DIAGNOSIS
AND
TREATMENT
The dishing Syndrome: An Update on Diagnostic Tests Todd B. Kaye, M D ; and Lawrence Crapo, M D
Study Objective: Review and evaluation of diagnostic tests for the Cushing syndrome based on reports published since 1978. Data Identification: Studies published in the English literature from 1978 through 1989 were identified using Index Medicus and cross searching of bibliographies. Study Selection and Data Extraction: Studies of five or more patients for general analysis and smaller studies and case reports when pertinent. To develop criteria for the corticotropin-releasing hormone (CRH) stimulation test, only studies reporting individual patient data were analyzed. Results: No new test is clearly better than existing tests in establishing a definitive diagnosis. Among tests to determine cause, the CRH stimulation test, by newly developed criteria, has a 9 1 % sensitivity (95% CI, 85% to 95%) and a 95% specificity (CI, 82% to 99%), and the overnight highdose dexamethasone suppression test has an 89% sensitivity (CI, 80% to 94%) and a 100% specificity (CI, 84% to 100%) for the pituitary Cushing syndrome. Magnetic resonance imaging has greater sensitivity for detecting adrenocorticotropin (ACTH)-producing pituitary adenomas than computed tomography. Inferior petrosal sinus sampling can correctly identify a pituitary cause in 88% (CI, 79% to 94%) of cases. Conclusions: Diagnosis is still best established by using 24-hour urine free Cortisol measurements or low-dose dexamethasone suppression testing. The CRH stimulation test is an outpatient alternative to determine cause, and the overnight high-dose dexamethasone test may become the test of choice along with plasma ACTH measurements by radioimmunoassay in the initial evaluation of cause. Magnetic resonance imaging should be used to evaluate the pituitary Cushing syndrome, and inferior petrosal sinus sampling is most useful in problematic cases with uncertain cause.
Annals of Internal Medicine. 1990;112:434-444. From Santa Clara Valley Medical Center, San Jose, California; and Stanford University School of Medicine, Stanford, California. For current author addresses, see end of text.
434
significant advances in the diagnostic evaluation of the Cushing syndrome have been made in the past decade. Our investigation takes a two-step approach. We use initial tests to determine whether a patient has the disorder (the definitive diagnosis). Once the diagnosis is established, the cause must be determined to direct the proper treatment. The three main causes of the Cushing syndrome are pituitary overproduction of adrenocorticotropin ( A C T H ) , the ectopic A C T H syndrome, and cortisol-producing adrenal tumors. We cover the literature from 1978 through 1989 and emphasize advances in testing to identify cause, with special attention to the corticotropin-releasing hormone ( C R H ) stimulation test, the overnight high-dose dexamethasone suppression test, advances in radiographic imaging, and inferior petrosal sinus sampling. Criteria for the C R H stimulation test previously have not been clearly defined. We develop criteria for responses to the C R H stimulation test that are indicative of either pituitary or ectopic or adrenal causes. Finally, we discuss new tests used to diagnose the Cushing syndrome. Determining Cause In a previous review (1) of diagnostic tests for the Cushing syndrome, cause was found to be best determined by combining repeated plasma A C T H measurements by radioimmunoassay ( R I A ) with the classic high-dose (8 mg) dexamethasone suppression test. Normal to elevated plasma A C T H levels occur in the pituitary and ectopic Cushing syndromes, whereas plasma A C T H values are low in the adrenal Cushing syndrome. A new immunoradiometric assay ( I R M A ) for A C T H that is more sensitive and specific than the RIA method has recently been developed. However, tumors producing A C T H ectopically may secrete biologically active A C T H fragments or "big" A C T H that would not be detected by I R M A ( 2 ) . Plasma A C T H determinations by IRMA in the ectopic A C T H syndrome, therefore, may be misleadingly low. Plasma A C T H measurement by R I A is still preferred for the initial evaluation of cause. The classic high-dose dexamethasone suppression test is done by obtaining a basal 24-hour urine collection for Cortisol metabolites, administering 2 mg of dexamethasone orally every 6 hours for 2 days, and collecting urine for Cortisol metabolites during the second day ( 3 ) . In pituitary cases, the urine Cortisol metabolite is suppressed to 5 0 % or less of the basal value. In patients with the ectopic A C T H syndrome and ad-
