

had lower antihypertensive requirements.

Comparing cure rates between patients with and with-

out preoperative venous sampling, the biochemical cure

rates based on the potassium level were 91% (with

sampling) versus 100% (without sampling). Based on the

aldosterone level, the cure rates were 88% versus 85%,

for persistent hypertension they were 60% versus 57%,

and for reduced antihypertensive medication use they

were 50% versus 38%.

DISCUSSION

Aldosteronomas are aldosterone-secreting adrenal

tumors that cause uncontrolled hypertension and hypo-

kalemia. Treatment is surgical excision. Aldosteronomas

should be clearly distinguished from IHA and nonfunc-

tioning adrenal cortical tumors, neither of which requires

resection. IHA affects the adrenal glands bilaterally and

should be treated medically. Nonfunctioning adrenal

cortical tumors occur in 1% to 4% of the population

undergoing CT scans of the abdomen.7 In patients with

hyperaldosteronism, they may be mistakenly diagnosed

as a hypersecreting aldosteronoma, leading the surgeon

to excise the adrenal gland unnecessarily. Several re-

ports have described patients with a nonfunctioning

adrenal cortical adenoma on one side and an aldostero-

noma on the other.8–10

In a patient with primary hyperaldosteronism confirmed

biochemically, a CT scan (or MRI) is the first step in

finding the adrenal tumor. In 65% to 95% of these pa-

Table 1.Characteristics of the study group of 65 patients

Parameter Results No. of patients

SexMale 39 (60%)Female 26 (40%)

Median age (years) 56 (20–74)Hypertension

Uncontrolled 28 (43%)Controlled 36 (55%)None 1 (2%)

PotassiumLow 52 (80%)Normal 13 (20%)Mean (mmol/L) 3.17 (2.5–4.7)

Median aldosteronelevel (ng/dl)

36.0 (9–650)

Median renin level(ng/ml/hr)

0.39 (0.02–3.00)

Median aldosterone/reninratio

112.7 (7–710)

CT/MRI scansIpsilateral mass 56 (86%)Ipsilateral prominence 7 (11%)Ipsilateral normal 2 (3%)Contralateral mass 1 (2%)Contralateral prominence 5 (8%)Contralateral normal 59 (91%)Median tumor size (cm) 1.60 (0.4–3.8)

SurgeryRight 23 (35%)Left 42 (65%)

PathologyAdenoma 53 (82%)Hyperplasia 10 (15%)Others 2 (3%)

Postoperative results(overall)

PotassiumNormal 63 (98%)Low 1 (2%)Unknown 1

AldosteroneNormal 35 (85%)High 6 (15%)Unknown 24

HypertensionControlled 48 (92%)Not controlled 4 (8%)Unknown 13

Antihypertensive medicationReduction 23 (44%)Off 22 (42%)Same 7 (14%)Unknown 13

882 Tan et al.: Adrenal Venous Sampling

tients, the scans can detect a tumor in the adrenal gland

that is likely to be the cause of hyperaldosteronism.11–15

In addition, AVS for aldosterone and cortisol can confirm

the laterality of the hypersecreting adrenal tumor. Some

investigators advocate more liberal usage of venous

sampling,4–6 whereas others argue that venous sampling

should be performed selectively.14,15 Venous sampling is

a technically challenging procedure because of the diffi-

culty catheterizing the right adrenal vein. Failure rates

depend on the experience of the interventional radiolo-

gist6 and may be up to 10%.6,16,17 A complication rate of

up to 3.6% has also been reported.18

Because aldosteronomas are usually extremely small,

older imaging studies could not identify them with high

sensitivity. During the past decade, however, the tech-

nology of soft tissue imaging has improved significantly.

Aldosteronomas have been diagnosed with greater

accuracy using thin-collimation CT.19 Low attenuation on

unenhanced CT scans19,20 and rapid washout of contrast

on an enhanced scan19 are diagnostic of an adenoma,

although it does not distinguish between functioning and

nonfunctioning adenomas. Adrenal gland limb measure-

ments have also been described for differentiating be-

tween an aldosteronoma and IHA; a mean limb width of

‡5 mm was thought to be 100% specific for bilateral

adrenal hyperplasia.21

Magnetic resonance imaging can also be used to

complement CT scan findings with high accuracy.15

Other tests, such as the postural test (to distinguish be-

tween aldosteronoma and IHA) and adrenal scintigraphy

(to look for unilateral increased uptake of iodo-choles-

terol), are much less frequently used.

Because CT scanning and MRI are quick and effective,

some suggest that venous sampling should be performed

Figure 2. Flow chart of the study group of 65patients.

Table 2.Cure rates after surgery by imaging findings

ParameterDefinitive AVS

(n = 3)Lateralization no AVS

(n = 49)Doubtful AVS

(n = 8)Lateralization no

AVS (n = 5)Overall(n = 65)

Potassium cure rate 3/3 (100%) 48/48 (100%) 7/8 (88%) 5/5 (100%) 63/64 (97%)Aldosterone cure rate 2/2 (100%) 26/30 (87%) 5/6 (83%) 2/3 (67%) 35/41 (85%)Persistent hypertension 1/3 (33%) 21/39 (54%) 5/7 (71%) 3/3 (100%) 30/52 (58%)Less antihypertensives 1/3 (33%) 15/39 (39%) 4/7 (57%) 1/3 (33%) 23/52 (44%)BP normalized 2/3 (67%) 18/39 (46%) 2/7 (29%) 0/3 22/52 (42%)

AVS: adrenal venous sampling; BP: blood pressure.

