How do You Diagnose Cushing's Syndrome?

The diagnosis of Cushing’s Syndrome requires blood and urine hormone measurements, x-rays of the adrenal gland, and a thoughtful and experienced doctor. The diagnostic process follows a three-step approach: Screening for the disease, Confirming the disease, and Performing subtype diagnosis.

The Diagnostic Workup of Cushing's Syndrome Involves

  1. A careful history and a thorough physical examination looking for the characteristic signs and symptoms of Cushing’ syndrome.
  2. Laboratory investigations to document the presence of hypercortisolism. This may include blood tests, 24h-urine tests, salivary cortisol measurements, dexamethasone suppression tests (this is a test where you are given a medication and then blood test are performed to see how your cortisol level responds).
  3. Determining the underlying cause of Cushing’s syndrome. Again, there are 2 major types: ACTH Dependent (60%) and ACTH Independent (40%).

  • ACTH Dependent (60%)
    • Pituitary tumors (55%)
    • Lung cancers (5%)
  • ACTH Independent 40%
    • Benign adrenal tumors (adenoma) (30%)
    • Malignant adrenal tumors (adrenal cell carcinoma) (10%)

Initial Screening: First-Line Biochemical Tests

In healthy individuals, the level of serum cortisol reaches a peak in the morning (7-9 am) and reach the lowest level between bedtime and 2 am. One of the first signs of Cushing’s syndrome, is the loss of this diurnal variation. Accordingly, the three first-line biochemical screening tests recommended for the diagnosis of endogenous hypercortisolism are too prove that the patients has lost this normal secretion of cortisol and thus it is recommended that patients are screened with these tests: 1) Low-dose dexamethasone suppression test is used to assess attenuated sensitivity to glucocorticoid negative feed-back 2) Measurement of late-night salivary cortisol is used to evaluate circadian rhythm and the presence or absence of normal nadir of cortisol secretion after bedtime 3) 24-h urine free cortisol (UFC) that evaluates for the overproduction of cortisol

Low-Dose Dexamethasone Suppression test

In contrast to normal subjects, patients with Cushing’s syndrome fail to suppress (lower) secretion of ACTH (adrenocorticotropic hormone; the pituitary hormone controlling the cortisol release from the adrenals) and cortisol when subjected to a high dose of a glucocorticoid (dexamethasone). This is the concept behind the dexamethasone suppression test and it is a very reliable test to diagnose Cushing’s syndrome, and quite straightforward to perform. Thus, it is often the #1 screening test for Cushing’s syndrome. The overnight and the less commonly used 48h dexamethasone suppression tests are the two most widely used low-dose dexamethasone suppression test: 1 mg of dexamethasone (a natural hormone; glucocorticoid; your endocrinologist will provide you a prescription for this) is given at 11 pm in the overnight test and the serum cortisol is measured the next day at 8-9 am (simple blood test). In most cases, to achieve an accurate diagnosis of Cushing’s disease most experts agree that recommended a cutoff for suppression of the serum cortisol after dexamethasone administration to less than 1.8 μg/dl (50 nmol/l: SI Units for international patients) is normal. Anything above, may indicated that you have Cushing’s syndrome.

It should be noted, that in children the dosing of dexamethasone has to be adjusted if the child’s weight is less than 40 kg. In addition, it is important to note that the dexamethasone suppression test may be influenced in patients with potential gastrointestinal malabsorption (previous gastric bypass, Crohn’s disease, etc) or those taking medications that increase liver clearance of dexamethasone (e.g., carbamazepine, phenytoin, phenobarbital, or rifampicin) or increase synthesis of cortisol-binding globulin (e.g., estrogens; important for women on birth control pills, and hormone replacement). Patients with liver or renal failure may have reduced dexamethasone clearance that may also interfere with the test.

Late-Night Salivary Cortisol

In healthy individuals, the level of serum cortisol reaches a peak in the morning (7-9 am) and reach the lowest level between bedtime and 2 am. One of the first signs of Cushing’s syndrome, is the loss of this diurnal variation. Although it has been shown that detecting increased midnight serum cortisol level has high sensitivity for patients with Cushing’s syndrome, obtaining a stress-free late-night blood sample in routine outpatient clinical practice is not always feasible. Saliva is easy to collect and cortisol is stable at room temperature that allows the samples to be mailed to the medical office or laboratory for analysis. These advantages make the late-night salivary cortisol a convenient, suitable, and reliable procedure for both inpatient and outpatient screening for Cushing’s syndrome. The salivary samples must be collected on two separate evenings between 11pm to midnight either by using a cotton pledget in the mouth and chewing for 1–2 min.

Normal subjects usually have salivary cortisol levels of less than 145 ng/dl (4 nmol/l) between 11pm to midnight. Salivary cortisol levels consistently greater than (0.09 mcg/dL; 7.0 nmol/l make the diagnosis of Cushing’s syndrome very likely, while values between 0.09 mcg/dL; 4.0 and 7.0 nmol/l prompt additional biochemical confirmation. This means these patients should also undergo low-dose dexamethasone suppression test and 24-h urine free cortisol (UFC) measurements.

Twenty-Four Hour Urine Free Cortisol (UFC)

Compared to the two methods “Late-night Salivary Cortisol” and “Low-Dose Dexamethasone Suppression” that evaluate total serum cortisol level, twenty-Four Hour Urine Free Cortisol (UFC) provides a unique perspective on pathophysiology of cortisol metabolism in that it measures the excess circulating cortisol that is filtered and excreted in the urine as free cortisol. Another advantage is it provides an assessment of cortisol secretion over a 24-h period. The recommendation is to use the upper limit of normal range for the particular UFC assay as the cutoff criterion for a positive test in order to achieve high sensitivity, and to perform the test twice, at least once.

