AJR 2003; 181:843-849
© American Roentgen Ray Society
CT of Primary Hyperaldosteronism (Conn's Syndrome): The Value of Measuring the Adrenal Gland
R. K. Lingam1,
S. A. Sohaib1,
I. Vlahos1,
A. G. Rockall1,
A. M. Isidori2,
J. P. Monson2,
A. Grossman2 and
R. H. Reznek1,3
1 Department of Diagnostic Imaging, St. Bartholomew's Hospital, West Smithfield,
London EC1A 7BE, United Kingdom.
2 Department of Endocrinology, St. Bartholomew's Hospital, London EC1A 7BE,
United Kingdom.
3 Academic Department of Radiology, St. Bartholomew's Hospital, Dominion House,
London EC1A 7BE, United Kingdom.
Received December 23, 2002;
accepted after revision March 10, 2003.
Presented in part at the annual meeting of the American Roentgen Ray
Society, Atlanta, April-May 2002.
Address correspondence to R. H. Reznek.
Abstract
OBJECTIVE. The objectives of our study of patients with primary
hyperaldosteronism (Conn's syndrome) were to determine whether the adrenal
glands are larger in patients with bilateral adrenal hyperplasia than in those
with aldosterone-producing adenomas or in healthy control subjects; and
whether a CT criterion based on adrenal gland size can be developed to
positively diagnose bilateral adrenal hyperplasia.
MATERIALS AND METHODS. A retrospective study of CT scans of 28
patients with primary hyperaldosteronism was performed. The means of two
observers' measurements of adrenal gland size were recorded and compared with
published normal values. In addition, a radiologist experienced in adrenal
imaging and unaware of the cause of the primary hyperaldosteronism diagnosed
either bilateral adrenal hyperplasia or aldosterone-producing adenoma by
visual inspection.
RESULTS. The adrenal glands in patients with bilateral adrenal
hyperplasia were significantly (p < 0.05) larger than those in
patients with aldosterone-producing adenoma or in healthy control subjects. A
sensitivity of 100% was achieved when a mean limb width of greater than 3 mm
was used to diagnose bilateral adrenal hyperplasia, and a specificity of 100%
was achieved when the mean limb width was 5 mm or greater. Receiver operating
characteristic curve analysis showed that the overall performance of the
radiologist and the mean adrenal limb width in detecting bilateral adrenal
hyperplasia were equivalent.
CONCLUSION. In patients with primary hyperaldosteronism, adrenal
limb measurements on CT can aid in differentiating bilateral adrenal
hyperplasia from aldosterone-producing adenoma because the adrenal glands in
bilateral adrenal hyperplasia are larger.
Introduction
Primary hyperaldosteronism (Conn's syndrome) is a disorder characterized by
aldosterone excess with suppressed renin activity that results in hypertension
and, usually, hypokalemia. The two principal causes of this disorder are
aldosterone-producing adenoma and bilateral adrenal hyperplasia
[1]. Differentiating between
these two causes is important because an aldosterone-producing adenoma is
usually best treated surgically, whereas bilateral adrenal hyperplasia is
generally managed medically
[1]. Biochemical
differentiation is often imprecise
[2]. CT is widely used to
differentiate between the two entities; until now, the diagnosis of bilateral
adrenal hyperplasia has been made by excluding the presence of an adenoma on
such imaging. However, the sensitivities and specificities recorded in the
literature for the detection of an adenoma vary widely, ranging from 71% to
100% and from 33% to 100%, respectively, and if the imaging results are
equivocal, adrenal venous sampling is indicated for further evaluation
[2-9].