© 1990 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a Penn State University Hershey User on 03/12/2017
renal tumors, there is generally lack of suppression. With this test, adrenal causes are reliably differentiated from pituitary causes, but pituitary and ectopic causes may occasionally be difficult to distinguish from each other. Further, the test usually requires hospitalization for at least 3 days to be done accurately and reliably because of the two 24-hour urine collections required and the need for precise timing in administering the dexamethasone. Significant progress has been made in developing more convenient and reliable tests. Corticotropin-Releasing Hormone Stimulation Test The major innovation in diagnostic testing for the Cushing syndrome came with the isolation and synthesis of CRH in 1981 by Vale and colleagues ( 4 ) . A CRH stimulation test was developed to evaluate patients with the Cushing syndrome. This test is based on the fact that the pituitary is responsive to CRH stimulation, whereas adrenal tumors and tumors producing ACTH ectopically are generally not responsive. The test is done by obtaining baseline serum ACTH and Cortisol values before administering CRH as an intravenous bolus injection. A dose of 1 jmg/kg body weight or 100 fxg of CRH is administered, and additional blood samples are obtained at 15, 30, 60, 90, and 120 minutes (and at even 150 and 180 minutes by some investigators) for measurement of ACTH and Cortisol levels. Values tend to peak from 15 to 60 minutes after CRH stimulation but may take longer. The test is well tolerated, with flushing and neck tightness reported in a minority of patients. At the above doses, tachycardia and hypotension are rare. The response to CRH tends to fall into three patterns (Figure 1). In controls, ACTH and Cortisol levels increase after injection of CRH. Patients with the pituitary Cushing syndrome have an exaggerated increase in plasma ACTH and Cortisol levels in response to CRH. Patients with the ectopic and adrenal Cushing syndromes have no increase in ACTH and Cortisol levels (a flat response) after administration of CRH. The overlap between the response in control subjects and patients with the pituitary Cushing syndrome is too great for this test to be used in the definitive diagnosis of the Cushing syndrome (5, 6). Instead, the CRH stimulation test is used to differentiate among the causes. In the studies analyzing the CRH stimulation test (7-16), the distinction between a pituitary cause and an adrenal or ectopic source is based on whether there is an exaggerated response or a flat response. However, the criteria for an exaggerated or a flat response are defined in only one study ( 9 ) , and these criteria are of limited clinical utility. Before the CRH test can be useful in determining cause, defined criteria for positive (exaggerated) and negative (flat) responses must be established. We have developed such criteria from analysis of the combined data from these studies. The percent change from basal to peak value is the most important
variable to examine, as considerable variation in baseline ACTH and Cortisol values in patients with the Cushing syndrome makes the peak value or the absolute change less meaningful for distinguishing the different causes. Table 1 depicts the distribution of the percent change from basal to peak values for both ACTH and Cortisol responses to CRH. We define a positive (exaggerated) response as an increase in ACTH value of 50% or greater or an increase in Cortisol value of 20% or greater from baseline, thus providing useful and simple criteria to indicate a pituitary cause. An increase in ACTH value of less than 50% or an increase in Cortisol value of less than 20% after CRH stimulation define a negative (flat) response, indicating an ectopic or adrenal cause. Table 2 contains a summary of the published CRH stimulation tests with these criteria applied. The sensitivity and specificity of the CRH test using ACTH response in 86% (95% CI, 79% to 91%) and 95% (CI, 84% to 99%), respectively. Using the Cortisol response, a sensitivity of 9 1 % (CI, 85% to 95%) and a specificity of 95% (CI, 82% to 99%) are achieved. These