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The Low Dose (1-µg) Adrenocorticotropin Stimulation Test in the Evaluation of Patients with Suspected Central Adrenal Insufficiency

Division of Endocrinology and Metabolism, Department of Internal Medicine, Emory University School of Medicine (L.M.T.), Atlanta, Georgia 30322; and the Division of Endocrinology and Diabetes, Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Address all correspondence and requests for reprints to: Leonard M. Thaler, M.D., Division of Endocrinology, 1639 Pierce Drive, Room 1301 WMRB, Atlanta, Georgia 30322. E-mail: lthaler{at}emory.edu

	Abstract

Top Abstract Introduction A Review of the... Further Analysis Conclusions and Recommendations References

 
Currently, the most popular test for adrenal insufficiency is the conventional rapid ACTH stimulation test (250 µg ACTH). This method is quick and safe, but incorporates a dose of ACTH that is supraphysiological and capable of transiently stimulating the adrenal cortex in many patients with documented central adrenal insufficiency. In recent years, several investigators have published substantial evidence for a more sensitive ACTH stimulation test using a lower dose of ACTH (1 µg). Further analysis of these data, including the calculation of likelihood ratios, demonstrates that the 1-µg test performs significantly better than the 250-µg test compared to the gold standard, insulin tolerance test. We suggest that the 1-µg ACTH stimulation test replace the conventional 250-µg test when evaluating for central adrenal insufficiency. A cortisol level below 500 nmol/L after 30 min signifies impaired adrenocortical reserve. An insulin tolerance test should be performed if this low dose test results in a borderline value and the diagnosis is questioned. The 1-µg test should not be used if recent pituitary injury is suspected. Pharmaceutical companies should be encouraged to provide synthetic ACTH in 1-µg vials.

	Introduction

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DURING the past 30 yr, the rapid ACTH stimulation test has become increasingly popular as a screening test for central adrenal insufficiency (AI). Its simplicity and quick results are clearly responsible for its widespread use. Strong evidence now exists, however, for a significant change in the way the test is performed.

Many other tests, of course, are also used in the evaluation of AI. Excellent reviews are available for detailed descriptions (1, 2). The insulin tolerance test (ITT), considered by many to be the gold standard, and metyrapone test are considered extremely accurate in the diagnosis of AI. They are physician intensive, however, and are contraindicated in certain patients. To avoid these tests, the rapid ACTH stimulation test is commonly used. Lack of continuous trophic stimulation of the adrenal glands by endogenous ACTH in patients with pituitary disease leads to adrenal atrophy and hyporesponsiveness to exogenous ACTH. Thus, the ACTH stimulation test is an indirect measurement of pituitary function. The conventional rapid ACTH stimulation test is performed by administering an iv or im injection of 250 µg ACTH; cortisol levels are determined at 0, 30, and 60 min. An ACTH-stimulated cortisol level above 500 nmol/L constitutes a normal response. This test has been described as "... the ideal method for evaluating adrenal function in all cases except those involving recent hypothalamic and/or pituitary dysfunction" (2). Although this test is highly specific, its sensitivity has been questioned (3, 4, 5, 6, 7, 8).

In recent years, several investigators have published substantial evidence for a more sensitive ACTH stimulation test using a lower dose of ACTH (1 µg) (4, 5, 6, 7). It is performed in a similar manner as the higher dose ACTH stimulation test, thereby retaining its ease, safety, and low cost. A serum sample for cortisol determination is obtained 30 min after the iv injection of 1 µg ACTH; a value over 500 nmol/L is considered a normal response. A baseline value is not necessary, and the test may be performed at any time of day. The basis for its superior accuracy in the diagnosis of AI may be that very low levels of circulating ACTH keep the adrenal cortex in a state capable of transiently responding to a supraphysiological, but not a physiological, dose of ACTH (8). The entire stored pool of endogenous ACTH in the anterior pituitary is approximately 600 µg (9). Thus, the conventional 250-µg dose is expected to be quite an adrenal stimulus. Far lower doses of ACTH, such as 1 µg, may provide a more realistic level of stimulation to which only normal adrenals can respond.

