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Clinical Studies |
Division of Clinical and Molecular Endocrinology and Health Care Research Section, Department of Veterans Affairs Medical Center, and Case Western Reserve University School of Medicine (D.C.A.), Cleveland, Ohio 44106; and the Endocrine-Diabetes Center, St. Luke’s Medical Center and Medical College of Wisconsin (H.R., J.W.F.), Milwaukee, Wisconsin 53215
Address all correspondence and requests for reprints to: David C. Aron, M.D., M.S., Medical Service 111(W), Veterans Administration Medical Center, 10701 East Boulevard, Cleveland, Ohio 44106. E-mail: aron.david{at}cleveland.va.gov
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Abstract |
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Cases were drawn from 112 consecutive patients with ACTH-dependent Cushing’s syndrome, who were then classified based upon results of inferior petrosal sinus sampling for ACTH levels. Analysis of test characteristics of high dose dexamethasone suppression testing was performed in the 73 patients for whom results are available. Statistical modeling was performed using the 68 cases with complete data on all assessed variables. Logistic regression models were used to predict the probability of pituitary-dependent Cushing’s syndrome (CD) given the results of high dose dexamethasone suppression testing before and after adjustment for the contribution of a series of potential covariates.
Of the 112 patients with ACTH-dependent Cushing’s syndrome, 15.2% had the ectopic ACTH syndrome, and the remainder had pituitary-dependent Cushing’s syndrome (CD). Patients with the ectopic ACTH syndrome were significantly older (mean, 51.9 vs. 40.2), were more likely to be male (58.8% vs. 27.4%), had shorter duration of clinical findings (mean, 11.6 vs. 39.9 months), were more likely to have hypokalemia (50% vs. 8.6%), had higher baseline 24-h urinary free cortisol [mean, 8317 vs. 1164 nmol/day (3015 vs. 422 µg)] and plasma ACTH levels [mean, 47 vs. 17 pmol/L (210 vs. 78 pg/mL)] and were less likely to suppress urinary free cortisol or plasma cortisol with high dose dexamethasone using the standard criterion of 50% or more suppression compared with patients with pituitary-dependent Cushing’s syndrome. Based upon the standard criterion, the sensitivity and specificity of the high dose dexamethasone suppression test for the diagnosis of pituitary-dependent Cushing’s syndrome were 81.0% and 66.7%, respectively. Although the mean percent suppression was significantly greater for patients with CD than for those with the ectopic ACTH syndrome (72.2% vs. 41.3%), the range of suppression was 0–99% for each diagnosis. The area under the receiver operating characteristic curve was 0.710 (95% confidence interval, 0.541–0.879). Logistic regression models were used to evaluate the probability of CD given the responsiveness to high dose dexamethasone suppression testing before and after adjustment for the potential contributions of other factors. A model including all of the variables (age, sex, duration, presence of hypokalemia, urinary free cortisol, and plasma ACTH) had a diagnostic accuracy of 92.7%. A model including all of these variables plus a binary variable indicating whether the patient met the criterion of suppression by 50% or more resulted in 95.6% accuracy, whereas substitution of this binary variable by percent suppression resulted in a model with 94.1% accuracy. There were no statistically significant differences among these models; their values for the c statistic, which is equivalent to the area under the curve in a receiver operating characteristic analysis, were all greater than 0.9.
Logistic regression models indicate that the results of the dexamethasone suppression test add little to the differential diagnosis of ACTH-dependent Cushing’s syndrome, especially after taking other clinical information into account. In our patient population, the sensitivity and specificity of the dexamethasone suppression test were less than those reported by others. However, because 20–33% of cases of ectopic ACTH syndrome are misdiagnosed with these logistic regression models, other techniques are necessary to achieve greater diagnostic accuracy.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cases were drawn from 112 consecutive patients with ACTH-dependent Cushing’s syndrome who were referred to a single clinician (J.W.F.) from 1982 to 1995. All patients underwent inferior petrosal sinus sampling for ACTH levels, for which informed consent was obtained. This procedure was used as the "gold standard" to classify patients because of its established high accuracy (1, 2, 13) and the variable results of pituitary surgery (14). Diagnosis of CD was established by a petrosal sinus:peripheral ACTH gradient of more than 2 either at baseline or after iv injection of CRH (13). Analysis of test characteristics of high dose dexamethasone suppression testing was performed in the 73 patients in whom that test was performed. Statistical modeling was performed using the 68 cases with complete data for all assessed variables (see below). Separate analysis of patients with pathologically proven diagnosis was performed. Logistic regression models were used to predict the probability of pituitary-dependent Cushing’s syndrome (CD) given the results of high dose dexamethasone suppression testing before and after adjustment for the contribution of a series of potential covariates.