It is important to note that the patient has to collect all urine over 24 hours to obtain an accurate test. Because high fluid intake (more than 5 l/day) can falsely increase and reduced kidney function can falsely decrease UFC results. In addition, the measurement of creatinine and urine volume need to be performed in order to assess completeness with more than two UFC measurement often required to avoid false results, detect cyclic hypercortisolism, and validate the diagnosis. A complete 24-h urine collection with appropriate total volume and urinary creatinine levels requires patient and or patient’s family education using clear instructions. The procedure begins after the first morning void is discarded with all subsequent voids throughout the day and night included and urine collection kept refrigerated. It has to be noted that the sample is considered complete only when the first morning void on the second day has been collected in the urine sample container.

Dr. Carling, Editorial note: There is significant confusion, and some controversy about how to interpret a low-dose dexamethasone suppression test, and other tests of cortisol overproduction. Dr. Carling has published widely about this. The below table indicate some of the suggested cutoffs how to interpret both low-dose dexamethasone suppression test, late-night salivary cortisol and 24-h urine free cortisol (UFC) levels. Bottomline, if you or your healthcare provider is unsure whether your test is positive or negative, just send us your results. Dr. Carling evaluates these tests every single day. We know how to interpret them, and we are here to help.

Additional Tests

Assessment of ACTH (adrenocorticotropic hormone; the pituitary hormone controlling the cortisol release from the adrenals)
Measurement of plasma ACTH concentration at 0900 h represents the first step and the best way to distinguish ACTH-dependent from ACTH-independent Cushing’s syndrome. To avoid falsely low results, the ACTH assay requires collection of blood into a precooled EDTA tube, placement on ice, and rapid delivery to the laboratory for refrigerated centrifugation, because ACTH is degraded quickly by plasma proteases.

DHEA-S
Dehydroepiandrosterone-sulfate (DHEA-S) is the most abundant circulating steroid hormone in humans. Reduction in DHEA-S levels is a frequent finding in adrenal incidentaloma. Adrenal steroid production is very sensitive to ACTH (adrenocorticotropic hormone; the pituitary hormone controlling the cortisol release from the adrenals), so it is possible that the reduced DHEA-S levels are indicative of very subtle decreases in HPA axis activity due to subclinical Cushing’s syndrome. However, DHEA-S levels also naturally decline with age. Low DHEA-S serum concentration has not been demonstrated to be a useful diagnostic test for subclinical Cushing’s syndrome, but high levels may be of concern, especially for adrenocortical carcinoma.

After the diagnosis of hypercortisolism has been established by the biochemical (blood, urine, saliva) test described above, the next step is to establish the underlying cause of Cushing’s Syndrome. Establishing the right diagnosis is essential, because the primary curative therapy for ACTH- independent Cushing’s syndrome is adrenal surgery. Thus, in cases with equivocal results in which ACTH is not fully suppressed, a test using CRH stimulation test can be performed to help in the differential diagnosis Cushing’s syndrome.

IMPORTANT TO NOTE: The surgeons of the Carling Adrenal Center are the most world’s expert surgeons of adrenal tumors and disease. That is what we do. We do not perform surgery on the brain, or pituitary gland. However, if you have Cushing’s disease due to an ACTH producing pituitary tumor, you can always contact us, and we will direct you to a high-volume surgeon who does pituitary surgery (usually a neurosurgeon). You want the most expert pituitary surgeon do your operation! Similar as adrenal surgery, pituitary surgery is tricky and requires significant expertise and experience.

Obviously, the treatment of this disease depends on the cause. Pituitary tumors are usually removed surgically and often treated with radiation therapy. Neurosurgeons and some ENT surgeons specialize in these tumors. If the cause is determined to be within a single adrenal gland, this is treated by surgical removal. If the tumor has characteristics of cancer on any of the imaging tests, then a larger, conventional operation may be in order (learn about adrenalectomy here). If a single adrenal gland possesses a small, well-defined tumor, it can usually be removed with a scope adrenalectomy (read about this curative, minimally invasive, safe, and swift operation here).

If the patient has one or more adrenal tumors causing Cushing’s syndrome, they will need adrenal surgery. Invariably, once the diagnosis is made, patients will undergo a CT scan (or possibly an MRI or ultrasound) of the adrenal glands to look for tumors in one or both of the glands. Read more about adrenal imaging below, and here. If the laboratory tests suggest a pituitary origin, a CT or MRI of the brain (and possibly of the chest) will be performed. Again, if you have Cushing’s disease due to an ACTH producing pituitary tumor, you can always contact us, and we will direct you to a high-volume surgeon who does pituitary surgery (usually a neurosurgeon). You want the most expert pituitary surgeon do your operation! Similar as adrenal surgery, pituitary surgery is tricky and requires significant expertise and experience.

Patients with bilateral adrenal incidentalomas should be managed similarly as those with unilateral lesions, except for inclusion of serum 17-hydroxyprogesterone measurements to exclude congenital adrenal hyperplasia. Bilateral adrenalectomy is not always warranted in cases of subclinical Cushing’s, although some cases with a dominant lesion can be treated with unilateral adrenalectomy. Read about partial (or cortical-sparing) adrenalectomy and watch Dr. Carling perform this operation here.
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What You Need to Know in One Sentence

Diagnosing Cushing's Syndrome is one of the most difficult things in endocrinology so you need a doctor that specializes in this. We know most of the top endocrinologists in the US and are happy to help you find one.