	A Review of the Literature

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From as early as 1964, studies have analyzed the effects of various doses of ACTH on the normal human adrenal gland (10, 11, 12, 13). Landon et al. noted that maximal cortisol stimulation was obtained with 3 µg ACTH as easily as it was with 100 µg ACTH (10). In 1965, the same researchers published the first study of a synthetic ACTH stimulation test using 250 µg ACTH (11). No justification was given for the choice of 250 µg other than a notation that it is clearly more than required to produce a maximal adrenal response. In 1985, in a study of 10 normal subjects Graybeal et al. showed that a 10-min infusion of only 0.02 µg/kg ACTH produced ACTH and cortisol levels as high as those found after the stress of insulin-induced hypoglycemia (12). In 1995, Daidoh et al. observed that doses as low as 0.5 µg ACTH resulted in similar peak and incremental cortisol values as 250 µg ACTH in normal volunteers (13). Significantly lower cortisol values were attained only when subjects were given 0.1 µg ACTH.

For reasons that are unclear, the practice of using 250 µg for an ACTH stimulation test has persisted to this day and has become the standard of evaluation. The realization that much lower doses of ACTH will maximally stimulate cortisol secretion has been slow to translate into an updated clinical test for AI. Major endocrinology textbooks recommend the 250-µg test as the primary screening tool for AI, describing it as the most convenient and reliable test, except in cases of recent pituitary injury when the adrenal glands would still be expected to respond to an exogenous dose of ACTH (14).

Several reports document normal responses to 250 µg ACTH in patients in whom a diagnosis of AI was established by the ITT or metyrapone stimulation test (3, 5, 7, 8, 15). Cunningham et al. compared the effectiveness of the 250-µg ACTH stimulation test with either the metyrapone test or ITT (3). Of 20 cases of AI diagnosed with either metyrapone or the ITT, only 8 were detected by the conventional ACTH stimulation test. In 1987, Lindholm published a study reevaluating the clinical utility of the 250-µg ACTH stimulation test (15). Of 162 patients who achieved adequate hypoglycemia with the ITT, 26 were found to have AI. Importantly, testing with 250 µg ACTH missed the diagnosis in 7 of these 26 patients. However, 2 of the 7 patients had evidence of recent pituitary injury and should be eliminated from the analysis. Regardless, relying on the standard ACTH stimulation test would have failed to identify approximately one fifth of cases of true AI.

In 1991, Dickstein et al. reported results of low dose ACTH stimulation (4). They noted that in normal subjects, 30 min cortisol values were similar after the injection of 250, 5, or 1 µg ACTH. They also analyzed six patients receiving chronic steroids who had normal cortisol responses to 250 µg ACTH. Five of them had subnormal cortisol responses to 1 µg ACTH. Unfortunately, no gold standard test was performed to confirm the diagnosis of AI in these patients. Tordjman et al. compared various doses of ACTH with either metyrapone or ITT (5). They studied a control group, a group documented to have an impaired hypothyroid-pituitary-adrenal (HPA) axis due to pituitary disease, and a group with similar pituitary pathology but with a normal HPA axis. Using 1 µg ACTH, all subjects with AI were identified. However, 7 of 10 cases of AI were missed using the 30 min cortisol values after the administration of both the 5- and 250-µg doses. Interestingly, 2 patients in the group with known pituitary disease but normal HPA axis had abnormal responses during the 1-µg ACTH test. These findings may suggest that the low dose test is an even more sensitive indicator of adrenal dysfunction than the metyrapone test or ITT. As Streeten et al. have shown, reliance on the conventional ACTH stimulation test and resultant failure to make a diagnosis of AI can have serious consequences for affected patients (8).

