Editing Hypercortisolism (section)

=== Labs ===

* '''<span style="color:#ff0000">Most frequently performed laboratory tests (3):'''
*# '''<span style="color:#ff0000">Overnight low-dose dexamethasone suppression test (LD-DST)</span>''' (sensitivity: 85-90, specificity: 95-99)
*# '''<span style="color:#ff0000">Late-night salivary cortisol</span>''' (sensitivity: 92-100, specificity: 93-100§)
*# '''<span style="color:#ff0000">24-hour urinary free cortisol</span>''' (sensitivity: 80-98 specificity: 45-98)
** '''<span style="color:#ff0000">2011 CUA Guidelines on Incidental Adrenal Mass recommend LD-DST</span>'''
* Second-line tests:
** 2-day low-dose dexamethasone suppression test
** Midnight plasma cortisol testing
* '''Low-dose dexamethasone suppression test (LD-DST)'''
** '''Recommended in the evaluation of an incidental adrenal mass (2011 CUA Guidelines on Incidental Adrenal Mass)'''
** '''Determines the presence of endogenous hypercortisolism, not the cause'''
*** To evaluate the patient’s glucocorticoid negative feedback system, a low-dose (1 mg) of dexamethasone is administered overnight followed by measurement of morning serum cortisol. The dose of dexamethasone administered is supraphysiologic and corresponds to 3-4x the level of physiologic glucocorticoids
*** '''In patients without hypercortisolism, the dexamethasone''' acts on the corticotropic cells of the anterior pituitary, suppresses ACTH production, and thereby '''results in a reduction of serum cortisol levels.'''
*** '''In patients with hypercortisolism due to endogenous causes, the dexamethasone fails to suppress cortisol production''' due to the relative insensitivity of pituitary adenomas to the inhibitory effects of glucocorticoid stimulation '''resulting in elevated serum cortisol levels''' despite dexamethasone.
** '''Exogenous steroid use cannot be ruled out with this test.'''
*** '''Exogenous steroids, including that used for the test, are not detected by the serum cortisol assay.'''
** Pharmaceuticals That Affect Overnight Low-Dose Dexamethasone Suppression Testing for Cushing Syndrome
*** Drugs that accelerate dexamethasone metabolism by induction of CYP3A4
**** Phenobarbital
**** Phenytoin
**** Carbamazepine
**** Primidone
**** Rifampin
**** Rifapentine
**** Ethosuximide
**** Pioglitazone
*** Drugs that impair dexamethasone metabolism by inhibition of CYP3A4
**** Aprepitant, fosaprepitant
**** Itraconazole
**** Ritonavir
**** Fluoxetine
**** Diltiazem
**** Cimetidine
*** Drugs that increase cortisol-binding globulin and may falsely elevate cortisol results
**** Estrogens
**** Mitotane
** '''LD-DST can yield as high as a 50% false-positive rate in women using oral contraceptives'''
*** Contraceptives increase total (but not bioavailable) cortisol levels by raising the patient’s cortisol-binding globulin concentrations
* '''Late night salivary cortisol and midnight plasma cortisol demonstrate a perturbation, and in some cases complete disruption, of the diurnal variation of cortisol levels'''
* '''24-hour urinary free cortisol'''
** '''May not be sensitive for subclinical Cushing syndrome, and the Endocrine Society recommends against it for metabolic evaluation of adrenal incidentalomas'''
** Drugs that increase urine free cortisol results
**# Carbamazepine
**# Fenofibrate (increase if measured by high-performance liquid chromatography)
**# Some synthetic glucocorticoids (immunoassays)
**# Drugs that inhibit 11β-hydroxysteroid dehydrogenase type 2 (licorice, carbenoxolone)

* '''After confirming hypercortisolism, serum ACTH is measured to distinguish ACTH-independent causes from ACTH-dependent causes'''
** '''Low serum ACTH'''
*** '''Suggests ACTH-independent pathology'''
*** '''Abdominal imaging is indicated to identify the adrenal source.'''
**** '''If the adrenals are unremarkable on imaging, exogenous steroids as a cause of Cushing syndrome, or much less commonly, primary pigmented nodular adrenocortical disease (PPNAD) should be suspected.'''
***** In PPNAD, the adrenal glands are normal in size and exhibit black or brown cortical nodules.
** '''High serum ACTH'''
*** '''Suggests pituitary source (Cushing disease) or ectopic ACTH syndrome'''
*** '''Can be difficult to distinguish Cushing disease from ectopic ACTH syndrome because both pituitary and ACTH-producing tumours can be very difficult to localize with imaging.'''
*** '''Direct measurements of ACTH in the inferior petrosal sinus, a downstream venous plexus that drains the pituitary, after CRH stimulation has become the gold standard approach for distinguishing ectopic ACTH production from Cushing disease.'''
*** '''High-dose dexamethasone suppression testing was used in the past''' to differentiate pituitary and ectopic ACTH sources, but the value of the test is limited.
**** The study is based on the principle that high enough doses of dexamethasone should suppress ACTH production by pituitary adenomas, whereas ectopic ACTH production continues despite the high-dose glucocorticoid administration
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