Cushing investigations
Posted: 06 Oct 2012, 00:03
Low-dose/overnight dexamethasone suppression tests
In normal subjects, administration of a supraphysiological dose of a glucocorticoid results in suppression of ACTH and hence cortisol secretion. In Cushing’s syndrome of whatever cause there is failure of this suppression when low doses of the synthetic glucocorticoid dexamethasone are given. The overnight test is often used as an outpatient screening test. Various doses of dexamethasone have been used, usually given at midnight, but most experience is with a dose of 1 mg. A plasma cortisol of less than 50 nmol/litre between 08.00 and 09.00 the following morning has a sensitivity of 95% and specificity of 80% in excluding Cushing’s syndrome. Thus the outpatient overnight test has high sensitivity but low specificity, and further investigation is often required.
The conventional low-dose 48-h test is more accurate, but usually requires inpatient admission. Here, plasma cortisol is measured at 09.00 on day 0 and 48 h later, following dexamethasone given at a dose of 0.5 mg every 6 h for 48 h. This test is reported as having a 97 to 100% true positive rate and a false positive rate of less than 1%. Certain drugs (phenytoin, rifampicin) may increase the metabolic clearance rate of dexamethasone, thereby giving false positive results. If pseudo-Cushing’s syndrome is suspected, physicians in North America have modified this test slightly by administering CRF at the end of the dexamethasone suppression; ….
CRF test
CRF is a peptide of 41 amino acids, identified by Vale in 1981 from ovine hypothalami. The ovine sequence differs by seven amino acid residues from that of the human peptide, but despite this stimulates the release of ACTH in humans. The test involves the intravenous injection of either ovine or human CRF at a dose of 1 µg/kg body weight or a single dose of 100 µg. The test can be performed in the morning or afternoon, and after basal sampling, blood samples for ACTH and cortisol are taken every 15 min for 1 to 2 h after administering CRF.
In normal subjects CRF elicits a rise in ACTH and cortisol, and this response is exaggerated in Cushing’s disease. It is typically absent in ectopic ACTH syndrome and patients with adrenal tumours. In distinguishing pituitary-dependent Cushing’s disease from ectopic ACTH syndrome, the response of ACTH to CRF has a specificity of 90%, and with cortisol as the endpoint, 95%. Using as an endpoint an ACTH increase of 100% over basal, or a cortisol rise of 50%, this positive response eliminates a possible diagnosis of ectopic ACTH syndrome.
Metyrapone test
Metyrapone is an 11β-hydroxylase inhibitor that blocks the conversion of 11-deoxycortisol to cortisol, and deoxycorticosterone to corticosterone (Fig. 13.7.1.1). This lowers plasma cortisol and, via negative feedback control, increases plasma ACTH. This in turn stimulates an increase in the secretion of adrenal steroids proximal to the block. When metyrapone is given in doses of 750 mg every 4 h for 24 h, patients with Cushing’s disease exhibit an exaggerated rise in plasma ACTH, with 11-deoxycortisol levels at 24 h exceeding 1000 nmol/litre. In most patients with ectopic ACTH syndrome there is little or no response, but occasional patients (possibly those producing both ACTH and CRF) have an 11-deoxycortisol response that may be similar to that in Cushing’s disease.
The metyrapone test was originally used to distinguish patients with Cushing’s disease from those with a primary adrenal cause. However, these can be more reliably distinguished by measuring plasma ACTH and CT scanning of the adrenal glands. As indicated, the test does not reliably distinguish between Cushing’s disease and ectopic ACTH syndrome, and the value of this test has been questioned. It should be reserved for patients in whom the results of other tests are equivocal.