Recent data also confirm the specificity of the 1-µg ACTH stimulation test (16). One microgram of ACTH has produced normal cortisol responses after 30 min in over 130 healthy subjects. This report demonstrates a low false positive rate, and hence high specificity, in addition to an extremely high sensitivity.

	Further Analysis

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When analyzing articles about a diagnostic test, it is helpful to look at likelihood ratios (LRs) in addition to test sensitivity and specificity (17, 18). LRs are ratios of two probabilities: (probability of test outcome given diseased patients)/(probability of test outcome given nondiseased patients) (19). The LR for a test of AI, for instance, indicates how many times more likely the test result is to occur with AI than without AI. In addition to their use in comparing test performance, LRs can be used to modify the probability that a patient has AI. Sensitivity and specificity are both incorporated into the calculation of a LR, and the information obtained is independent of the prevalence of disease in a given population. This is in direct contrast to positive and negative predictive values, which vary with changes in prevalence. When multiple independent tests are performed for which LRs are available, the LRs for each may be multiplied to derive a summary LR.

The LR for a positive test result [(+)LR] is calculated most easily by the formula, sensitivity/(1 - specificity). The LR for a negative test result [(-)LR] is calculated using the formula, (1 - sensitivity)/specificity. Once the LRs are calculated, and the pretest probability of disease is estimated by the physician, calculating the posttest probability of disease is straightforward. First, the pretest probability is converted to odds using the formula: [probability/(1 - probability)] = odds. This result multiplied by the LR yields the posttest odds. The odds are then converted into the posttest probability using the formula: odds/(odds + 1) = probability. Employing these calculations, one can show that a LR for a positive or negative test result of 1 does not change the pretest probability. LRs of greater than 10 and less than 0.1 generate large changes from pretest to posttest probability. LRs of 5–10 and 0.1–0.2 generate moderate changes from pretest to posttest probability. LRs of 2–5 and 0.2–0.5 generate small (but often important) changes in probability (18). Increases in LRs do not yield linear increases in probability; the relationship is more logarithmic (19). For example, if a clinician’s pretest probability of disease is 50%, then a change in (+)LR from 2 to 20 improves posttest probability from 67% to 95%, whereas a change in (+)LR from 20 to 200 improves posttest probability from 95% to 99.5%.

The several studies cited above provide enough information to calculate LRs for both the conventional and low dose ACTH stimulation tests. When a comparison of LRs is performed, inclusion of confidence intervals (CIs) for the LRs provides a more meaningful interpretation (20). Because the conventional ACTH stimulation test is extremely reliable when a positive result occurs, its (+)LR will be consistently high. However, given the reports of false negative results, its (-)LR may be less powerful. When investigating a condition such as AI, false negative results have serious repercussions. Therefore, the (-)LR will be the focus of this analysis and the means to compare the performances of the 250- and 1-µg ACTH tests (Table 1).

Lindholm’s study of the 250-µg ACTH stimulation test is perhaps one of the strongest in favor of its accuracy (15). After eliminating the two patients with evidence of recent pituitary injury from the analysis, the (+)LR is 108 (95% CI, 15.1,767), and the (-)LR is 0.21 (95% CI, 0.10,0.46). These results indicate assurance of the diagnosis when the test is positive due to the markedly high (+)LR. For instance, if the pretest probability of AI is 50%, a positive test result magnifies this to 99%. Conversely, given the moderately low (-)LR, a negative test result provides a less striking change from pretest probabilities. For instance, given the same pretest probability of 50%, a negative test result reduces this to 17%, clearly not ruling out the presence of AI.

