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CUSHING'S SYNDROME (HYPERCORTISOLISM)   SX   |  DX  |  Causes  |  RX       REF: Cushings2008.pdf  

SX:
the classic Sx are moon facies, central obesity, plethora, red striae, hirsutism, ecchymoses, proximal muscle weakness, and osteoporosis; hypokalemia, hypertension.

Diagnostic Strategies:

• The single-dose overnight 1 mg dexamethasone suppression test at 11 pm
  (next morning 8 am plasma cortisol level should fall to less than 5 ug/dl)
  is an excellent screening test in the diagnosis of Cushing syndrome when the probability of disease is low. A negative result virtually ensures the absence of disease.
  Suppression of cortisol secretion when a larger dosage of dexamethasone, 2 mg q6h for 2 days is given (During the second day of suppression at this dose, 8-am plasma cortisol values normally should fall to less than 6 µg/dL, urinary free cortisol excretion to less than 20 µg/dL, and 17-hydroxycorticosteroid levels to less than 4 mg/day), the urinary 17 OHS  (hydroxysteroids) & 17 KS levels fall to < 50% of control levels, or plasma cortisol < 10 ug/dl.
• An elevated 24-hour urinary free cortisol excretion (usually to > 150 ug/24 h) or
  Midnight plasma cortisol level (greater than 10 ug/dl) confirms the diagnosis of Cushing syndrome when the pretest probability of disease is high.
• Radiographic examinations of the sella turcica or adrenal glands are not useful screening tests in the initial evaluation of hypercortisolism.

Causes of Cushing's Syndrome:

• The presence of adrenocorticotropin (ACTH) producing pituitary tumors:
  Cushing's disease (Excess Pituitary ACTH producing microadenomas or bilateral adrenal hyperplasia)
  Characterized by the following lab findings:
  • Loss of diurnal rhythm of plasma ACTH & cortisol: evening cortisol levels are greater than 10 ug/dl; excretion of urinary 17 hydroxysteroids also loses its daily thythm.
  • Loss of ACTH suppressibility by physiologic doses of glucocorticoid: 1 mg dexamethasone at hs does not prevent the 8 am rise of cortisol to greater than 10 ug/dl.
  • Suppression of cortisol secretion when a larger dosage of dexamethasone, 2 mg q6h for 2 days, is given: urinary 17 OHS & 17 KS levels fall to < 50% of control levels, or plasma cortisol < 10 ug/dl.
  • Elevation of urinary free cortisol levels, usually to > 150 ug/24 h.
• Autonomous adrenal tumors  (ACTH independent):
  Adrenocortical carcinoma autonomous hypersecretion of cortisol, or  
  Benign adrenal adenoma in about 10% of cases
  • The high dose 2 mg dexamethasone q6h x 2d does not suppress the ACTH or cortisol secretion; 8 am plasma cortisol >10 ug/dl & urin. 17 OHS > 50% of baseline, but has low plasma ACTH level.
• Extra-pituitary tumors producing ectopic ACTH.
  Ectopic ACTH tumors: oat cell lung Ca, pancreatic islet Ca, thymoma, etc.
  • The high dose 2 mg dexamethasone q6h x 2d does not suppress the ACTH or cortisol secretion; 8 am plasma cortisol >10 ug/dl & urin. 17 OHS > 50% of baseline, also has high plasma ACTH level.
• Administration of exogenous corticosteroids

The pituitary syndrome, or Cushing disease, is the most common of the three types of Cushing syndrome, accounting for about two thirds of the cases in one collected series (1), and generally affects women of childbearing age. The other two forms occur with nearly equal frequency, but adrenal tumors are more common in children and the ectopic ACTH syndrome generally occurs in older persons.  

RX of Cushing's Syndrome

Transsphenoidal removal of a pituitary microadenoma in Cushing's disease is very successful (80% remission rate) and has few complications. Unilateral micoadrenalectomy is appropriate for treating an adenoma. Bilateral adrenalectomy is necessary for ACTH-dependent Cushing's syndrome not treatable by pituitary surgery or removal of the ectopic ACTH source and for the rare case of bilateral adrenal adenomas. In all cases, corticosteroid replacement is required in the intraoperative and immediate postoperative periods. After a pituitary adenoma or a unilateral adrenal adenoma has been successfully removed, recovery from the hypothalamic-pituitary-adrenal (HPA) axis suppression can be expected in 3 to 12 months. During the recovery period, corticosteroid coverage for stressful situations, including pregnancy, is required. After bilateral adrenalectomy, lifelong adrenal glucocorticoid and mineralocorticoid replacement are needed (see Treatment Of Adrenal Insufficiency, below). Patients with pituitary-dependent Cushing's syndrome treated with bilateral adrenalectomy should be carefully monitored for enlargement of an ACTH-secreting adenoma (Nelson's syndrome) and for the return of Cushing's syndrome from ACTH stimulation of adrenal rest tissue.

Single-Dose Dexamethasone Suppression Test

The single-dose overnight dexamethasone suppression test is a simple method of determining pituitary suppressibility by corticosteroids. The test is done by administering 1 mg of dexamethasone orally at midnight and measuring the plasma cortisol at 0800 h (8:00 am). The test is considered positive if the morning cortisol level is above a predetermined value (3.5 to 10 µg/dL), depending on assay type and institution. This test has been found to be extremely sensitive (greater than 98%) and moderately specific (approximately 80%). False-negative results are probably due to episodic low rates of cortisol secretion that occur in cases unrelated to dexamethasone administration. False-positive results are common in obese patients, those who consume excessive ethanol, patients taking phenytoin or potent estrogens, and patients with severe depression. Patients receiving spironolactone therapy can also have false-positive results when fluorescent assays for cortisol are used.

Low-Dose Dexamethasone Suppression Test

The low-dose dexamethasone suppression test is considered to be definitive in confirming the diagnosis of Cushing syndrome. The test is done by administering dexamethasone, 0.5 mg every 6 hours for 2 days, and measuring the 24-hour urine excretion of 17-hydroxysteroids during the final 24 hours of dexamethasone administration. Patients with Cushing syndrome fail to suppress cortisol production and excrete more than 4 mg/d of 17-hydroxysteroids during this period. This test has a sensitivity of about 95% and a specificity of nearly 100%, even in those suspected of having the disease. Rarely, patients with hypercortisolism will have a false-negative test result because of delayed metabolism of dexamethasone , which results in markedly increased plasma dexamethasone levels compared with those usually obtained. The elevated dexamethasone levels may then cause adrenal suppression in some patients with hypercortisolism, particularly in those with Cushing disease. False-positive results for this test may occur in patients with severe depression or in patients receiving phenytoin therapy. Measurement of urinary free cortisol during this suppression test is also sensitive and specific.

REF: ACP Library on Disk 2- (c) 1997 - American College of Physicians

REF:

A Physiologic Approach to Diagnosis of the Cushing Syndrome
Hershel Raff, PhD; and James W. Findling, MD   Ann Intern Med. June 17, 2003;138:980–991.

2008