Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
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        Cushing Syndrome, Serum Screening Test
Cushing's work up
Endogenous Cushing's syndrome affects an estimated 13 to 15 cases per million people in the USA...70% by pituitary lesion, 15% from ectopic lesions, and 15% from adrenal lesions. Cushing's is an increased concentration of glucocorticoid hormone in the bloodstream. The earliest clues are emotional & historical. One common presentation is that of poor glycemic control in obese (BMI >25) diabetics. Ectopic Cushing syndrome refers to the production of ACTH or glucocorticoid hormone in a location other than the pituitary gland or adrenal gland. Examples of ectopic sites include thymoma, medullary carcinoma of the thyroid, pheochromocytoma, islet cell tumors of the pancreas, and oat cell carcinoma of the lung. On the other hand, some prefer that "Cushing's disease" specify the disorder of the pituitary gland in the head wherein too much pituitary ACTH is produced. Even if no masses or nodules are found in the pituitary, adrenals, or ectopic sites, there is the possible situation of supranormal adrenal steroidogenesis.

  1. ACTH dependent
  2. ACTH independent
  3. factitious...exogenous
  4. pseudo-Cushing's syndrome:
    • polycystic ovary (PCOS)
    • obesity
    • alcoholism
    • depression
    • anorexia nervosa
    • bulimia
    • acute stress
    • ovarian tumors
Signs and symptoms include the "buffalo hump" (a 'hump" of fat on the back between the shoulders at the base of the neck (dorsicocervical fat pad over C7), supraclavicular fat pad enlargement, large violaceous (purple) stretch marks, a moon (wide & round) face, and being fat in the trunk but not as much in the limbs, and cortisol induced acne. If it is due to a pituitary tumor, there could be associated headaches due to increased intra-sellar pressure and flushing as the LH and FSH gland areas atrophy and cause menopausal symptoms.

Various...often highly precise...lab tests may be needed to distinguish Cushing's & pseudo-Cushing's states from normals.

Blood Test:

In normals, the serum cortisol level regularly fluctuates (diurnal variation), being highest at about 8AM (=/> 18 micro/dl) and nearly undetectable at midnight. So, a midnight level > 5 micro/dl is suspicious for Cushing's.

Screen with the overnight 1 mg low dose Dexamethasone Suppression Test1 (DST)..

This test is a reasonable screening test for Cushing's syndrome. Dexamethasone 1.0 mg should be taken by mouth at 11:00 PM. A snack can be consumed with the medication. Report to the specified laboratory or physician's office so that a sample of blood can be obtained for determination of the serum cortisol level at 8:00 AM the very next morning.

False positives causes:

  1. Dexa is rapidly metabolized, by: (a) Stress, Depression and other psychiatric disorders. When the distinction between hypercortisolism and deppression cannot be made on clinical grounds alone, endocrine tests are abnormal, an Insuline Tolerance Test may help distinguish them.
    (b) Drugs: Phenytoins, phenobarbital, carbamazepine, Tyreotoxicose & likely others.
  2. Serum CBG (cortisol binding globulin) is elevated: High estrogen states: (oral estrogen replacement, oral contraceptives, PCOS, ovarian tumors). About 50% of normal women taking these pills could lack suppression. In order to improve the accuracy, oral estrogens pills must be discontinued for 6 weeks and the test repeated. Obesity.
  3. Dexa is poorly absorbed: Renal failure & alcoholism:

False negative causes:

  1. Rare cases of only periodic hormonogenesis or
    patients who metabolize dexa slowly.

Gold standard Screening Test is UFC:

Urine from 24 hours is collected and urinary free cortisol (UFC) is determined. If it is higher than 100mg/day, hypercortisolism is present. Thus, the daily UFC measurement emerges as a very simple, cost effective and accurate assessment confirming or not the presence of Cushing syndrome. A result above 3 times the upper limit of normal is nearly diagnostic of Cushing's; but, there are some surgically proven Cushing's cases with normal UFC3.

For less than 5% of obese patients, the UFC measurements may be above the normal range; however, as many as 10-15% will have elevations in urinary 17OHCS excretion (derived from the metabolism of cortisol). The diagnostic sensitivity and specificity of UFC values were 100% and 98%, compared to only 73% and 94%, respectively for 17OHCS. So, UFC determination, will usually provide clearcut distinction between patients with hypercortisolism and obese non-cushing’s patients. As discussed above, in obese patients the CBG increases, giving us a false positive Dexa diagnosis. 

UFC is considered the "gold-standard" of the screening tests, since it excludes many of false positives and negatives.

Diagnostic radiographic imaging:

Adrenals are commonly  nonfunctionally enlarged (9% of autopsies have a nodule 2mm or larger & 1.5% have 1CM or larger) or nodular (too many false positive images). About 50% of pituitary tumors are imaging occult (too many false negatives). If an adrenal mass is found, >4CM cutoff is useful: for the large masses, only 1 in 9 will be malignant.


  1. Vanderbilt Pituitary Center DST protocols
  2. website
  3. William H. Ludlam, M.D., Ph.D., in web file of Oregon Health & Science U., Portland.
  4. Gail Alder, M.D., et. al., E-Medicine website
  5. other web sources
(posted 28 February 2004; update 1 March 2004)

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