results compare favorably with those of the classic high-dose dexamethasone suppression test. The sensitivity and specificity of this test (using 17-hydroxycorticosteroids) are 92% (CI, 82% to 97%) and 94% (CI, 85% to 97%), respectively ( 1 ) . The CRH stimulation test successfully distinguishes pituitary from adrenal causes. There have been no reported cases of an adrenal tumor with a positive CRH stimulation test using the ACTH response and only one reported case using the Cortisol response (11). However, the major challenge, distinguishing pituitary from ectopic causes, is reliably accomplished by this test. When comparing only these two causes, the ACTH response to CRH has a specificity of 90%; the Cortisol response to CRH has a specificity of 95%. Further, there is only one reported case of the ectopic Cushing syndrome with an increase in ACTH of greater than 100% (17). (Data on the Cortisol response in that case were not provided.) There are no reported cases of a Cortisol response greater than 50% in the ectopic Cushing syndrome. Thus, for practical purposes, an ACTH increase of greater than 100% or a Cortisol increase greater than 50% eliminates the possibility of the ectopic ACTH syndrome. False-positive and false-negative responses have been noted in published case reports (17-22). Again, no defined criteria are used to judge these contradictory responses to CRH. Suda and colleagues (18) report three cases of the ectopic ACTH syndrome that "responded" to CRH. Using our criteria, two of the three cases did have a positive response of ACTH to CRH, but none had a positive response of Cortisol to CRH. In differentiating pituitary from ectopic causes, the Cortisol response to CRH is more specific than the ACTH response for a pituitary cause. Suda and colleagues postulate that this difference in specificity may be related to the "big" ACTH produced in the ectopic ACTH syndrome; "big" ACTH has less bioactivity to promote steroidogenesis. They have also postulated that with the higher basal levels of ACTH in the ec-
15 March 1990 • Annals of Internal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a Penn State University Hershey User on 03/12/2017
435
Figure 1. Responses of plasma adrenocorticotropin {ACTH) and Cortisol to ovine corticotropin-releasing hormone in, left, controls {open circles) and patients with the pituitary Cushing syndrome {closed circles) and, right, patients with the ectopic ACTH syndrome {closed triangles) and adrenal tumor {open squares). (Adapted from ref. 7 and 64. Reproduced with permission from the authors and publishers.)
topic Cushing syndrome, the adrenal glands are already maximally stimulated and will not respond to a further increase in the ACTH level. Some aspects of doing the CRH stimulation test warrant further comment. There is no appreciable difference in distribution of test results whether one administers 1 ]mg/kg of CRH at 0800 hours or 100 jug at 2000 hours. To facilitate outpatient use of this test, the CRH should be given at 0800 hours. Both ovine and human CRH have been used, but using ovine CRH achieves a greater sensitivity (23). Patients with the ectopic and adrenal Cushing syndromes who, in a hypercortisolemic state, lack a response to CRH, have
436
been reported to respond positively to CRH stimulation when their serum Cortisol levels are normalized by medical therapy (7-9). Thus, the test must be conducted with the patient in an untreated state. Corticotropin-releasing hormone is available from Bachem, Inc. (Torrance, California) on an investigational-newdrug basis. The CRH stimulation test has been criticized for providing little advantage over other current approaches to determining cause (24, 25). As previously shown, the sensitivity and specificity of the CRH stimulation test are similar to those of the classic high-dose dexamethasone suppression test in distinguishing pitu-
15 March 1990 • Annals ofInternal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a Penn State University Hershey User on 03/12/2017
