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Original Studies |
arkovi
,
Jasmina 
iri,
Milo Stojanovi,
Zorana Penezi,
Bo
o Trbojevi,
Milka Drezgi and
Milica Neovic
Institute of Endocrinology, University of Belgrade School of Medicine, 11000 Belgrade, Yugoslavia
Address all correspondence and requests for reprints to: Dr. Milo arkovi, Institute of Endocrinology, Dr. Subotica 13, 11000 Belgrade, Yugoslavia. E-mail:
mzarkov{at}eunet.yu
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Abstract |
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Introduction |
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The insulin tolerance test (ITT) has been extensively used in the diagnosis of adrenal insufficiency, but both positive and negative discrepancies have been reported between the ITT and the ACTH test (10, 11, 12). Therefore, the "gold standard" does not exist. Due to the lack of a confirmatory test for adrenal insufficiency we chose a group of patients treated with corticosteroids for 6 months as a group with proven HPA axis suppression.
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Subjects and Methods |
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Studies were performed in 14 corticosteroid-treated patients and
28 control subjects. Patient data are presented in Table 1
. Patients were treated for Graves’
ophtalmopathy. During the entire treatment period, patients were
euthyroid. The corticosteroid treatment lasted for 6 months and
consisted of 6 therapy cycles. Each cycle was started with 500 mg
methylprednisolone, iv, daily for 2 days, followed by 40 mg prednisone,
orally, daily. The prednisone dose was reduced by 10 mg every 7 days
until the daily dose was 10 mg a day. Prednisone 10 mg/day was
continued for a week, and then next cycle was started. In the last
therapy cycle corticosteroids were tapered in the same fashion as in
previous cycles.
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In all subjects the LDT and the SDT were performed in random order on 2 consecutive days. Tests were started at 0800 h with the iv injection of 1 µg or 250 µg ACTH-(1–39) (ICN Yugoslavia, Belgrade, Yugoslavia). Blood samples for cortisol determination were taken from the iv cannula at 0, 15, 30, and 60 min. In the corticosteroid-treated patients the first ACTH test was performed 3–4 days after the last 10-mg prednisone dose.
For the LDT a vial of 250 µg ACTH was diluted in normal saline solution to a concentration of 0.5 µg/mL. The solution was used immediately.
Cortisol measurement
All blood samples was immediately separated and kept frozen at -20 C until assayed. The plasma cortisol concentration was determined using a RIA [Kort RIA-CT, INEP (Zemun, Yugoslavia) and ICN Yugoslavia]. The procedure has an intraassay coefficient of variation of 5.8%, and an interassay coefficient of variation of 6.5%.
Statistical analysis
The patient data and the raw test data are presented as the mean ± SD and compared using t test. Tests were analyzed using the receiver operating characteristic (ROC) curve method. The ROC curve area was the measure of the test quality, and the test areas were compared (13). For the ROC analysis, ROCKIT software was used (The University of Chicago, Chicago, IL) (14).
For each test, diagnostic values and specificity for 93% and 100% sensitivities were calculated. Ninety-three percent instead of 95% sensitivity was chosen due to calculation constraints imposed by the number of patients (possible choices were 86% and 93%).
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Results |
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). We evaluated adrenal function using the SDT and LDT according to previously published criteria. Using the SDT for diagnosis of adrenal insufficiency, the highest sensitivity was 50.0% with a specificity of 89.3% (serum cortisol, >580 mmol/L and an increment of >200 mmol/L 60 min after ACTH injection), and the highest specificity was 100% with sensitivity of 28.6% (serum cortisol, >550 mmol/L) (2, 3). The LDT sensitivity was 28.6%, and specificity 96.4% for the diagnostic value of serum cortisol greater than 500 mmol/L. With an increase in the cut-off point to 550 mmol/L, neither sensitivity nor specificity was changed (7, 9, 12).
As a possible test for the assessment of adrenal insufficiency, we
evaluated the serum cortisol concentration at each sampling time, the
cortisol increment at each sampling time, the maximal cortisol
concentration, and the maximal cortisol increment in both the SDT and
LDT (Table 2 and Fig. 1).
