Cushing's Syndrome

Excess cortisol.

Etiology:

• • Most cases are due to exogenous steroid use.

  • Cushing's disease (ACTH-secreting pituitary microadenoma) has f:m 8:1; pituitary microadenoma. Account for 80% of cases of endogenous Cushing's syndrome.

  • Ectopic ACTH from non-pituitary neoplasms: SCLC, bronchial carcinoids.

  • Adrenal adenoma, carcinomas, or nodular adrenal hyperplasia.

Diagnosis:

• • Truncal obeseity, moon facies, fat deposits in the supraclavicular fossae and over the posterior neck (buffalo hump), HTN, hirsutism, amenorrhea, and depression. Specific findings include thin skin, easy bruising, reddish, violaceous striae, proximal muscle weakness, acanthosis nigricans, and osteoporosis.

  • Hyperpigmentation, metabolic alkalosis, hypokalemia suggest Cushing's syndrome due to ectopic ACTH secretion.

  • Hypercalciuria, leucocytosis with relative lymphopenia, hyperglycemia, and glucose intolerance, diabetes.

Evaluation and Dx of Cushing's:

• • Diagnosis is based on increased cortisol secretion and lack of normal feeback inhibition of ACTH and cortisol secretion.

  • Best initial test is the 24-hour urine cortisol measurement test. Alternatively an overnight dexamethasone suppression test.

    • Give 1 mg dexamethasone PO to patient at 11 PM. Check cortisol following morning between 8 AM. If 8 AM cortisol level is <5 mcg/dL; normal, no Cushing's. If higher than these, Cushing's Syndorme.

    • If >2 - 5 mcg/dL, check 24-h urine free cortisol.

    • If 24-h urine free cortisol is elevated more than 4 times upper limit of normal in a patient (levels of >50 mcg/d or >140 nnmol/d) with compatible clinical findings, the diagnosis of Cushing's syndrome is established.

    • If 24-h urine free cortisol is mildly elevated, a low-dose dexamethasone suppression test should be performed. Also done in difficult cases (obese, depressed patients).

  • Dexamethasone, 0.5 mg PO q6h, is given for 48 hours, starting at 8 AM. Urine cortisol is measured during the last 24 hours, and plasma cortisol is measured 6 hours after the last dose of dexamethasone. Failure to suppress plasma cortisol to <5 mcg/dL, or <140 nmol/L and urine cortisol to less than the normal reference range (<10 mcg/d or <25 nmol/d) is diagnostic of Cushing's disease.

    • Testing should not be done if Pt has severe illness or depression, which may cause false-positive results. Phenytoin therapy also causes a false-positive test by accelerating metabolism of dexamethasone.

  • Absence of the normal fall of plasma cortisol at midnight is consistent with Cushing's syndrome as there is a loss of the diurnal cortisol rhythm.

  • Consult Endocrinologist for further evaluation.

  • Basal ACTH levels often distinguish patients with ACTH-independent (adrenal or exogenous glucocorticoid) from those with ACTH-dependent (pituitary, ectopic ACTH) Cushing's syndrome.

    • Mean basal ACTH levels are about 8 times higher in Pts with ectopic ACTH secretion compared to those with pituitary ACTH-secreting adenomas. Since there is considerable overalp of ACTH levels in these two d/o it is not used to make the distinction.

Where is the location or origin?

Check ACTH.

If ACTH is >10 pg/mL, think pituitary and ectopic causes.

If ACTH <5 pg/mL, think adrenal causes.

The next step is to do a high-dose dexamethasone suppression test.

If high dose dexamethasone suppression test suppresses cortisol, the origin is pituitary.

Check MRI for pituitary mass. Most ACTH-secreting pituitary tumors are <5 mm in diameter, and about half are undetectable by sensitive MRI. If no pituitary mass do IPSS (inferior petrosal sinus sampling). If gradient is greater from pituitary; suggests central source. If gradient greater from periphery, suggests peripheral source.

If high dose dexamethasone suppression test does not suppresses cortisol, the origin is either adrenal or ectopic source.

Check CT adrenals for unilateral or bilateral masses, and chest for lung cancer.