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Diagnosis of Adrenal Insufficiency

Richard I. Dorin, MD; Clifford R. Qualls, PhD; and Lawrence M. Crapo, MD, PhD
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From New Mexico Veterans Administration Health Care System and University of New Mexico, Albuquerque, New Mexico; Santa Clara Valley Medical Center, San Jose, California; and Stanford University, Palo Alto, California.

Ann Intern Med. 2003;139(3):194-204. doi:10.7326/0003-4819-139-3-200308050-00017
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Background: The cosyntropin stimulation test is the initial endocrine evaluation of suspected primary or secondary adrenal insufficiency.

Purpose: To critically review the utility of the cosyntropin stimulation test for evaluating adrenal insufficiency.

Data Sources: The MEDLINE database was searched from 1966 to 2002 for all English-language papers related to the diagnosis of adrenal insufficiency.

Study Selection: Studies with fewer than 5 persons with primary or secondary adrenal insufficiency or with fewer than 10 persons as normal controls were excluded. For secondary adrenal insufficiency, only studies that stratified participants by integrated tests of adrenal function were included.

Data Extraction: Summary receiver-operating characteristic (ROC) curves were generated from all studies that provided sensitivity and specificity data for 250-g and 1-g cosyntropin tests; these curves were then compared by using area under the curve (AUC) methods. All estimated values are given with 95% CIs.

Data Synthesis: At a specificity of 95%, sensitivities were 97%, 57%, and 61% for summary ROC curves in tests for primary adrenal insufficiency (250-g cosyntropin test), secondary adrenal insufficiency (250-g cosyntropin test), and secondary adrenal insufficiency (1-g cosyntropin test), respectively. The area under the curve for primary adrenal insufficiency was significantly greater than the AUC for secondary adrenal insufficiency for the high-dose cosyntropin test (P < 0.001), but AUCs for the 250-g and 1-g cosyntropin tests did not differ significantly (P > 0.5) for secondary adrenal insufficiency. At a specificity of 95%, summary ROC analysis for the 250-g cosyntropin test yielded a positive likelihood ratio of 11.5 (95% CI, 8.7 to 14.2) and a negative likelihood ratio of 0.45 (CI, 0.30 to 0.60) for the diagnosis of secondary adrenal insufficiency.

Conclusions: Cortisol response to cosyntropin varies considerably among healthy persons. The cosyntropin test performs well in patients with primary adrenal insufficiency, but the lower sensitivity in patients with secondary adrenal insufficiency necessitates use of tests involving stimulation of the hypothalamus if the pretest probability is sufficiently high. The operating characteristics of the 250-g and 1-g cosyntropin tests are similar.


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Figure 1.
Summary receiver-operating characteristic (SROC) curves for high-dose (250-µg) and low-dose (1-µg) cosyntropin tests in secondary adrenal insufficiency.white circleswhite squares

The SROC curve for the high-dose cosyntropin test was derived from SROC analysis of 20 independent studies (Table 2), where each point ( ) represents an individual study. The SROC curve for the low-dose cosyntropin test was derived from 9 independent studies (Table 4), where each point ( ) represents an individual study.

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Figure 2.
Diagnostic pathway for suspected chronic adrenal insufficiency.

The evaluation begins with a high-dose 250-µg cosyntropin stimulation test (intramuscular or intravenous); plasma cortisol levels are then measured 30 to 60 minutes after the test. The test result is considered positive (abnormal) when the stimulated cortisol level is less than 500 nmol/L. Because a negative (normal) test result does not exclude mild or recent-onset adrenal insufficiency, additional testing is necessary to confirm a clinical suspicion of these disorders. ACTH = adrenocorticotropic hormone.

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Appendix Figure.
Receiver-operating characteristic curves for high-dose (250-µg) and low-dose (1-µg) cosyntropin stimulation tests for plasma cortisol levels obtained at 30 minutes in secondary adrenal insufficiency.

The curve for each test is generated from the raw data by determining the sensitivity and specificity for each test at many different plasma cortisol cutoff levels; the sensitivity increases as the plasma cortisol cutoff levels increase. The arrow denotes the point at which both tests yield identical sensitivities of 70% at a specificity of 95%; this breakpoint corresponds to plasma cortisol cutoff levels of 630 nmol/L for the high-dose test and 560 nmol/L for the low-dose test. For this assay, these plasma cortisol levels correspond to serum cortisol levels of 570 nmol/L for the high-dose cosyntropin test and 500 nmol/L for the low-dose cosyntropin test. These cutoff levels also produce identical positive and negative likelihood ratios (14.6 and 0.3, respectively). Data to calculate these curves were derived from a previously published study (18), and raw data were provided by Dr. Wolfgang Oelkers (University of Berlin).

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