There is no CT criterion based on adrenal size to differentiate between
adenoma and bilateral adrenal hyperplasia in patients with primary
hyperaldosteronism. We previously documented normative adrenal gland sizes on
CT [10] and used these data
for comparison with adrenal size in patients with adrenal hypertrophy caused
by adrenocorticotrophic hormone-dependent Cushing's syndrome
[11]. However, adrenal gland
sizes in primary hyperaldosteronism on CT are not well documented. One of the
aims of this study was to determine whether adrenal gland size on CT is
greater in patients with bilateral adrenal hyperplasia than in those with
adenoma and compare these data with published values for healthy control
subjects [10]. Furthermore, we
wished to determine whether we could establish a CT criterion based on adrenal
size to positively diagnose bilateral adrenal hyperplasia in an attempt to
increase diagnostic accuracy in differentiating between bilateral adrenal
hyperplasia and aldosterone-producing adenoma.
Materials and Methods
A retrospective study was performed using all patients with primary
hyperaldosteronism from 1987 to 2001 in whom CT examinations were available.
The study group consisted of 28 patients (19 women and nine men; mean age, 48
years; age range, 30-71 years): 13 with aldosterone-producing adenoma and 15
with bilateral adrenal hyperplasia. The mean age of the patients with
bilateral hyperplasia (52.7 years; SD, 10.6 years) was significantly higher
than that of the patients with adenoma (43.8 years; SD, 11.6 years). Adrenal
venous sampling was not performed routinely; instead, it was performed only
when a confident radiologic diagnosis of the cause of the primary
hyperaldosteronism could not be made. All the cases of aldosterone-producing
adenomas were established by histology after surgery, as was one case of
bilateral nodular adrenal hyperplasia. In the latter, adrenal venous sampling
was not performed because a confident radiologic diagnosis of adenoma was
made. Five cases of bilateral adrenal hyperplasia were diagnosed by a good
biochemical and clinical response after medical treatment alone and by the
absence of a unilateral radiologic abnormality. Adrenal venous sampling was
additionally performed to establish the diagnosis in the remaining nine cases
of bilateral adrenal hyperplasia. CT scans were obtained on a 9800 scanner
(General Electric Medical Systems, Milwaukee, WI) from 1987 to 1993 (six
patients) and on a HiSpeed Advantage RP scanner (General Electric Medical
Systems) from 1993 onward (17 patients). Five patients had scans obtained at
their referring institutions. In all patients, 10-mm-thick unenhanced and
5-mm-thick contrast-enhanced sections were available for review.
The size of the adrenal glands was measured independently by two
radiologists who were unaware of the underlying cause for primary
hyperaldosteronism. Adrenal gland size was measured using the technique
previously described in a study for measuring normal adrenal glands on CT
[10]. The measurements were
performed on the 10-mm-collimated unenhanced CT images in order to compare
these measurements with the published historic controls
[10]. At the computer console,
the reviewers measured the maximal adrenal gland body and limb widths for each
gland (Fig. 1). The widths were
measured at the widest point at any part not involved in an obvious nodule and
perpendicular to the long axis of the body or limbs of the gland. The means of
three measurements of each limb and of the body were recorded, and the average
of the two observers' measurements was compared with normal control
measurements [10]. The mean
widths of both adrenal bodies and all the adrenal limbs were also compared in
patients with aldosterone-producing adenomas and those with bilateral adrenal
hyperplasia. In glands with aldosterone-producing adenomas, the maximum
diameter of the adenomatous nodule was also recorded. If soft-copy images were
not available, the hard-copy images together with their corresponding scales
were scanned and converted into digital images using Photo-Paint software
(version 5, Corel, Ottawa, ON, Canada) to enable measurements to be made
electronically.
The 5-mm-thick contrast-enhanced CT scans were reviewed by a radiologist
experienced in adrenal imaging and who was unaware of the cause of the primary
hyperaldosteronism. Each gland was categorized either as being a normal or
hyperplastic gland or as having an aldosterone-producing adenoma. The
diagnosis of an aldosterone-producing adenoma was made only if a single nodule
was visible with the remainder of the ipsilateral and contralateral glands
appearing smooth and not enlarged. The radiologic confidence in the CT
diagnosis of an adenoma or bilateral adrenal hyperplasia was scored on a
5-point scale with a score of 1 indicating a confident diagnosis of bilateral
adrenal hyperplasia; a score of 2, probable bilateral adrenal hyperplasia; 3,
possible bilateral adrenal hyperplasia; 4, probable aldosterone-producing
adenoma; and 5, a confident diagnosis of an aldosterone-producing adenoma.