itary from ectopic causes. These observations are corroborated by two studies (9, 12) directly comparing these tests. However, the CRH stimulation test can be done reliably in the outpatient setting in one morning. Not requiring hospitalization, the CRH stimulation test is a cost-effective alternative to the classic highdose dexamethasone suppression test in the initial evaluation to determine cause. The CRH stimulation test is also of value in problematic cases, such as patients with equivocal highdose dexamethasone suppression test results or when the biochemical data point to a pituitary source but radiographic examination shows a normal pituitary. Additional data are frequently needed to determine the cause in challenging cases. The two studies (9, 12) directly comparing the CRH stimulation test to the high-dose dexamethasone suppression test both concluded that the diagnostic power of each test is enhanced when the two tests are combined. However, the number of cases in which the two tests did not agree was small. Concern has been expressed that the same ectopic ACTH-secreting carcinoid tumors that suppress with high doses of dexamethasone (a false-positive response) will have a false-positive response to CRH stimulation (24). There is one case report (19) of a patient with a carcinoid tumor that was suppressible with dexamethasone and that had a positive response to the CRH stimulation test. But there are also cases of carcinoid tumors that have negative CRH stimulation tests (with unknown high-dose dexamethasone suppression test results) (7, 16). In one case of a carcinoid tumor, there was suppression with high-dose dexamethasone and a positive response of the ACTH level to CRH but no response of the Cortisol level to CRH ( 9 ) . Whether CRH stimulation testing will have any advantages over the high-dose dexamethasone test in these challenging cases of carcinoid tumors is not yet clear. One final area of difficulty is bilateral macronodular adrenal hyperplasia. The number of cases studied are small, and it is unclear whether nonpigmented macroTable 1.
Respomie to Corticotropin-Releasing
Change
% 9 or less 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99 100 or more Total
Hormone
nodular hyperplasia is distinguished from pigmented micronodular dysplasia. Two of six cases had positive ACTH responses to CRH, and three of six cases had positive Cortisol responses to CRH (11, 13, 26). This inconsistency may reflect the dual pituitary and adrenal influences in cases of this type. A plasma CRH measurement itself is not widely available and plays little role in determining cause. Corticotropin-releasing hormone values tend to be low in the pituitary Cushing syndrome, the ectopic ACTH syndrome, and adrenal tumors (25). Only in very rare cases due to ectopic CRH production is the plasma CRH value elevated and, therefore, helpful in diagnosis. The CRH stimulation test reliably differentiates between pituitary and nonpituitary causes. The diagnostic accuracy of this test is equal to that of the classic high-dose dexamethasone suppression test and provides a reasonable alternative in the initial investigation of cause. It also is useful in providing additional information in problematic cases. Using the Cortisol rather than the ACTH response to CRH affords superior sensitivity and specificity, lower testing cost and complexity, and avoids multiple ACTH assays. Overnight High-Dose Dexamethasone Suppression Test The classic high-dose (8 mg) dexamethasone suppression test developed by Liddle (3) in 1960 has been a key test in determining cause ( 1 ) . However, as previously mentioned, doing this test is cumbersome, and an overnight high-dose dexamethasone suppression test, therefore, has been developed (27, 28). A baseline serum Cortisol is drawn at 0800 hours, and 8 mg of dexamethasone are taken orally at 2300 hours that same day. The next morning, another serum Cortisol is drawn. No adverse effects have been reported with this test. Like the classic high-dose dexamethasone suppression test, this overnight high-dose dexamethasone suppression test is based on the ability of high doses of
(CRH)
Stimulat ion *
Adrenocorticotropin ( A C T H ) Response Pituitary Ectopic Adrenal
n
3 6 7 2 2 8 5 2 5 7 95 142
9 5 4 1
14 3 1 1
1 1
21
19
6 7 11 17 10 16 13 8 5 6 43 142
19 1 1
11 4 1
21
16
* Summary of the literature for the C R H stimulation test (7-16 ) using 1 u,g/kg of CFLH at 2000 hours or 100 jag of CRH at 0800 houirs in patients with the Cushing syridrome of pituitary, ectc>pic, or adrenal cause. The above data represt;nt the number of pa tients with the stated percent: change from basal to peak value c)f ACTH or Cortisol.
15 March 1990 • Annals of Internal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a Penn State University Hershey User on 03/12/2017
437
Table 2.