Biochemical and radiological testing
All patients were examined by one clinician (J.W.F.), who estimated the duration of disease from the patients’ history. Most biochemical test results were provided by the referring physician(s). Hypokalemia was defined as a serum K+ below 3.5 mEq/L. Measurement of urinary free cortisol used a variety of methods, and no adjustments were made in the models; all but four patients had values above the upper limit of normal of all the urinary free cortisol assays. Of those four patients, only the one who had complete data was included in logistic models. High dose dexamethasone suppression testing was performed by the referring physician or the consultant using either the overnight (34 patients) or 2-day test (39 patients). The results from these two tests were pooled; no special efforts were made to assess the validity of the data, e.g. correctness of test performance. All patients had measurements of plasma ACTH in a single laboratory using a two-site immunoradiometric assay (15). Interpretation of magnetic resonance imaging (MRI) or high resolution computed tomographic (CT) scanning of the sella was made independently of the results of petrosal sinus sampling.
Statistical analysis
In addition to descriptive, parametric, and nonparametric statistics, we used contingency tables and receiver operating characteristic (ROC) curves. Logistic regression models were used to predict the probability of CD (pituitary ACTH-dependent Cushing’s syndrome) given the results of high dose dexamethasone suppression testing before and after adjustment for the contribution of potential covariates. These models take the following mathematical form: ln{[P(CD)]/\[1 - P(CD)\]} = ß0 + ß1 (variable) + ß2 (variable) + ... , where P(CD) is the probability of CD, and the variables include age, sex, ACTH, etc.
Differences between models were assessed with likelihood ratio tests and the c statistic, which is equivalent to the area under the curve in a ROC curve analysis (16, 17, 18, 19). Analyses were performed using SPSS 6.12 (Chicago, IL) and ROC Analyzer (20). P < 0.05 was assumed to be statistically significant; no correction was made for multiple statistical tests (21).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The patient characteristics for the entire series, stratified by
diagnosis (n = 112), are shown in Table 1
and
stratified by whether dexamethasone suppression testing was performed
(n = 73) or not (n = 39) in Table 2. The
frequency of the EAS in the entire series was 15.2% (Table 1). As a
whole, patients with EAS were significantly older (mean, 51.9
vs. 40.2 yr), were more likely to be male (58.8%
vs. 27.4%), had a shorter duration of clinical findings
(mean, 11.6 vs. 39.9 months), and were more likely to have
hypokalemia (50% vs. 8.6%) than patients with CD. Patients
with EAS also had significantly higher baseline 24-h urinary free
cortisol [mean, 8317 vs. 1164 nmol/day (3015 vs.
422 µg)] and plasma ACTH levels [mean, 47 vs. 17 pmol/L
(210 vs. 78 pg/mL)] and were less likely to suppress with
high dose dexamethasone using the standard criterion of 50% or greater
suppression (Fig. 1). However, one third of the patients
with EAS met this criterion for suppression (see below). Imaging of the
sella turcica (MRI or high resolution CT scanning) was performed in 108
patients. There was no significant difference in the frequency of
abnormal pituitary imaging between those with CD and those with EAS
(18.5% vs. 12.5%). The positive predictive value of an
abnormal pituitary imaging study (true positives/all positives) was
89.5%, which compares with the frequency of CD of 85.2% among those
who underwent pituitary imaging. Among the patients who had undergone
high dose dexamethasone suppression, the positive predictive value of
pituitary imaging was 77.9%, which compares with the frequency of CD
of 80.0% in this subgroup. Follow-up information on pathological
diagnosis was available for 74 patients diagnosed as having CD who
underwent trans-sphenoidal surgical exploration. Confirmation of
the diagnosis was based on the presence of a pituitary tumor or cure
after partial or total hypophysectomy in the absence of an identifiable
pituitary lesion. Two patients had corticotroph cell hyperplasia. Thus,
pituitary-dependent disease was confirmed in 84%. Of the 17 patients
diagnosed with EAS, a pathological diagnosis was made in 13 (71%),
most of which were bronchial carcinoid tumors.
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Results were available for 73 patients; EAS occurred in 20.5% of
this subgroup (Table 2
). Based upon the standard criterion,
i.e. suppression by 50% or more of the baseline, the
sensitivity and specificity of the test were 81.0% and 66.7%,
respectively. The mean ± 1 SD percent suppression was
significantly greater for patients with CD than for those with EAS
(72.2 ± 28.9% vs. 41.3 ± 37.2%;
P = 0.001, by unpaired t test). The range of
suppression was 0–99% for each diagnosis. There was no cut-off point
that yielded 100% specificity. The ROC curve for this test is shown in
Fig. 2. The area under the curve is 0.710, which was
significantly greater than that occurring by chance (95% confidence
interval, 0.541–0.879).