Table 3.Cure rates after surgery by adrenal venous sampling

Parameter AVS done (n = 11) AVS not done (n = 54)

Potassium cure rate 10/11 (91%) 53/53 (100%)Aldosterone cure rate 7/8 (88%) 28/33 (85%)Blood pressure normalized 4/10 (40%) 18/42 (43%)Less antihypertensive medication 5/10 (50%) 16/42 (38%)

Tan et al.: Adrenal Venous Sampling 883

only when clinical, biologic, and CT scan features are not

fully concordant.15,18,22 Venous sampling has also been

suggested for patients with primary hyperaldosteronism if

the adrenal tumor is <1 cm on the CT scan.14

Other authors, however, advocate routine venous

sampling with only rare exceptions. Because adrenal in-

cidentalomas are more common in older patients,23

Young3 recommended routine venous sampling for all

patients older than 40 years. For patients younger than

40, in whom a solitary adenoma >1 cm and normal con-

tralateral adrenal gland are seen on CT scan, a unilateral

adrenalectomy may be offered without venous sampling.

Young et al.4 further justified using venous sampling as

an essential diagnostic step to distinguish between uni-

lateral and bilateral aldosterone hypersecretion. In these

Mayo Clinic series, if the diagnosis was based on CT

scans alone, 48 of 203 patients (24.7%) would have had

an unnecessary adrenalectomy. In 36 of these patients,

the CT scan suggested a unilateral aldosteronoma,

whereas AVS revealed bilateral hypersecretion. In the

other 12 patients, venous sampling showed the hy-

persecreting gland to be contralateral to that suggested

by the CT scan.

In a another series of 25 patients, McAlister and

Lewanczuk5 reported that CT scans had a sensitivity of

100% for diagnosing aldosteronomas, but the specificity

was only 58% and the positive predictive value was only

72%. Altogether, 18 of the patients had adrenal masses

visualized on CT scans, but only 13 had an aldostero-

noma by venous sampling. The remaining 5 patients had

bilateral adrenal hyperplasia with nonfunctioning adrenal

tumors. The likelihood ratio for the diagnosis of an

aldosteronoma in patients with primary hyperaldostero-

nism and an adrenal mass on CT scan was calculated to

be only 2.4 in this series. Hence the authors recom-

mended full biochemical and physiologic testing before

offering adrenalectomy to patients suspected of having

an aldosteronoma.

Similarly, Magill et al.24 described another series of 38

patients with CT scans that were either inaccurate or

provided no useful information in 68% of the patients with

primary hyperaldosteronism. They concluded that CT

imaging was not reliable for differentiating the etiology of

primary aldosteronism and that venous sampling was

essential to establish the correct etiology on which to

base management decisions.

The UCSF protocol for managing patients with pri-

mary hyperaldosteronism does not require routine use

of AVS in the preoperative workup if a definite mass is

seen on CT or MRI scans. This is the case in more

than 80% of the patients. On the other hand, when CT

or MRI scans show only normal adrenal glands, only

an adrenal prominence, or bilateral adrenal abnormali-

ties, venous sampling is necessary to determine if

there is a unilateral hypersecreting adrenal gland and

on which side it is located. This selective approach is

supported by others, with the accuracy of CT imaging

for diagnosing aldosteronoma ranging from 75% to

95%.14,15,25

In our current series of 65 patients, 86% had a definite

adrenal mass on preoperative scanning. Hence fewer

than one in five patients would require an additional

angiographic procedure to localize the adrenal tumor

based on our protocol. Using this selective approach, our

cure rate for primary hyperaldosteronism is comparable

to that in other series. Among 49 patients with CT findings

of an adrenal mass without AVS, 100% were cured of

hypokalemia, and 46% had normalized blood pressure.

Of the remaining patients with persistent hypertension, 15

of 21 patients were on fewer antihypertensive drugs than

before the operation. These percentages are not different

from the those found for the subset of 11 patients who

had successful venous sampling regardless of CT

findings. In this subset, 40% had normalized blood

pressure; five of six of the remaining patients with per-

sistent hypertension had reduced antihypertensive drug

requirements.

Our cure rates with this approach are similar to that

described by others. Normalization of blood pressure was

seen in 28% to 77%.25–31 In those with residual hyper-

tension after adrenalectomy, fewer antihypertensive

drugs were required in 76% to 92%28–31 Hypokalemia

was cured in up 95% to 100% of patients.29,30,32 Other

series have found that factors related to persistent

hypertension included a long duration of hypertension

before operation,28,30,32 the severity of preoperative

hypertension,27,32 a family history of hypertension,27,32

lesser response to spironolactone,26,31,32 and older

age.25,26,32

CONCLUSIONS

Although AVS is useful for confirming the laterality of an

aldosteronoma, it is invasive and not always necessary if

preoperative imaging scans have definitively localized an

adrenal mass with a normal contralateral adrenal gland.

Following a selective approach to venous sampling (used

in fewer than 20% of patients), we have success rates

comparable to those reported by centers advocating

routine venous sampling.

884 Tan et al.: Adrenal Venous Sampling

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