Investigations of Cushing Syndrome

1. Lab Studies

Biochemical evaluation of Cushing syndrome

The diagnosis of Cushing syndrome due to endogenous overproduction of cortisol requires the demonstration of inappropriately high serum or urine cortisol levels.

Currently, 4 methods are accepted for the diagnosis of Cushing syndrome: urinary free cortisol level, low-dose dexamethasone suppression test, evening serum and salivary cortisol level, and dexamethasone–corticotropin-releasing hormone test.

- Urinary free cortisol (UFC) determination provides measurement of cortisol over a 24-hour period. Urine free cortisol values higher than 3-4 times the upper limit of normal are highly suggestive of Cushing syndrome.

- Dexamethasone suppression tests mimic the physiology of the pituitary, which in the presence of steroids decreases the release of ACTH causing a fall in plasma and urine cortisol. In Cushing syndrome, a loss of sensitivity to glucocorticoids occurs and ACTH is therefore not suppressed and adrenal production of cortisol is not affected. The overnight 1-mg dexamethasone suppression test requires administration of 1 mg of dexamethasone at 11 pm with subsequent measurement of cortisol level at 8 am. In healthy individuals, the serum cortisol level should be less than 2-3 mcg/dL. A cutoff value of less than 1.8 mcg/dL (50 nmol/L) excludes Cushing syndrome. Its ease of administration makes the 1-mg dexamethasone suppression test a widely used screening tool.
- Late night serum and salivary cortisol levels take advantage of the alterations in circadian rhythm of cortisol secretion in patients with Cushing syndrome. Normally, nighttime cortisol values are at their lowest level; in patients with Cushing syndrome, elevated nighttime cortisol can be an early but not definitive finding. This test requires hospitalization with blood samples obtained within 5-10 minutes of waking a patient and is not a practical test.

- Measuring salivary cortisol level is a simple and convenient way of obtaining a nighttime sample. This measurement allows patients to collect their own samples at home. With repeated measurements, levels less than 1.3 ng/mL (radioimmunoassay) or 1.5 ng/mL (competitive protein-binding assay) exclude Cushing syndrome. Less experience has been gathered for this assay, and it is expensive. Readings are obtained over several evenings to increase accuracy.

- The dexamethasone-CRH test is intended to distinguish patients with Cushing syndrome from those with pseudo-Cushing states. It combines a 48-hour low-dose dexamethasone suppression test with CRH stimulation. Dexamethasone (0.5 mg every 6 hours) is given 8 times, CRH is then administered intravenously and plasma cortisol and ACTH levels are obtained at 15-minute intervals for 1 hour. A cortisol value greater than 50 nmol/L (1.4 mcg/dL) identifies Cushing syndrome. This test is reserved for patients with high clinical suspicion for Cushing syndrome but equivocal results on other diagnostic tests.

Unfortunately, mild Cushing syndrome is often difficult to distinguish from normal cortisol secretion or pseudo-Cushing states. The aforementioned tests can produce both false-positive and false-negative results. False-positive results are associated with obesity, alcoholism, chronic renal failure, affective disorders, strenuous exercise, or eating disorders. Other potential confounders in the interpretation of tests include the following:

Medications that increase corticosteroid-binding globulin, such as estrogen and tamoxifen, may cause appropriate increases in serum cortisol levels.
Medications that facilitate the metabolism of dexamethasone, such as phenobarbital, phenytoin, and rifampin, may cause false-positive results with the dexamethasone suppression test.

Acute illness activates the Hypothalamic- Pituitary- Adrenal (HPA) axis, resulting in increases in ACTH and cortisol, the laboratory workup for Cushing syndrome should not be performed when subjects are acutely ill.

Other laboratory abnormalities seen in Cushing syndrome include the following:
Elevated white blood cell count greater than 11,000/mm3
Hypokalemic metabolic alkalosis may occur in patients with urinary free cortisol levels higher than 1500 mcg/24 h.

Once the diagnosis is established, the next step requires determining the etiology of Cushing syndrome. This first involves identifying if the hypercortisolism is an ACTH-dependent or ACTH-independent disorder.

· A plasma ACTH level that is undetectable is diagnostic of ACTH-independent Cushing syndrome. There are patients with cortisol-producing adrenal adenomas, where the ACTH may be undetectable; therefore, several collections should be obtained.
· A plasma ACTH (measured by an immunoradiometric assay) of less than 5 pg/mL is suggestive of a primary adrenal tumor.
· An ACTH level greater than 10-20 pg/mL is consistent with ACTH-dependent Cushing syndrome.
· For ACTH-dependent disease, the high dose (8-mg) overnight dexamethasone suppression test and the 48-hour high-dose dexamethasone test determine whether a patient who has pituitary-dependent or ectopic ACTH disease.

8-mg overnight dexamethasone suppression test: Individuals ingest 8 mg dexamethasone orally at 11 pm, with measurement of an 8 am cortisol level the next day. Suppression of serum cortisol level to less than 50% of baseline is suggestive of a pituitary source of ACTH rather than ectopic ACTH.

48-hour high-dose dexamethasone suppression test: Patients ingest 2 mg dexamethasone every 6 hours for 8 doses. A decrease in urinary free cortisol of greater than 50% is suggestive of an anterior pituitary adenoma rather than ectopic ACTH.

· Testing with CRH is also used in the differential diagnosis of ACTH-dependent Cushing syndrome. In most patients with pituitary ACTH secretion, the intravenous administration of CRH causes a rise in plasma ACTH and cortisol levels. In patients with ectopic secretion of ACTH, CRH does not affect ACTH or cortisol levels. ACTH and cortisol samples are obtained before administration of ovine CRH (oCRH), and subsequently at 15, 30, 45, 60, 90, and 120 minutes after administration of 1 mcg/kg of CRH.

· If concern for adrenal carcinoma exists, measurement of 17-ketosteroid or other cortisol precursors (eg, serum dehydroepiandrosterone sulfate [DHEAS]) is useful.

2. Imaging Studies:

Imaging studies for Cushing syndrome should be performed after the biochemical evaluation has been performed. The rationale for this is that unguided imaging of the pituitary or adrenal glands may yield a 10% incidence of incidental nonfunctioning pituitary or adrenal adenomas, which may mislead one from proper therapy and surgery. Ideally, the biochemical abnormalities should reconcile with the anatomic abnormalities before definitive therapy is offered.

- An abdominal CT scan is recommended if a primary adrenal problem is suspected. The presence of an adrenal mass larger than 4-6 cm raises the possibility that the mass is an adrenal carcinoma.
- If a pituitary source of excess ACTH is suspected, patients should undergo a contrast-enhanced magnetic resonance imaging (MRI) study of the pituitary.
- Chest and abdominal CT scans should be performed in patients with suspected ectopic ACTH production.

Contributed by John Lee

Source: http://www.emedicine.com/emerg/topic117.htm