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Original Studies |
Departments of Endocrinology and Clinical Chemistry (R.N.), North Staffordshire Hospitals; and the Department of Medicine, School of Postgraduate Medicine, Keele University, Staffordshire, Stoke on Trent, United Kingdom ST4 6QG
Address all correspondence and requests for reprints to: Dr. T. A. M. Abdu, Department of Endocrinology and Diabetes, North Staffordshire Hospitals, National Health Service Trust, City General Hospital, Stoke on Trent, United Kingdom ST4 6QG.
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Abstract |
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There was a high correlation between the ITT and LDSST peak cortisol responses (r = 0.89; P < 0.0001), the ITT and SST 30 min cortisol levels (r = 0.83; P < 0.0001), and the LDSST peak cortisol response and the SST 30 min cortisol level (r = 0.85; P < 0.0001). In the LDSST, all but six patients achieved maximal cortisol response by 30 min.
A plasma cortisol cut-off of 600 nmol/L is more helpful than 500 nmol/L for clinical decision-making using either the SST 30 min cortisol level or the LDSST peak cortisol response. The sensitivity of the LDSST was 100% (cortisol response of >600 nmol/L indicates intact HPA axis), with no falsely reassuring results. SST (pass cortisol level, >600 nmol/L) was less sensitive than LDSST, it produced 2 of 64 (3%) falsely reassuring results. Even the ITT (pass cortisol level, >500 nmol/L) failed to identify one patient with clinically evident cortisol deficiency. The results of this study indicate that both SST and LDSST, at a cortisol cut-off of 600 nmol/L, are safe for the purpose of clinical decision-making with regard to steroid replacement therapy in patients with pituitary disease. As the LDSST produced no falsely reassuring decisions, we suggest that this could replace the SST and ITT for initial evaluation of the HPA axis in patients with pituitary disease. We suggest administering 1 µg tetracosactrin, iv, with sampling at 0, 20, and 30 min.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The rationale for using the SST is the assumption that endogenous ACTH is required for maintenance of the integrity and acute responsiveness of the zona fasciculata. When the secretion of ACTH falls the zona fasciculata atrophies and fails to mount an adequate cortisol response when stimulated by exogenous tetracosactrin. A highly significant correlation between the short synacthen test and the insulin tolerance test (ITT) has been a consistent finding in the literature (4, 5, 6, 7, 8, 9). The short synacthen test gradually gained popularity as a reliable simple alternative first line test, as evidenced by two surveys of UK endocrinologists 5 yr apart, showing an increase in the number of those who use the short synacthen test from 25% in 1988 (6) to 50% in 1994 (10). The short synacthen test, however, has been falsely reassuring in some reports, with potentially serious consequences (11, 12, 13, 14, 15).
It is well recognized that the 250-µg dose used in the conventional short synacthen test is a supraphysiological dose originally designed as a test for primary adrenal failure. Several groups have reduced this dose considerably and demonstrated that the cortisol response to 1 µg is equivalent to that obtained with 250 µg in normal subjects (16, 17, 18). It seems logical to assume that the supraphysiological dose of 250 µg used in the conventional dose test might overstimulate partially atrophied adrenals and produce a deceivingly adequate cortisol response. This could account for the various reported failings of the short synacthen test.
Over the last few years a number of small studies have looked at the clinical usefulness of the low dose (1 µg) synacthen test (LDSST) compared to the conventional dose (250 µg) test in patient receiving long term steroid therapy (18) and in patients with pituitary disease (19, 20). These studies showed that the low dose produced fewer falsely reassuring decisions than the conventional dose test. However, two recent reports suggested no difference between the low and conventional dose tests in adults with pituitary disease (21) and in children with idiopathic multiple pituitary hormone deficiency (22).
The present study was designed to consider the following questions in a large group of patients with pituitary disease. 1) Can the low dose, 1-µg test (LDSST) provide a better indication of the state of the HPA axis than the conventional dose, 250-µg test (SST)? 2) Can the low dose test replace the ITT for assessment of the HPA axis?