Corticotropin-!Releasing Hormone
Study (Reference)
(CRH)
Stimulation
Test*
AND
TREATMENT
The dishing Syndrome: An Update on Diagnostic Tests Todd B. Kaye, M D ; and Lawrence Crapo, M D
Study Objective: Review and evaluation of diagnostic tests for the Cushing syndrome based on reports published since 1978. Data Identification: Studies published in the English literature from 1978 through 1989 were identified using Index Medicus and cross searching of bibliographies. Study Selection and Data Extraction: Studies of five or more patients for general analysis and smaller studies and case reports when pertinent. To develop criteria for the corticotropin-releasing hormone (CRH) stimulation test, only studies reporting individual patient data were analyzed. Results: No new test is clearly better than existing tests in establishing a definitive diagnosis. Among tests to determine cause, the CRH stimulation test, by newly developed criteria, has a 9 1 % sensitivity (95% CI, 85% to 95%) and a 95% specificity (CI, 82% to 99%), and the overnight highdose dexamethasone suppression test has an 89% sensitivity (CI, 80% to 94%) and a 100% specificity (CI, 84% to 100%) for the pituitary Cushing syndrome. Magnetic resonance imaging has greater sensitivity for detecting adrenocorticotropin (ACTH)-producing pituitary adenomas than computed tomography. Inferior petrosal sinus sampling can correctly identify a pituitary cause in 88% (CI, 79% to 94%) of cases. Conclusions: Diagnosis is still best established by using 24-hour urine free Cortisol measurements or low-dose dexamethasone suppression testing. The CRH stimulation test is an outpatient alternative to determine cause, and the overnight high-dose dexamethasone test may become the test of choice along with plasma ACTH measurements by radioimmunoassay in the initial evaluation of cause. Magnetic resonance imaging should be used to evaluate the pituitary Cushing syndrome, and inferior petrosal sinus sampling is most useful in problematic cases with uncertain cause.
Annals of Internal Medicine. 1990;112:434-444. From Santa Clara Valley Medical Center, San Jose, California; and Stanford University School of Medicine, Stanford, California. For current author addresses, see end of text.
434
significant advances in the diagnostic evaluation of the Cushing syndrome have been made in the past decade. Our investigation takes a two-step approach. We use initial tests to determine whether a patient has the disorder (the definitive diagnosis). Once the diagnosis is established, the cause must be determined to direct the proper treatment. The three main causes of the Cushing syndrome are pituitary overproduction of adrenocorticotropin ( A C T H ) , the ectopic A C T H syndrome, and cortisol-producing adrenal tumors. We cover the literature from 1978 through 1989 and emphasize advances in testing to identify cause, with special attention to the corticotropin-releasing hormone ( C R H ) stimulation test, the overnight high-dose dexamethasone suppression test, advances in radiographic imaging, and inferior petrosal sinus sampling. Criteria for the C R H stimulation test previously have not been clearly defined. We develop criteria for responses to the C R H stimulation test that are indicative of either pituitary or ectopic or adrenal causes. Finally, we discuss new tests used to diagnose the Cushing syndrome. Determining Cause In a previous review (1) of diagnostic tests for the Cushing syndrome, cause was found to be best determined by combining repeated plasma A C T H measurements by radioimmunoassay ( R I A ) with the classic high-dose (8 mg) dexamethasone suppression test. Normal to elevated plasma A C T H levels occur in the pituitary and ectopic Cushing syndromes, whereas plasma A C T H values are low in the adrenal Cushing syndrome. A new immunoradiometric assay ( I R M A ) for A C T H that is more sensitive and specific than the RIA method has recently been developed. However, tumors producing A C T H ectopically may secrete biologically active A C T H fragments or "big" A C T H that would not be detected by I R M A ( 2 ) . Plasma A C T H determinations by IRMA in the ectopic A C T H syndrome, therefore, may be misleadingly low. Plasma A C T H measurement by R I A is still preferred for the initial evaluation of cause. The classic high-dose dexamethasone suppression test is done by obtaining a basal 24-hour urine collection for Cortisol metabolites, administering 2 mg of dexamethasone orally every 6 hours for 2 days, and collecting urine for Cortisol metabolites during the second day ( 3 ) . In pituitary cases, the urine Cortisol metabolite is suppressed to 5 0 % or less of the basal value. In patients with the ectopic A C T H syndrome and ad-
