Progressive muscle weakness: More there than meets the eye
HOW TO TEST FOR CUSHING SYNDROME
2. In any practice, you may meet many perimenopausal women who have complaints of weight gain, amenorrhea, and acne. How can you determine if this is Cushing syndrome? What are the screening tests?
- 24-Hour urinary cortisol excretion
- A late-night salivary cortisol level
- A low-dose dexamethasone suppression test
- All of the above
- None of the above
Any of the tests listed here can be used to determine whether this is truly Cushing syndrome.
24-Hour urinary cortisol excretion has a reference range of 20 to 100 μg/24 hours. However, results may be falsely high in patients who are depressed or who abuse alcohol.
The late-night salivary cortisol level is another useful test.14,16,18 Patients with Cushing syndrome are found to have high late-night salivary cortisol levels as compared with normal people, indicating the loss of natural circadian rhythm.14,16,18
The low-dose dexamethasone suppression test, as first described by Liddle in 1960,19 involved giving dexamethasone 0.5 mg by mouth every 6 hours for 48 hours and measuring the serum cortisol level 6 hours after the last dose. In healthy people, this low dose of dexamethasone suppresses the production of corticotropin by the pituitary gland and in turn the production of cortisol, but in patients with Cushing syndrome the cortisol level remains high. An alternative is the overnight 1-mg dexamethasone suppression test—ie, giving 1 mg of dexamethasone at 11:00 pm and measuring the serum cortisol level early the next morning. Failure of the cortisol level to drop to less than 1.8 μg/dL suggests Cushing syndrome and warrants a complete evaluation for it.
Confirmatory testing is sometimes needed if patients have mild abnormalities in their screening tests. A combination low-dose dexamethasone suppression test and corticotropin-releasing hormone test can be used to differentiate Cushing syndrome from pseudo-Cushing syndrome. This is performed by giving dexamethasone orally 0.5 mg every 6 hours for 48 hours and then giving ovine-sequence corticotropin-releasing hormone 1 μg/kg intravenously 2 hours after the last dose of dexamethasone. The plasma cortisol value 15 minutes after the dose of corticotropin-releasing hormone is greater than 1.4 μg/dL (38 nmol/L) in patients with Cushing syndrome but remains low in patients with pseudo-Cushing syndrome.
Is this corticotropin-dependent or corticotropin-independent?
Once Cushing syndrome is diagnosed by one of the screening methods described above, the source of the excess glucocorticoids needs to be determined. Measuring the serum corticotropin level early in the morning would be the next step.
A low corticotropin level (< 10 pg/mL) indicates a corticotropin-independent source, most likely in the adrenal glands. Hence, computed tomography or magnetic resonance imaging (MRI) of the adrenal glands is warranted. Of note: adrenal incidentalomas are quite common, present in 5% of the general population, and a lesion on the adrenal gland does not prove that the patient has primary adrenal disease.16,20
IS THE EXCESS CORTICOTROPIN FROM A PITUITARY OR AN ECTOPIC SOURCE?
3. If the corticotropin level is elevated, how can you determine if it is from the pituitary or from an ectopic source?
- MRI of the pituitary gland
- High-dose dexamethasone suppression test
- Corticotropin-releasing hormone stimulation test
- Bilateral inferior petrosal sinus sampling
If the corticotropin level is high (> 10 pg/mL), it is of paramount importance to determine whether the corticotropin comes from the pituitary gland or from an ectopic source.
MRI of the pituitary gland should be done in patients with suspected corticotropin-dependent Cushing syndrome. However, MRI may be negative in 50% of patients with Cushing disease, and it should therefore not be used for screening. In addition, 10% of the population may have pituitary incidentalomas on MRI.
Most cases of corticotropin-dependent Cushing syndrome are caused by microadenomas (smaller than 1 cm), while a few cases are caused by macroadenomas (larger than 1 cm). If a microadenoma is found on MRI, further testing with bilateral inferior petrosal sinus sampling is recommended (described below); if a macroadenoma is found, then no further testing is required.21,22 In fact, patients who have biochemical findings compatible with Cushing disease (ie, due to an overactive pituitary) and who have an adenoma larger than 6 mm do not require further evaluation.23
A high-dose dexamethasone suppression test involves giving 8 mg of dexamethasone in the evening and measuring the cortisol level the next morning. If the cortisol level declines to 50% of the baseline level after this dose, this suggests a pituitary cause.
Corticotropin-releasing hormone stimulation testing. In most cases of pituitary tumors and a few cases of ectopic corticotropin-secreting tumors, giving corticotropin-releasing hormone leads to an increase in serum corticotropin and cortisol levels. In contrast, these levels do not respond to corticotropin-releasing hormone stimulation if the problem is in the adrenal gland. The test is performed by giving 1 μg/kg or 100 μg synthetic or human corticotropin-releasing hormone. A 35% to 50% increase above baseline in corticotropin suggests a pituitary cause.23
Bilateral inferior petrosal sinus sampling can be used to confirm a pituitary source, as it is the gold standard for differentiating ectopic from pituitary corticotropin production. Once this is confirmed, a neurosurgical consult is warranted.16,18
This procedure is usually done by advancing a sheath from the femoral vein to reach the inferior petrosal sinuses. Blood samples are obtained from both the inferior petrosal sinuses and from a peripheral vein to measure corticotropin levels before and after giving corticotropin-releasing hormone (1 μg/kg). Before corticotropin-releasing hormone is given, a gradient of central-peripheral corticotropin levels of 2.0 or greater indicates a pituitary source. With ectopic corticotropin production, the corticotropin gradient is usually less than 1.5. Corticotropin-releasing hormone is given to increase the sensitivity: after it is given, a gradient of 3.0 or greater is considered indicative of Cushing disease.24
If the corticotropin level is elevated and the above tests indicate ectopic production, the source should be sought. The most common site of ectopic corticotropin production is the chest. Common causes are bronchial, thymic, and pancreatic carcinoid tumors. Other causes are small-cell lung cancer, medullary cell cancer, and pheochromocytoma.15,18,25