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Subjects and Methods |
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Patients with suspected or proven pituitary disease (n = 64) were recruited from the endocrine service at Stoke on Trent. Forty-two of these patients (mean ± SD age, 47.5 ± 11.5 yr; range, 28–70) underwent an ITT, a conventional dose SST, and a LDSST in random order. The remaining 22 (mean ± SD, 50.6 ± 14.5 yr; range, 26–86), underwent SST and LDSST only. The minimum and maximum intervals between tests were 48 h and 6 weeks, respectively. In each test a cannula was inserted in the anticubital fossa 15 min before initiation of sampling. In the ITT we injected soluble insulin (0.1 U/kg BW, iv), with sampling at -15, 0, 30, 45, 60, 90, and 120 min. In three patients it was necessary to give a second injection of insulin at a dose of 0.15 U/kg BW to achieve adequate hypoglycemia (plasma glucose, <2.2 mmol/L). For the SST we injected 250 µg tetracosactrin, with sampling at 0, 30, and 60 min. In the LDSST 1 µg tetracosactrin was injected after obtaining a basal blood sample with subsequent sampling at 20, 30, 40, and 60 min.
Eighteen patients were tested before any treatment, 14 patients were tested 6 weeks to 27 yr after surgery (12 transsphenoidal pituitary adenomectomies and 2 craniotomies, 1 for a craniopharyngioma and the other for a parasellar meningioma), and 16 patients were tested 2–25 yr postradiotherapy. An additional group of 16 patients was tested after undergoing both surgery (13 transsphenoidal pituitary adenomectomies and 3 craniotomies for a parasellar chordoma, a sphenoid ridge meningioma, and an optic nerve glioma) and radiotherapy; the minimum and maximum intervals between intervention and testing in these cases were 28 weeks and 28 yr, respectively.
The categories of pituitary disease were 25 nonfunctioning macroadenomas, 10 somatotropinomas, 7 prolactinomas, 3 suspected hypopituitarism (presenting with spontaneous hypoglycemia), 6 craniopharyngiomas, 2 chordomas, 2 meningiomas, and 1 patient each with idiopathic partial hypopituitarism, isolated ACTH deficiency, psychogenic polydypsia, pituitary incidentaloma, Rathke’s cleft cyst, pineal germ cell tumor, optic nerve glioma, pituitary apoplexy, and lymphocytic hypophysitis.
The 1-µg synacthen dose was prepared by diluting 0.2 mL of a 250-µg/mL ampule to 10 mL with normal saline (5 µg/mL); this was stored at 4 C for up to 7 days (18). Immediately before use, 0.2 mL of this stock solution was diluted to 1 mL in normal saline, giving a final concentration of 1 µg/mL.
Cortisol assay. Plasma cortisol was measured using a nonisotopic immunoassay based on fluorescence polarization (TDX, Abbott Diagnostics, North Chicago, IL), with intra- and interassay coefficients of variation of 4–7%.
Sensitivity and specificity. When considering the reliability of any test against a reference test, the sensitivity and specificity are evaluated as follows: sensitivity = number of patients with true deficiency on the test/number of all patients with deficiency on the reference test x 100. Specificity is the number of patient without deficiency on the test/number of all patients without deficiency on the reference test x 100. We used the SPSS package (Standard Version, 1996) for calculation of correlation.
The study was approved by the North Staffordshire District ethical committee, and informed consent was obtained from all patients.
Definitions of response criteria
A peak plasma cortisol of 500 nmol/L or more (5, 6) was considered an adequate response to hypoglycemia of less than 2.2 mmol/L on ITT. Plumpton and Besser (23) suggested a cortisol level greater than 580 nmol/L as indicative of an adequate response to ITT using a fluorimetric assay for cortisol measurement. Fluorimetric assays for cortisol have a 20–30% positive bias compared to the current, more specific RIAs (24) or a mean positive bias of 96 nmol/L (25), i.e. 580 nmol/L in the former assay is equivalent to 484 nmol/L in the latter. Therefore, we consider that with the present cortisol assays a value of 500 nmol/L represents an acceptable pass on ITT. We compared the performance of the SST (30 min cortisol response) and LDSST (peak cortisol response) with that of the ITT at two cut-off cortisol levels (500 and 600 nmol/L). We looked at these two cut-off value because although the commonly used figure for SST is 500 nmol/L (26), Patel et al. (27) have shown that all 50 endocrinologically normal patients admitted as acute medical emergencies achieved a minimum plasma cortisol of 600 nmol/L, 30 min after 250 µg synacthen in a test performed within 24 h of admission. Hurel et al. (4) also found 600 nmol/L to be a more reliable cut-off level.