© 1990 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a Penn State University Hershey User on 03/12/2017
renal tumors, there is generally lack of suppression. With this test, adrenal causes are reliably differentiated from pituitary causes, but pituitary and ectopic causes may occasionally be difficult to distinguish from each other. Further, the test usually requires hospitalization for at least 3 days to be done accurately and reliably because of the two 24-hour urine collections required and the need for precise timing in administering the dexamethasone. Significant progress has been made in developing more convenient and reliable tests. Corticotropin-Releasing Hormone Stimulation Test The major innovation in diagnostic testing for the Cushing syndrome came with the isolation and synthesis of CRH in 1981 by Vale and colleagues ( 4 ) . A CRH stimulation test was developed to evaluate patients with the Cushing syndrome. This test is based on the fact that the pituitary is responsive to CRH stimulation, whereas adrenal tumors and tumors producing ACTH ectopically are generally not responsive. The test is done by obtaining baseline serum ACTH and Cortisol values before administering CRH as an intravenous bolus injection. A dose of 1 jmg/kg body weight or 100 fxg of CRH is administered, and additional blood samples are obtained at 15, 30, 60, 90, and 120 minutes (and at even 150 and 180 minutes by some investigators) for measurement of ACTH and Cortisol levels. Values tend to peak from 15 to 60 minutes after CRH stimulation but may take longer. The test is well tolerated, with flushing and neck tightness reported in a minority of patients. At the above doses, tachycardia and hypotension are rare. The response to CRH tends to fall into three patterns (Figure 1). In controls, ACTH and Cortisol levels increase after injection of CRH. Patients with the pituitary Cushing syndrome have an exaggerated increase in plasma ACTH and Cortisol levels in response to CRH. Patients with the ectopic and adrenal Cushing syndromes have no increase in ACTH and Cortisol levels (a flat response) after administration of CRH. The overlap between the response in control subjects and patients with the pituitary Cushing syndrome is too great for this test to be used in the definitive diagnosis of the Cushing syndrome (5, 6). Instead, the CRH stimulation test is used to differentiate among the causes. In the studies analyzing the CRH stimulation test (7-16), the distinction between a pituitary cause and an adrenal or ectopic source is based on whether there is an exaggerated response or a flat response. However, the criteria for an exaggerated or a flat response are defined in only one study ( 9 ) , and these criteria are of limited clinical utility. Before the CRH test can be useful in determining cause, defined criteria for positive (exaggerated) and negative (flat) responses must be established. We have developed such criteria from analysis of the combined data from these studies. The percent change from basal to peak value is the most important
variable to examine, as considerable variation in baseline ACTH and Cortisol values in patients with the Cushing syndrome makes the peak value or the absolute change less meaningful for distinguishing the different causes. Table 1 depicts the distribution of the percent change from basal to peak values for both ACTH and Cortisol responses to CRH. We define a positive (exaggerated) response as an increase in ACTH value of 50% or greater or an increase in Cortisol value of 20% or greater from baseline, thus providing useful and simple criteria to indicate a pituitary cause. An increase in ACTH value of less than 50% or an increase in Cortisol value of less than 20% after CRH stimulation define a negative (flat) response, indicating an ectopic or adrenal cause. Table 2 contains a summary of the published CRH stimulation tests with these criteria applied. The sensitivity and specificity of the CRH test using ACTH response in 86% (95% CI, 79% to 91%) and 95% (CI, 84% to 99%), respectively. Using the Cortisol response, a sensitivity of 9 1 % (CI, 85% to 95%) and a specificity of 95% (CI, 82% to 99%) are achieved. These