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Fig. 1).
The best overall test was the cortisol increment at 15 min of the LDT.
It was significantly better than the cortisol concentration at 15 min
of the SDT, the best test obtained during the SDT (P =
0.0113; Fig. 3 and Table 2). There was no difference in test quality among the cortisol
concentration at 15 min, the maximal cortisol concentration, and the
maximal cortisol increment during the SDT.
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, Fig. 3). |
Discussion |
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As adrenal insufficiency can be a life-threatening condition, the sensitivity of the test for the presence of the disease should be high. We also have to sacrifice specificity for high sensitivity if we choose the ACTH test as the initial test in the battery, because only patients with no risk of adrenal insufficiency will require no further investigations. Therefore, we decided to calculate test diagnostic values for the optimum sensitivity and not for the optimum test efficiency. Because of that, the diagnostic values we have calculated are higher then those usually used, but are comparable to the cortisol response to the SDT recently reported (17). The other reason for the difference in diagnostic values could be our group of patients and controls and the cortisol assay we used. It was shown that there are significant differences in cortisol concentrations determined by different assays (17).
Another reason for the difference in diagnostic values could be the use of ACTH-(1–39) in our study instead of ACTH-(1–24), which was used in previous studies. We do not think that it is a probable cause, as the absolute values of cortisol as well as the kinetics of the cortisol response are comparable to those in previous studies (8, 17). Therefore, the use of ACTH-(1–39) instead of ACTH-(1–24) has a minimal, if any, influence on the obtained results.
We have confirmed the finding of the earlier study that the sensitivity
and specificity of the SDT and LDT were the same using the previously
published diagnostic values (8). The optimizing test criteria improved
both the SDT and LDT in the diagnosis of adrenal insufficiency. The
best overall test was cortisol increment at 15 min of the LDT. It was
significantly better than the cortisol concentration at 15 min of the
SDT (P = 0.0113; Fig. 2). The test quality of the
cortisol concentration at 15 min of the SDT was not significantly
different from the quality of the most used test, the maximal cortisol
response and the maximal cortisol increment during the SDT. The
specificity of the 15 min cortisol increment during the LDT at 100%
sensitivity is 96%, whereas the specificity of the cortisol
concentration at 15 min of the SDT at the same sensitivity level is
32%.
According to our data, the adrenal gland in secondary adrenal insufficiency loses the capacity for a prompt response to ACTH stimulation, but the total response capacity is preserved. Therefore, the largest differences in cortisol response occur early after ACTH injection. It may be postulated that the cause of this is the difference in blood flow through the adrenal, because the delivery of ACTH to the adrenal gland is flow dependent (18). As the standard dose, but not the low dose ACTH, increases blood flow through the adrenal glands, the early cortisol response is significantly smaller during the LDT (19). Also, the loss of the early adrenal response to ACTH stimulation could be an inherent property of adrenal insufficiency, analogous to a loss of early insulin response to glucose stimulation in noninsulin-dependent diabetes. Therefore, the loss of early cortisol response to ACTH stimulation could be an important indicator of adrenal insufficiency, because it may represent the first sign of diminishing adrenal function. Although the average response to ACTH was reduced in the corticosteroid-treated group at any time during the test, that does not mean that each individual subject had a reduced response at every time point. Therefore, to maximize the diagnostic yield of the test we assessed the early cortisol response to ACTH stimulation. Accordingly, the highest diagnostic yield was obtained by assessing the results at 15 min of the test.
The aim of our study was to optimize diagnostic usefulness for both LDT and SDT ACTH tests. Compared with the previous criteria, which had high specificity, our optimized criteria have high sensitivity, making the ACTH test an optimal screening test. Moreover, we found that cortisol increment at 15 min of the LDT has both high sensitivity and specificity, making this a good diagnostic test, thus giving an important advantage to the LDT compared to the SDT. In conclusion, the LDT is superior to the SDT in the assessment of secondary adrenal insufficiency, although only long term clinical experience and continuous auditing can truly validate any test.
Received February 12, 1999.
Revised May 4, 1999.
Accepted May 19, 1999.
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