These scores were subsequently used to perform receiver operating
characteristic curve analysis for the radiologist's diagnosis for
aldosterone-producing adenoma or bilateral adrenal hyperplasia.
Receiver operating characteristic curve analysis of the mean adrenal limb
widths and the radiologist's diagnosis for bilateral adrenal hyperplasia by
exclusion of an aldosterone-producing adenoma were compared. Statistical
analysis was performed using the Statistical Package for the Social Sciences
(version 9, SPSS, Chicago, IL). The Mann-Whitney U test for
nonnormally distributed variables and the Student's two-sample t test
for normally distributed variables were performed on various data sets, with
statistical significance considered as a p value of less than 0.05.
Tests for normality were performed using the Wilks-Shapiro test. Descriptive
statistical values including sensitivity and specificity were also
determined.
Results
A comparison of adrenal gland sizes in patients with aldosterone-producing
adenoma and in those with bilateral adrenal hyperplasia is shown in
Table 1. No significant
difference in the size of the body of the adrenal glands was detected between
aldosterone-producing adenoma and bilateral adrenal hyperplasia. However, each
adrenal limb was significantly larger in patients with bilateral adrenal
hyperplasia than in those with aldosterone-producing adenoma, and this
difference was compounded when the sums of the four limb widths were compared.
Scatterplots of the mean widths of the adrenal limbs in aldosterone-producing
adenoma and bilateral adrenal hyperplasia are shown in
Figure 2.
A comparison of adrenal size in patients with primary hyperaldosteronism
and the published values for adrenal size in healthy control subjects
[10] is shown in
Table 2. The Student's
t test was used as only the mean, and the SD value was available from
the published results. The adrenal glands in patients with bilateral adrenal
hyperplasia were also larger than in healthy control subjects
[10], with the difference
between the limb widths being more significant than that between the body
widths. A comparison of the adrenal gland sizes in aldosterone-producing
adenoma and in normal controls showed that the only statistically significant
result was the larger size of the left adrenal limbs in aldosterone-producing
adenoma.
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TABLE 2 Comparison of Sizes of Normal Adrenal Glands
[10] with Gland Sizes in
Aldosterone-Producing Adenoma and Bilateral Adrenal Hyperplasia
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Receiver operating characteristic curve analysis
(Fig. 3) showed that the
overall performance of the radiologist's diagnosis of adenoma or bilateral
adrenal hyperplasia and the mean adrenal limb width for the detection of
bilateral adrenal hyperplasia were equivalent. The area under the receiver
operating characteristic curve (Az) for adrenal limb thickness was
0.86 (standard error of the mean [SEM], 0.07), and the Az value for
the radiologist's diagnosis was 0.91 (SEM, 0.06). A specificity of 100% was
obtained when a mean adrenal limb width of 5 mm or more was used to diagnose
bilateral adrenal hyperplasia, but the sensitivity was only 47%. A sensitivity
of 100% was obtained when an adrenal limb width of greater than 3 mm was used,
but the specificity was only 54%. When the exclusion of an
aldosterone-producing adenoma was used to diagnose bilateral adrenal
hyperplasia by the radiologist, a sensitivity of 93.3% and a specificity of
84.6% were obtained.
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Fig. 3. —Receiver operating characteristic curves for radiologist
assessment of bilateral adrenal hyperplasia or aldosterone-producing adenoma
(dashed line) and using mean adrenal limb widths (solid
line) for positively diagnosing bilateral adrenal hyperplasia.
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The adenomatous nodules ranged from 1.00 to 4.75 cm in diameter, with a
mean of 2.20 cm and a median of 2.00 cm.