results compare favorably with those of the classic high-dose dexamethasone suppression test. The sensitivity and specificity of this test (using 17-hydroxycorticosteroids) are 92% (CI, 82% to 97%) and 94% (CI, 85% to 97%), respectively ( 1 ) . The CRH stimulation test successfully distinguishes pituitary from adrenal causes. There have been no reported cases of an adrenal tumor with a positive CRH stimulation test using the ACTH response and only one reported case using the Cortisol response (11). However, the major challenge, distinguishing pituitary from ectopic causes, is reliably accomplished by this test. When comparing only these two causes, the ACTH response to CRH has a specificity of 90%; the Cortisol response to CRH has a specificity of 95%. Further, there is only one reported case of the ectopic Cushing syndrome with an increase in ACTH of greater than 100% (17). (Data on the Cortisol response in that case were not provided.) There are no reported cases of a Cortisol response greater than 50% in the ectopic Cushing syndrome. Thus, for practical purposes, an ACTH increase of greater than 100% or a Cortisol increase greater than 50% eliminates the possibility of the ectopic ACTH syndrome. False-positive and false-negative responses have been noted in published case reports (17-22). Again, no defined criteria are used to judge these contradictory responses to CRH. Suda and colleagues (18) report three cases of the ectopic ACTH syndrome that "responded" to CRH. Using our criteria, two of the three cases did have a positive response of ACTH to CRH, but none had a positive response of Cortisol to CRH. In differentiating pituitary from ectopic causes, the Cortisol response to CRH is more specific than the ACTH response for a pituitary cause. Suda and colleagues postulate that this difference in specificity may be related to the "big" ACTH produced in the ectopic ACTH syndrome; "big" ACTH has less bioactivity to promote steroidogenesis. They have also postulated that with the higher basal levels of ACTH in the ec-
15 March 1990 • Annals of Internal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a Penn State University Hershey User on 03/12/2017
435
Figure 1. Responses of plasma adrenocorticotropin {ACTH) and Cortisol to ovine corticotropin-releasing hormone in, left, controls {open circles) and patients with the pituitary Cushing syndrome {closed circles) and, right, patients with the ectopic ACTH syndrome {closed triangles) and adrenal tumor {open squares). (Adapted from ref. 7 and 64. Reproduced with permission from the authors and publishers.)
topic Cushing syndrome, the adrenal glands are already maximally stimulated and will not respond to a further increase in the ACTH level. Some aspects of doing the CRH stimulation test warrant further comment. There is no appreciable difference in distribution of test results whether one administers 1 ]mg/kg of CRH at 0800 hours or 100 jug at 2000 hours. To facilitate outpatient use of this test, the CRH should be given at 0800 hours. Both ovine and human CRH have been used, but using ovine CRH achieves a greater sensitivity (23). Patients with the ectopic and adrenal Cushing syndromes who, in a hypercortisolemic state, lack a response to CRH, have
436
been reported to respond positively to CRH stimulation when their serum Cortisol levels are normalized by medical therapy (7-9). Thus, the test must be conducted with the patient in an untreated state. Corticotropin-releasing hormone is available from Bachem, Inc. (Torrance, California) on an investigational-newdrug basis. The CRH stimulation test has been criticized for providing little advantage over other current approaches to determining cause (24, 25). As previously shown, the sensitivity and specificity of the CRH stimulation test are similar to those of the classic high-dose dexamethasone suppression test in distinguishing pitu-
15 March 1990 • Annals ofInternal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a Penn State University Hershey User on 03/12/2017