Alcohol-associated pseudo-Cushing’s syndrome
In the original description of this syndrome, urinary and plasma cortisol levels were elevated, but were not suppressed with dexamethasone. Plasma ACTH may be normal or suppressed. The frequency and pathogenesis of this condition remain unknown, but a two-hit hypothesis has been put forward to explain its aetiology. Chronic liver disease, irrespective of the cause, is associated with impaired cortisol metabolism, but in alcoholics this is associated with an increase in the cortisol secretion rate, rather than concomitant suppression in the face of impaired metabolism. With abstinence from alcohol the biochemical abnormalities rapidly revert to normal
In normal subjects, administration of a supraphysiological dose of a glucocorticoid results in suppression of ACTH and hence cortisol secretion. In Cushing’s syndrome of whatever cause there is failure of this suppression when low doses of the synthetic glucocorticoid dexamethasone are given. The overnight test is often used as an outpatient screening test. Various doses of dexamethasone have been used, usually given at midnight, but most experience is with a dose of 1 mg. A plasma cortisol of less than 50 nmol/litre between 08.00 and 09.00 the following morning has a sensitivity of 95% and specificity of 80% in excluding Cushing’s syndrome. Thus the outpatient overnight test has high sensitivity but low specificity, and further investigation is often required.
The conventional low-dose 48-h test is more accurate, but usually requires inpatient admission. Here, plasma cortisol is measured at 09.00 on day 0 and 48 h later, following dexamethasone given at a dose of 0.5 mg every 6 h for 48 h. This test is reported as having a 97 to 100% true positive rate and a false positive rate of less than 1%. Certain drugs (phenytoin, rifampicin) may increase the metabolic clearance rate of dexamethasone, thereby giving false positive results. If pseudo-Cushing’s syndrome is suspected, physicians in North America have modified this test slightly by administering CRF at the end of the dexamethasone suppression; ….
CRF test
CRF is a peptide of 41 amino acids, identified by Vale in 1981 from ovine hypothalami. The ovine sequence differs by seven amino acid residues from that of the human peptide, but despite this stimulates the release of ACTH in humans. The test involves the intravenous injection of either ovine or human CRF at a dose of 1 µg/kg body weight or a single dose of 100 µg. The test can be performed in the morning or afternoon, and after basal sampling, blood samples for ACTH and cortisol are taken every 15 min for 1 to 2 h after administering CRF.
In normal subjects CRF elicits a rise in ACTH and cortisol, and this response is exaggerated in Cushing’s disease. It is typically absent in ectopic ACTH syndrome and patients with adrenal tumours. In distinguishing pituitary-dependent Cushing’s disease from ectopic ACTH syndrome, the response of ACTH to CRF has a specificity of 90%, and with cortisol as the endpoint, 95%. Using as an endpoint an ACTH increase of 100% over basal, or a cortisol rise of 50%, this positive response eliminates a possible diagnosis of ectopic ACTH syndrome.
Metyrapone test
Metyrapone is an 11β-hydroxylase inhibitor that blocks the conversion of 11-deoxycortisol to cortisol, and deoxycorticosterone to corticosterone (Fig. 13.7.1.1). This lowers plasma cortisol and, via negative feedback control, increases plasma ACTH. This in turn stimulates an increase in the secretion of adrenal steroids proximal to the block. When metyrapone is given in doses of 750 mg every 4 h for 24 h, patients with Cushing’s disease exhibit an exaggerated rise in plasma ACTH, with 11-deoxycortisol levels at 24 h exceeding 1000 nmol/litre. In most patients with ectopic ACTH syndrome there is little or no response, but occasional patients (possibly those producing both ACTH and CRF) have an 11-deoxycortisol response that may be similar to that in Cushing’s disease.
The metyrapone test was originally used to distinguish patients with Cushing’s disease from those with a primary adrenal cause. However, these can be more reliably distinguished by measuring plasma ACTH and CT scanning of the adrenal glands. As indicated, the test does not reliably distinguish between Cushing’s disease and ectopic ACTH syndrome, and the value of this test has been questioned. It should be reserved for patients in whom the results of other tests are equivocal.
Alcohol-associated pseudo-Cushing’s syndrome
In the original description of this syndrome, urinary and plasma cortisol levels were elevated, but were not suppressed with dexamethasone. Plasma ACTH may be normal or suppressed. The frequency and pathogenesis of this condition remain unknown, but a two-hit hypothesis has been put forward to explain its aetiology. Chronic liver disease, irrespective of the cause, is associated with impaired cortisol metabolism, but in alcoholics this is associated with an increase in the cortisol secretion rate, rather than concomitant suppression in the face of impaired metabolism. With abstinence from alcohol the biochemical abnormalities rapidly revert to normal