Discussion
The adrenal gland measurements obtained on CT in this study show that
adrenal gland limbs are significantly larger in bilateral adrenal hyperplasia
than in aldosterone-producing adenoma or normal controls. To our knowledge,
the sizes of adrenal glands in patients with primary hyperaldosteronism have
not been previously quantified or compared using CT. Our data also show that
the size of the adrenal limbs is affected more than the size of the adrenal
body in patients with primary hyperaldosteronism caused by bilateral adrenal
hyperplasia. This finding is consistent with the predominance of
adrenocortical tissue in the adrenal limbs
[12] and is also seen in
hyperplastic glands in other adrenal hyperstimulation diseases, such as
adrenocorticotrophic hormone-dependent Cushing's syndrome
[11]. Larger adrenal glands
with a similar pattern of enlargement in bilateral adrenal hyperplasia
compared with aldosterone-producing adenoma was also shown in a recent MRI
study on primary hyperaldosteronism
[13]. In that MRI study, as in
our study, only the mean limb width—and not the mean body
width—was shown to be significantly larger in bilateral adrenal
hyperplasia than in aldosterone-producing adenoma. However, in that study
these data were not compared with normal adrenal gland size measurements on
MRI. Also, the authors of that MRI study on primary hyperaldosteronism
[13] did not set out to
positively diagnose bilateral adrenal hyperplasia on MRIs, whereas we did in
this CT study.
After clinical and biochemical diagnosis of primary hyperaldosteronism, CT
and MRI are used to differentiate aldosterone-producing adenomas from
bilateral adrenal hyperplasia. Traditionally, this distinction is made by
detecting an aldosterone-producing adenoma; hence, the diagnosis of bilateral
adrenal hyperplasia is reached by exclusion. A high specificity for the
detection of an adenoma is desirable because it will avert unnecessary surgery
in patients with bilateral adrenal hyperplasia. However, as mentioned before,
there is a wide variation in the literature in the diagnostic performance for
the detection of an adenoma. Several reasons have been given for the lack of
specificity for the detection of an adenoma, including the detection of a
concomitant nonhyperfunctioning nodule, the presence of a dominant nodule in
macronodular bilateral adrenal hyperplasia, and increased nodularity with age
and hypertension [3,
14]. The lack of sensitivity,
however, has been attributed to the small size of aldosterone-producing
adenomas, which are generally less than 2.0 cm in maximal diameter
[2,
6]. In our study, the
adenomatous nodules ranged from 1.00 to 4.75 cm in diameter, with a mean of
2.20 cm and a median of 2.00 cm.
To our knowledge, no CT criterion based on adrenal size is available to
differentiate an aldosterone-producing adenoma from bilateral adrenal
hyperplasia. In light of the current findings showing that the adrenal gland
limbs in bilateral adrenal hyperplasia are significantly greater than in
aldosterone-producing adenoma, it follows that a CT criterion based on adrenal
gland limb size could help differentiate the two entities from one another by
positively identifying bilateral adrenal hyperplasia. Our study suggests an
accurate test based on adrenal limb measurements for positively identifying
bilateral adrenal hyperplasia. Receiver operating characteristic curve
analysis shows that the CT size criterion has an overall diagnostic
performance similar to that of the traditional method of diagnosing bilateral
adrenal hyperplasia by the exclusion of an adenoma. A specificity of 100% was
obtained for positively identifying bilateral adrenal hyperplasia when the
mean limb width was 5 mm or larger. However, a high sensitivity for positively
diagnosing bilateral adrenal hyperplasia is preferred, just as a high
specificity is required in diagnosing an adenoma. The use of a test with a
high sensitivity for positively diagnosing bilateral adrenal hyperplasia will
avoid unnecessary surgery in patients with bilateral adrenal hyperplasia. A
sensitivity of 100% is achieved when a mean limb width of greater than 3 mm is
used to positively diagnose bilateral hyperplasia, although this criterion
necessarily lowers the associated specificity of positively diagnosing
bilateral hyperplasia to only 54%.