itary from ectopic causes. These observations are corroborated by two studies (9, 12) directly comparing these tests. However, the CRH stimulation test can be done reliably in the outpatient setting in one morning. Not requiring hospitalization, the CRH stimulation test is a cost-effective alternative to the classic highdose dexamethasone suppression test in the initial evaluation to determine cause. The CRH stimulation test is also of value in problematic cases, such as patients with equivocal highdose dexamethasone suppression test results or when the biochemical data point to a pituitary source but radiographic examination shows a normal pituitary. Additional data are frequently needed to determine the cause in challenging cases. The two studies (9, 12) directly comparing the CRH stimulation test to the high-dose dexamethasone suppression test both concluded that the diagnostic power of each test is enhanced when the two tests are combined. However, the number of cases in which the two tests did not agree was small. Concern has been expressed that the same ectopic ACTH-secreting carcinoid tumors that suppress with high doses of dexamethasone (a false-positive response) will have a false-positive response to CRH stimulation (24). There is one case report (19) of a patient with a carcinoid tumor that was suppressible with dexamethasone and that had a positive response to the CRH stimulation test. But there are also cases of carcinoid tumors that have negative CRH stimulation tests (with unknown high-dose dexamethasone suppression test results) (7, 16). In one case of a carcinoid tumor, there was suppression with high-dose dexamethasone and a positive response of the ACTH level to CRH but no response of the Cortisol level to CRH ( 9 ) . Whether CRH stimulation testing will have any advantages over the high-dose dexamethasone test in these challenging cases of carcinoid tumors is not yet clear. One final area of difficulty is bilateral macronodular adrenal hyperplasia. The number of cases studied are small, and it is unclear whether nonpigmented macroTable 1.
Respomie to Corticotropin-Releasing
Change
% 9 or less 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99 100 or more Total
Hormone
nodular hyperplasia is distinguished from pigmented micronodular dysplasia. Two of six cases had positive ACTH responses to CRH, and three of six cases had positive Cortisol responses to CRH (11, 13, 26). This inconsistency may reflect the dual pituitary and adrenal influences in cases of this type. A plasma CRH measurement itself is not widely available and plays little role in determining cause. Corticotropin-releasing hormone values tend to be low in the pituitary Cushing syndrome, the ectopic ACTH syndrome, and adrenal tumors (25). Only in very rare cases due to ectopic CRH production is the plasma CRH value elevated and, therefore, helpful in diagnosis. The CRH stimulation test reliably differentiates between pituitary and nonpituitary causes. The diagnostic accuracy of this test is equal to that of the classic high-dose dexamethasone suppression test and provides a reasonable alternative in the initial investigation of cause. It also is useful in providing additional information in problematic cases. Using the Cortisol rather than the ACTH response to CRH affords superior sensitivity and specificity, lower testing cost and complexity, and avoids multiple ACTH assays. Overnight High-Dose Dexamethasone Suppression Test The classic high-dose (8 mg) dexamethasone suppression test developed by Liddle (3) in 1960 has been a key test in determining cause ( 1 ) . However, as previously mentioned, doing this test is cumbersome, and an overnight high-dose dexamethasone suppression test, therefore, has been developed (27, 28). A baseline serum Cortisol is drawn at 0800 hours, and 8 mg of dexamethasone are taken orally at 2300 hours that same day. The next morning, another serum Cortisol is drawn. No adverse effects have been reported with this test. Like the classic high-dose dexamethasone suppression test, this overnight high-dose dexamethasone suppression test is based on the ability of high doses of
(CRH)
Stimulat ion *
Adrenocorticotropin ( A C T H ) Response Pituitary Ectopic Adrenal
n
3 6 7 2 2 8 5 2 5 7 95 142
9 5 4 1
14 3 1 1
1 1
21
19
6 7 11 17 10 16 13 8 5 6 43 142
19 1 1
11 4 1
21
16
* Summary of the literature for the C R H stimulation test (7-16 ) using 1 u,g/kg of CFLH at 2000 hours or 100 jag of CRH at 0800 houirs in patients with the Cushing syridrome of pituitary, ectc>pic, or adrenal cause. The above data represt;nt the number of pa tients with the stated percent: change from basal to peak value c)f ACTH or Cortisol.
15 March 1990 • Annals of Internal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a Penn State University Hershey User on 03/12/2017
437
Table 2.
Corticotropin-!Releasing Hormone
Study (Reference)
(CRH)
Stimulation
Test*