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Results |
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No side-effects were reported with either SST or LDSST. Two patients lost consciousness during ITT; both recovered quickly after iv glucose infusion.
LDSST
In the LDSST, peak cortisol was reached in 27 patients at 20 min, in 24 patients at 30 min, and in 6 patients at 40 min. In these latter patients, the difference between the 40 and 30 min cortisol values ranged between 8–26 nmol/L, with a mean of 15.4 nmol/L. In 7 patients, the response was flat, with a cortisol response of less than 50 nmol/L at all time points.
Correlation
Pearson’s correlation coefficient between ITT and SST (30 min cortisol value) was r = 0.83; P < 0.0001, that between ITT and LDSST (peak cortisol value) was r = 0.89; P < 0.0001, and that between SST and LDSST was r = 0.85; P < 0.0001 (Fig. 1).
SST vs. ITT
At a cortisol cut-off level of 500 nmol/L, the SST achieved a
sensitivity of 100% and a specificity of 90% (Table 1a
). At a cortisol cut-off level of 600
nmol/L, the SST achieved a sensitivity of 100%, with a specificity of
77%.
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At a cortisol cut-off level of 500 nmol/L, the LDSST achieved a
sensitivity of 100% and a specificity of 93.3% (Table 1b
). At a
cortisol cut-off level of 600 nmol/L, the LDSST achieved a sensitivity
of 100% and a specificity of 80%. All patients who failed the ITT
also failed the LDSST.
LDSST vs. SST
Of the 64 patient who underwent SST and LDSST, when the cortisol
cut-off level was taken as 500 nmol/L, 14 failed both tests, and 44
passed both tests with 6 discordant results, 4 of these passed the SST
and failed the LDSST (Table 2). All 4
had unequivocal clinical evidence of cortisol deficiency (Table 3), giving a false reassurance rate of
4 of 64 (6%) for the conventional dose test. At a cortisol cut-off
level of 600 nmol/L, 21 patients failed both tests, and 39 passed both
tests with 4 discordant results. Three of these passed the SST while
failing the LDSST, 2 had unequivocal clinical evidence of cortisol
deficiency (Table 3), giving a false reassurance rate of 2 of 64 (3%)
for the SST. Thus, the overall sensitivity of LDSST is slightly greater
than that of SST.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). On the other hand, Lindholm and
Kehlet (7) have shown that in some patients with normal HPA axis
function, who underwent major surgery with no problem, a maximum plasma
cortisol response may not be elicited during insulin-induced
hypoglycemia despite blood glucose levels usually assumed to be
sufficiently low for this purpose. Thus, even the gold standard ITT can
give misleading results, and when discrepancy between clinical data and
test results is encountered, the decision-making process is best
informed by clinical judgment. Our results suggest that the SST is safe for the purpose of clinical decision-making at a cortisol cut-off of 600 nmol/L with a false reassurance rate of 2 of 64 (3%). This is in keeping with other retrospective data from our center (30) and with findings from other studies (4, 7, 8, 22). A false reassurance rate of less than 3.5% is probably small enough to justify the use of the conventional SST as a simple alternative to ITT provided that certain precautions are observed (31).
The sensitivity for the LDSST compared to the ITT in 42 patients as
well as to decisions made on biochemical and/or clinical grounds in all
64 patients is 100%. The LDSST did not give any falsely reassuring
results. This finding supports the evidence that the synacthen test can
be more sensitive if physiological or near-physiological doses of
synacthen are used (32, 33). The study by Crowley et al.