We suggest a diagnostic algorithm incorporating both adrenal size
measurements and the detection of an adrenal nodule to differentiate
aldosterone-producing adenoma from bilateral adrenal hyperplasia more
accurately in patients with established primary hyperaldosteronism
(Fig. 4) so that the use of
adrenal venous sampling is limited to a smaller proportion of cases—only
those for which the diagnosis remains equivocal. By virtue of its high
specificity, this algorithm can be used to confidently positively diagnose
bilateral adrenal hyperplasia when the mean limb width is 5 mm or greater
(Fig. 5); likewise, bilateral
adrenal hyperplasia is excluded when the mean limb width is 3 mm or less, due
to the high sensitivity of positively diagnosing bilateral adrenal hyperplasia
when the mean limb width is greater than 3 mm
(Fig. 6). However, the
difficulty in making a radiologic diagnosis of bilateral adrenal hyperplasia
or adenoma arises when the mean limb width lies between 3 and 5 mm. If the
mean limb width is between 3 and 5 mm and a nodule is seen, then the diagnosis
of adenoma or nodular bilateral adrenal hyperplasia depends on the confidence
of the radiologist in detecting the presence of other nodules in either gland.
The correct distinction is especially important to avoid unnecessary surgery
in patients with nodular bilateral adrenal hyperplasia. In our series, the
four cases that fell into this category were all adenomas, and the two cases
of nodular bilateral adrenal hyperplasia were correctly detected by the size
criterion. Nevertheless, the radiologist can resort to adrenal venous sampling
when the diagnosis is in doubt. When the mean limb width is between 3 and 5 mm
and no nodule is seen, we suggest that adrenal venous sampling be used to
confirm the diagnosis, which will usually be bilateral adrenal hyperplasia. In
our series, eight cases of bilateral adrenal hyperplasia and one case of
adenoma (Figs. 7A, and
7B) fell into this
category.
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Fig. 6. —37-year-old woman with primary hyperaldosteronism due to left
aldosterone-producing adenoma. Unenhanced CT image shows 4-cm low-density
nodule (curved arrow) in left adrenal gland. Limbs (straight
arrows) are not enlarged.
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Fig. 7A. —50-year-old man with left aldosterone-producing adenoma
diagnosed on adrenal venous sampling and histology after surgery but
incorrectly diagnosed by radiologist as bilateral adrenal hyperplasia.
Unenhanced CT image of right adrenal gland shows no obvious adrenal nodule,
but its limbs (arrows) appear hyperplastic.
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Fig. 7B. —50-year-old man with left aldosterone-producing adenoma
diagnosed on adrenal venous sampling and histology after surgery but
incorrectly diagnosed by radiologist as bilateral adrenal hyperplasia.
Unenhanced CT image of left adrenal gland shows its limbs (straight
arrow) appear hyperplastic. However, mean limb width of both glands is
4.3 mm and algorithm suggests adrenal venous sampling. In retrospect, slightly
nodular appearance of medial limb (curved arrow) could represent
missed adenoma.
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Interestingly, the three cases that were mis-diagnosed by the radiologist
(one false-negative and two false-positives for bilateral adrenal hyperplasia
detected by excluding an aldosterone-producing adenoma) can be correctly
diagnosed by applying the algorithm. In all these cases, the radiologist erred
mainly on the assessment of whether the limbs were otherwise normal or
hyperplastic rather than on the detection of the nodule. The mean limb width
in the false-negative case (Figs.
8A, and
8B), where a 2.5-cm left
adrenal nodule was seen, was more than 5 mm and therefore would have been
correctly diagnosed as nodular bilateral adrenal hyperplasia using the
algorithm. In both the false-positive cases, where a nodule was not seen in
one case (Figs. 7A, and
7B), the mean adrenal limb
width was between 3 and 5 mm and the algorithm suggests adrenal venous
sampling to locate a presumed adenoma. These cases clearly illustrate the
advantage of using adrenal gland limb size measurements over visual inspection
in assessing for enlargement of the adrenal limbs.