At least two published reports permit calculations of LRs for both the conventional and low dose tests (Table 1). Using the data from Tordjman et al. (5) for the 250-µg test the (+)LR is (95% CI, 0.62,), and the (-)LR is 0.70 (95% CI, 0.47,1.06). Corresponding values for the 1-µg ACTH stimulation test are 8.0 (95% CI, 2.18,29.25) and 0 (95% CI, 0.0,0.81). For Rasmuson et al. (7), the (+)LR for the 250-µg test is 9.63 (95% CI, 1.47,62.95), and the (-)LR is 0.14 (95% CI, 0.04,0.51). For the 1-µg test, the (+)LR is (95% CI, 1.45,), and the (-)LR is 0.06 (95% CI,0.01,0.42). The data from these two studies may be combined to increase the power of a comparison. The integrated data for the 250-µg test reveal a (+)LR of 17.65 (95% CI, 2.53,123.29) and a (-)LR of 0.36 (95% CI, 0.21,0.61). Corresponding data for the 1-µg test reveal a (+)LR of 12.98 (95% CI, 3.41,49.37) and a (-)LR of 0.04 (95% CI, 0.01,0.28). As expected, CIs for the (+)LRs overlap because both tests are accurate when a positive result occurs. CI values for the (-)LRs slightly overlap, probably because the sample size is limited. A 90% CI is 0.008,0.21 for the (-)LR of the 1-µg test and 0.23,0.56 for the 250-µg test. These CIs do not overlap and indicate a significantly better (-)LR for the 1-µg ACTH test with 90% confidence. This translates to greater assurance of normal adrenal function with a normal test result. Applying the same example used in the analysis of Lindholm’s study illustrates this point well. If the pretest probability of AI is 50%, a negative result with the 250-µg test reduces this to 26%; however, a negative result with the 1-µg test would reduce this to 4%.

	Conclusions and Recommendations

Top Abstract Introduction A Review of the... Further Analysis Conclusions and Recommendations References

 
Compared to the ITT and metyrapone tests, the 1-µg test shows extremely high sensitivity, specificity, and, therefore, LRs that generate significant changes from pretest to posttest probability. Compared to the conventional 250-µg ACTH test, the 1-µg test has a lower (-)LR at the 90% confidence level, providing greater assurance that adrenal corticosteroid-producing ability is intact when a normal test result occurs. The clinical significance of these results has been substantiated by relevant literature that is replete with cases of AI initially misdiagnosed by the conventional 250-µg ACTH stimulation test (3, 5, 8, 15). The ramifications of a missed diagnosis of AI have been clearly illustrated by Streeten et al. and have been appreciated by most practicing endocrinologists (8).

We propose that the 1-µg ACTH stimulation test replace the standard 250-µg test when evaluating for central AI. A cortisol level below 500 nmol/L after 30 min signifies adrenal dysfunction. A baseline level is unnecessary, and the test may be performed at any time of day. If this low dose test results in a borderline value, for instance a 30 min cortisol value of 450–500 nmol/L, and the clinical picture is not consistent with AI, then an ITT should be performed. This strategy should result in an extremely high diagnostic accuracy. The 1-µg test should not be used if recent pituitary injury is suspected. Pharmaceutical companies should be encouraged to provide synthetic ACTH in 1-µg vials to facilitate testing, and until that time, extreme care is warranted when diluting a 250-µg vial. If too little of the drug is administered, the 30 min cortisol value may appear low, and a patient may be falsely suspected of having AI and thus subjected to unnecessary treatment with corticosteroids. If too much of the drug is inadvertently administered, the 30 min cortisol value may be normal (as seen with 250 µg ACTH), and a patient with true AI may have potentially life-saving treatment withheld. Our current policy is to add 250 µg ACTH to 250 mL 0.9% saline. One milliliter is then removed from the solution for iv injection. Preferably, a 1-mL syringe connected directly to a needle is used to inject the solution into a vein; this should be done because additional plastic tubing may reduce the amount of ACTH delivered (21). Although the stability of diluted ACTH has been established (4), our practice has been to discard the solution at the end of each day.

	Acknowledgments

 
Dr. James H. Christy provided several insightful comments after his review of the manuscript.

Received December 9, 1997.

Revised March 13, 1998.

Accepted May 11, 1998.

	References

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