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Logistic regression models were used to evaluate the probability
of CD given responsiveness to high dose dexamethasone suppression
testing before and after adjustment for the potential contributions of
other factors. These studies were based on a subset of 73 patients who
underwent high dose dexamethasone suppression testing and for whom
complete data were available. There were 68 such patients in this
subset, and 77.9% of them had CD. The diagnostic accuracy of the
models is shown in Table 3. Model 1 included the
variables age, sex, duration, presence of hypokalemia, urinary free
cortisol, and plasma ACTH plus suppression by 50% or more (a binary
variable). Model 2 included these variables, except for percent
suppression (a continuous variable), which was substituted for
suppression by 50% or more. These models were more accurate than
models 5 and 6, which included only the response to dexamethasone.
Similar results were observed using criteria for suppression of 60%,
70%, 80%, and 90% or more. Model 3 included the variables age, sex,
duration, presence of hypokalemia, urinary free cortisol, and plasma
ACTH, but not the results of high dose dexamethasone suppression
testing. Model 4 was developed using a stepwise technique (forward
likelihood ratio). There were no statistically significant differences
among models 1, 2, 3, and 4 (by likelihood ratio test,
P > 0.1). These models had values for the c statistic,
which is equivalent to the area under the curve in a ROC analysis, of
0.946, 0.936, 0.937, and 0.912, respectively. These models correctly
diagnosed 53, 52, 52, and 52 of the 53 cases of CD and 12, 12, 11, and
10 of the 15 cases of EAS, respectively. Evaluation of these models in
patients with pathologically confirmed diagnoses yielded similar
results (data not shown).
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. There were
no significant differences between those patients who underwent
dexamethasone suppression testing and those who did not, except for the
lower frequency of EAS in the latter group. Differences in the results
of the logistic regression models for these two populations would
suggest selection bias (in who undergoes dexamethasone suppression
testing) or other problems, e.g. overfitting. However, there
were insufficient numbers of patients with EAS who did not undergo high
dose dexamethasone suppression testing. Therefore, we analyzed logistic
regression models for the entire population who had complete data
(n = 102). Model 3 had a diagnostic accuracy of 91.2% and
correctly identified 86 of 87 patients with CD, but only 7 of 15 with
EAS. Model 4 had a diagnostic accuracy of 90.2%. We also evaluated models that included the results of pituitary imaging in the subgroup of patients who had also undergone high dose dexamethasone suppression. Models 1 and 2 had diagnostic accuracies of 95.4% and 93.9%, respectively. Addition of pituitary imaging (binary variable) to either of these models resulted in a diagnostic accuracy of 93.9%, which was the same as the model analogous to model 3 with the addition of pituitary imaging results. There were insufficient cases of the EAS who had pituitary tumors detected by MRI or CT to evaluate a model in the subset of patients with positive results on pituitary imaging. However, of the two patients with EAS who had abnormal pituitary imaging, one showed no suppression in response to high dose dexamethasone, and the other suppressed by 82%.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Traditionally, high dose dexamethasone suppression testing has been used in the differential diagnosis of Cushing’s syndrome. The diagnostic accuracy of dexamethasone suppression testing may be compromised by incomplete urine collections, daily fluctuation in basal steroid excretion, improper timing of plasma cortisol collection, as well as possible inaccuracy in measurement of urinary steroid levels caused by noncompliance, medications, renal and hepatic disease, or poor laboratory performance. The major problem with high dose dexamethasone suppression tests is their diagnostic inaccuracy, which is readily apparent in series with a substantial number of patients with EAS (1, 2). At least 20–30% of patients with EAS will suppress plasma and urinary steroids to less than 50% of baseline values during dexamethasone suppression testing. In addition, as many as 20–30% of patients with CD fail to suppress steroid levels to less than 50%. Consequently, the diagnostic accuracy of high dose dexamethasone suppression testing is only 70–80%. This must be compared with a pretest probability of CD in patients with ACTH-dependent CD of about 85–90%, which exceeds the sensitivity, specificity, and diagnostic accuracy of dexamethasone suppression testing. A recent study analyzed new criteria for the standard low and high dose dexamethasone suppression to identify better specificity, sensitivity, and accuracy. Flack et al. (12) evaluated 118 patients with surgically confirmed causes of CD (94 with CD, 14 with primary adrenal disease, and 10 with EAS). Their study confirmed the very poor sensitivity, specificity, and accuracy of the high dose dexamethasone suppression test when the 50% suppression criterion was used. However, a decrease in urinary free cortisol of more than 90% and a decrease in 17-hydroxycorticosteroid secretion of more than 64% had 100% diagnostic specificity for CD and excluded EAS. Some patients with CD did not suppress to these levels, and the overall accuracy using these new criteria is 85%, which is about the same as the pretest probability of the disease. Moreover, in subsequent publications, the cut-off point to achieve 100% specificity had to be revised (11). Our data indicate that there is no such cut-off point. Analysis of the ROC curve generated from our data confirm the poor performance of high dose dexamethasone suppression testing. The area under the curve, although significantly better than chance (0.5), was still only 0.710. This value is less than those reported by Dicheck for the standard test (0.903) and the overnight test (0.867), although statistical comparisons cannot be made using the published data.