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Fig. 8A. —43-year-old woman with histologically confirmed nodular
bilateral adrenal hyperplasia that was incorrectly diagnosed as
aldosterone-producing adenoma by radiologist. Enhanced CT image shows 2.5-cm
nodule (arrow) in left adrenal gland.
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Fig. 8B. —43-year-old woman with histologically confirmed nodular
bilateral adrenal hyperplasia that was incorrectly diagnosed as
aldosterone-producing adenoma by radiologist. Enhanced CT image obtained more
caudally shows measurably hyperplastic limbs (arrows) bilaterally
with mean limb width of 5.2 mm. Right medial limb width is 4.7 mm; right
lateral limb width, 5.1 mm; left medial limb width, 6.1 mm; and left lateral
limb width, 5.2 mm.
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When we applied the algorithm to our sample, a total of 13 of 28 patients
would have required adrenal venous sampling because a large number of cases
had mean limb widths between 3 and 5 mm. Nevertheless, the algorithm is
useful. When a nodule is seen and the mean limb width is 5 mm or greater, an
incorrect diagnosis of an adenoma (and unnecessary surgery) will be avoided.
Conversely, with no visible nodule and a mean limb width of 3 mm or less,
adrenal venous sampling to locate a presumed adenoma should be recommended.
The algorithm highlights the value of limb width measurements in managing
patients with primary hyperaldosteronism. Although all the cases in our series
would have been correctly managed using our proposed diagnostic algorithm,
further validation of the algorithm is required because the sample size is
small.
There are other limitations to our study apart from the small sample size.
First, our institution is a referral center for endocrine disorders: thus, our
study population is skewed toward patients with more difficult diagnoses, with
underrepresentation of the number of cases of adenomas as a cause for primary
hyperaldosteronism. Second, histologic diagnosis of bilateral adrenal
hyperplasia was not obtained routinely when there was a good response to
appropriate medical treatment. Another notable limitation is the retrospective
nature of the study with consequent introduction of methodologic variables
such as different scanners, scanning parameters (milliampere-seconds, peak
kilovoltage), and contrast medium enhancement regimens that were used. For the
visual assessment of the glands, the radiologist was aware of this fact.
However, slice thickness and partial volume effect would have a significant
effect on adrenal gland size measurements; thus, in our study all the patients
had 10-mm-collimated images available for measurements to be made. As with
small lesions, accurate measurements of the adrenal gland parts on
10-mm-collimated images can be difficult in part because of partial volume
effects. However, the coefficients of variation for inter- and intraobserver
measuring of limb widths have been reported at 12% and 10%, respectively
[11]. Indeed, with the advent
of multidetector CT (MDCT), which will soon be the "norm," our
absolute measurement results may differ from those acquired on these newer
MDCT scanners because of the higher resolution of the images and less partial
voluming artifact. However, the overall difference in size between the
entities should remain the same. The visual assessment of the gland may also
be different on MDCT; the glands may look larger and perhaps less regular.
Radiologists will obviously have to "get their eye in" on the
newer MDCT images, and with experience, results as good as, if not better,
should be obtainable with MDCT.
Finally, the control measurements were obtained from a separate study
[10], and therefore only
limited clinical and statistical inferences can be made. However, we believe
that comparison with this control group is valid because the technique of
measurement was identical and data collection for the cohort in the control
group was performed at our institution.
In conclusion, in primary hyperaldosteronism, the adrenal limbs in
bilateral adrenal hyperplasia are significantly larger than those in either
aldosterone-producing adenoma or in normal controls, as measured on CT, a
finding not previously documented. We therefore propose a diagnostic algorithm
based on both the adrenal limb size measurements and the detection of an
adrenal nodule in an attempt to improve the differentiation between bilateral
adrenal hyperplasia and adenoma on CT. Use of this algorithm may decrease the
necessity for the cumbersome and more invasive adrenal venous sampling.
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Abstract
Introduction