(16) confirmed the reproducibility of the cortisol response to low dose
ACTH stimulation. The high sensitivity combined with good
reproducibility make the LDSST an attractive simple reliable
alternative to the ITT. The specificity of the LDSST at a cut-off of
600 is 80% in the 42 patients who also underwent ITT. Looking at the
whole study population, 7 of 64 (11%) patients failed the LDSST
without any clinical or biochemical evidence of cortisol deficiency
(peak response to ITT, >500 nmol/L). To avoid unnecessary cortisol
replacement based on the LDSST result, careful clinical evaluation of
these patients is needed. If any doubt remains about the HPA axis
status, an ITT can be employed. Thus, by using the LDSST as the initial
test, 57 of 64 ITTs (89%) could be avoided. The clinical
characteristics of the 7 patients are shown in Table 4. Patients 3 and 6 achieved maximum
cortisol of 580 and 587 nmol/L, respectively. In the absence of
clinical evidence of cortisol deficiency or other axis impairment, it
would be safe to "pass" both. In patients 1, 2, 5, and 7 (achieving
maximum cortisol levels of 587, 502, 578, and 554 nmol/L),
because of other axis impairment, a safe practice would be to recommend
hydrocortisone cover for stressful situations, supply a steroid card,
and maintain close follow-up. For patient 4, an ITT or, alternatively,
a repeat LDSST may be required. Perhaps only this 1 patient of all 64
may require an ITT for evaluation of HPA axis. Thus, 98.4% (63 of 64)
of ITTs could be avoided without exposing any patient to the risks of
either unrecognized cortisol deficiency or unnecessary long term
steroid treatment. In other words, careful consideration of the
clinical data greatly improved the specificity of the LDSST. Thus, the
low dose test is a simple reproducible, sensitive, and, in conjunction
with clinical evaluation, specific test.
A small, but definite, superiority of the LDSST over the SST has been demonstrated in most studies examining the usefulness of LDSST compared to SST (19, 20, 32), with two exceptions (21, 22). The study by Weintrob et al. (22) in children with idiopathic multiple pituitary hormone deficiency, although suggesting no difference between the low and conventional dose SSTs, in fact shows that both are equivalent to the insulin stress test in detecting ACTH insufficiency. The latter finding is in agreement with our finding in the adult population. The study by Mayenknecht et al. (21) concluded that there is no difference between the low dose and conventional dose synacthen tests, but their data clearly show that of 14 patients who failed the reference test, 1 passed the conventional dose test at both 30 and 60 min, i.e. this means a 1 in 14 false reassurance rate for the conventional dose test. All those who failed the reference test, however, also failed the low dose test. The low dose test seemed to be more sensitive than the high dose test (100% vs. 93%, respectively). However, because of the small number of patients failing the reference test in their study, firm conclusions are not warranted. Interestingly, Mayenknecht et al. (21) clearly confirmed previous evidence that the adrenals are maximally stimulated by 1 µg synacthen, iv (32). Thus, it may be worth exploring the use of a lower dose of ACTH in future studies, as it may be even more sensitive than the 1-µg test. However, the concern might be that lower synacthen doses would result in more false failures (lower specificity) and may therefore potentially trigger more ITTs.
Our results suggest that in the LDSST, sampling at 0, 20, and 30 min should be sufficient. Crowley et al. (32) have shown that the maximum cortisol level during low dose testing is attained at 15 min in the majority of their observations in normal subjects; all had attained maximum response by 35 min. All but six of our patients attained the maximum cortisol by 30 min. These six patients achieved a maximum cortisol response by 40 min. The deference between the 30 and 40 min responses in these six patients was small, and the classification into pass or fail was not affected when the 30 min cortisol value was used instead of the 40 min cortisol value.
Clinical data are crucial in the process of evaluation of the HPA axis in patients with pituitary disease. Our study confirms that both SST and LDSST, when used in conjunction with clinical information, are safe for clinical decision-making with regard to hydrocortisone replacement therapy. LDSST is potentially safer, particularly in patients with partial adrenal atrophy. Our study indicates a false positive (failure) rate of 11% (7 of 64) for LDSST. Careful clinical evaluation of these patients would obviate the risk of unnecessary cortisol replacement. Only the occasional patient may still require the ITT.
Our results suggest that the LDSST can replace the SST and ITT for initial assessment of the HPA axis in patients with pituitary disease. This will confine the use of an insulin stress test to only a minority of patients. Pharmaceutical companies should be encouraged to provide synthetic ACTH-(1–24) in 1-µg vials to facilitate testing, and until that time, care is required when diluting a 250-µg vial (34).
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Acknowledgments |
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Received August 26, 1998.
Revised November 4, 1998.
Accepted December 2, 1998.
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