We studied the effectiveness of high dose dexamethasone suppression testing, not its efficacy. Our analyses relied upon the results supplied by the referring physicians. Although no special effort was made to assess the correctness of the test performance, these are the results that are used in actual practice. Moreover, this means that a variety of clinical laboratories and methods were used to measure plasma and urinary free cortisol. This approach is not likely to provide the precision found in efficacy studies performed in research centers using a single methodology and batch assays. Similarly, it is not likely that dexamethasone suppression testing in a "real world" setting can match that achieved in the research setting. Therefore, our data are more representative of the results likely to be obtained by practicing physicians. A limitation of the study is the possibility of selection bias, especially because disease prevalence is important in generalizing clinical prediction rules (22). Ideally, evaluation of dexamethasone suppression testing should be performed on a population-based, rather than referral-based, sample. Naturally occurring Cushing’s syndrome is a rare disease. Consequently, all large series of patients reflect referral patterns. Bias may result from the referral of "difficult cases" for specialized expertise, such as inferior petrosal sinus sampling. These difficult cases may be those with atypical laboratory results, e.g. the low frequency of abnormal pituitary imaging in the patients with CD (18.5%) (23, 24). Interestingly, the frequency of abnormal pituitary imaging in patients with the EAS (12.5%) was similar to that reported in normal subjects (25). However, the frequency of EAS in our series was similar to that in other reports. Moreover, 39 patients were referred without having undergone dexamethasone suppression testing, and the models performed similarly when these patients were included.
Our study used inferior petrosal sinus sampling as the gold standard, raising the possibility that patients may have been misclassified. Surgical confirmation of a pituitary source of ACTH was achieved in 84% of cases diagnosed as CD. Confirmation of the ectopic source of ACTH was achieved in 71% of cases diagnosed as EAS. In addition to the possibility of misclassification, these results may reflect variation in surgical results as well as the occult nature of many of these ACTH-secreting tumors. However, similar results for the statistical models were observed when the analyses were limited to patients with pathologically confirmed diagnoses. Estimation of duration of disease is subject to both ascertainment and recall bias. Finally, validation of the models in other populations is needed, recognizing that application of clinical prediction rules to individual patients is problematic (26, 27, 28).
Determining cost-effective diagnostic strategies requires careful
evaluation not only of a test in isolation, but also in the context of
the other information available and the likelihood of disease.
Consideration must be given to the question of the value added by a
test or procedure. Flagle wrote that "the value of information is
equal to the enhanced value of outcomes based on that information"
(29). We conclude that high dose dexamethasone suppression testing has
limited incremental value in the differential diagnosis of EAS.
Clinical prediction rules notwithstanding, given a male patient with a
rapid course and high plasma ACTH and urinary free cortisol levels, the
probability of EAS is sufficiently high that the results of
dexamethasone suppression testing should not influence the decision
about management. Furthermore, given the range of suppression from
0–99% for both CD and EAS, it is clear that, all other things being
equal, the pretest probability of CD (usually 
90%) will exceed the
diagnostic accuracy of dexamethasone suppression testing. On this basis
alone, we can recommend that the high dose dexamethasone suppression
test be abandoned. We used clinical prediction rules to confirm the
probability of CD, and diagnostic accuracy using simple clinical
measures was high. However, even if our clinical prediction rules were
validated using other series, their utility in individual patients may
be limited. We found that 20–33% of cases of EAS are misdiagnosed
with these models. Neither clinical features nor routine biochemical
tests alone or in combination can establish the diagnosis with
sufficient diagnostic accuracy to ensure that appropriate therapy is
given to all patients. Although in individual cases, the diagnosis may
be clear, in most, if not all, other techniques, such as petrosal sinus
sampling, are necessary to achieve the requisite diagnostic
accuracy.
Received October 28, 1996.
Revised January 10, 1997.
Revised February 24, 1997.
Accepted February 28, 1997.
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