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Endocrine:
6. Cushing's Syndrome: Overproduction of Cortisol
25
Medical
Graduate
01/26/2008

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Term
When would a physician entertain a high index of suspicion of Cushing's syndrome in a patient?
Definition
When diabetes and hypertension are present.
Term
What are classical features of Cushing's Syndrome?
Definition
  • Central obesity
  • Hypertension/edema/hypokalemia
  • Hirsutism/amenorrhea/acne
  • Purple cutaneous striae
  • Ecchymoses
  • Proximal myopathy
  • Diabetes mellitus
  • Osteoporosis
Term
What are some of the effects of cortisol?
Definition
  • Cortisol counteracts the effects of insulin on glucose and favores gluconeogenesis & breakdown of proteins.
  • Cortisol increases proteolysis (increase in urinary nitrogen excretion) in multiple organs (thinned skin with purplish striae; muscle weakness with reduced mass and reduced bone matrix).
  • Cortisol inhibits the positive effect of vitamin D on calcium absorption by the intestine.
  • Cortisol increases calcium excretion and inhibits bone formation.
  • Cortisol is vasoprotective, immunosuppressant, decreases threshold for epileptic seizures and emotional lability.
Term
What are the 3 types of spontaneous Cushing's?
Definition
  1. pituitary tumor, often (up to 40%) below the CAT and NMR detection limit.
  2. adrenal tumor, usually benign.
  3. ectopic ACTH- or CRH- producing tumor (most often small cell cancer of the lung or carcinoid).
Term
What is the single most common cause of Cushing's syndrome?
Definition
Use of supraphysiologic doses of synthetic glucocorticoids (prednisone, dexamethasone, others) to treat patients w/chronic inflammatory or autoimmune disorders.
Term
What is the most common endogenous etiology of Cushing's?
Definition
small benign tumor (microadenoma) of the pituitary gland hypersecreting ACTH.
Term
What do screening tests for Cushing's attempt to document?
Definition
  1. Excessive production of cortisol
  2. Abnormal HPA feedback
Term
What are screening tests for Cushing's syndrome?
Definition
  • Overnight dexamethasone (1 mg at midnight) Suppression test Normal:  8:00 AM plasma cortisol <1.8 ug/dl
  • Urinary free cortisol:Normal:  <100 ug/day
Term
What two conditions can elevate cortisol levels measured in Cushing's screening tests?
Definition
  1. Obesity.
  2. Depression. 
Term
If a patient tests positive for any of the screening tests for Cushings, what would be a confirmatory test?
Definition
The prolonged (2-day) low-dose (.5mg) dexamethasone suppression test.  This test confirms Cushing's, but doesn't identify its cause.
Term
If screening tests were positive for Cushing's, what test results thereafter are most consistent w/an autonomous overproduction of cortisol by an adrenal tumor?
Definition
  1. Low ACTH in plasma
  2. Absent response to high dose dexamethasone. 
Term
Why is the high does dexamethasone test able to differentiate a pituitary adenoma hypersecreting ACTH from the other two common etiologies (ectopic & adrenal)?
Definition
Most pituitary ACTH hypersecreting tumors are semiautonomous, meaning that they respond to feedback inhibition by rising cortisol levels; wherease the other two tumor types are completely autonomous and are not regulated.
Term
Failure of high dose dexamathasone to suppress urinary exretion of cortisol or serum cortisol by >50% is evidence against what type of source of Cushing's syndrome?
Definition
Pituitary.
Term
What makes testing using CRH stimulation of ACTH a good test for differentiating between a pituitary and an ectopic source of ACTH?
Definition
Most ACTH secreting pituitary tumors are hyperresponsive to CRH relative to the normal pituitary and most tumors producing ectopic ACTH do not secrete ACTH in response to CRH.
Term
What is used in conjunction to CRH infusion for determination of the source of an ACTH secreting tumor?
Definition
Selective venous sampling from the petrosal sinuses, which receive venous blood from the pituitary, is often employed to confirm the pituitary as the source of excess ACTH secretion.
Term
What kind of petrosal aCTH gradient confirms a positive result consistent with a pituitary source of ACTH?
Definition
petrosal to peripheral ACTH gradient of ≥ 3:1 after CRH is a positive result. (85% sensitive, 100% specific).
Term
Why would the adrenal display hyperplasia in the context of an ACTH secreting tumor (be it pituitary or ectopic)?
Definition
The 'T' in ACTH stand for 'Trophic', meaning that it stimulates growth as well.
Term
What is Cushing's Disease?
Definition
Cushing's Syndrome due to a pituitary tumor.
Term
Who should be screened for Cushing's Syndrome?
Definition
  • Obese, poorly controlled diabetics even if they do not have all of the typical CS features
  • Women with hyperandrogenism or symptoms of PCOS (irregular menses, hirsutism, weight gain, acne) particularly if hx of sudden onset in adulthood  
  • Patients with abnormal weight gain and osteoporosis / non-traumatic fractures
  • Patients with sudden onset of hypokalemia, hypertension, and muscle weakness (ectopic ACTH)
  • Patients with hx of incidentally discovered adrenal adenoma or pituitary adenoma who have any signs or symptoms of CS
Term
How is Cushing's Disease treated?
Definition
Transsphenoidal resection of the pituitary adenoma is the treatment of choice by an experienced surgeon.
Term
What is the best postoperative index of remission of resection of a pituitary adenoma?
Definition
A low serum cortisol post-op. (<1.8μg/dl within 14 days after surger)
Term
What options exist for patients with failed resection of a pituitary adenoma?
Definition
  1. Reoperation, but success of only 50-71%.
  2. Medical therapy w/ketoconazole, which is an adrenal steroidogenesis inhibitor, blocks synthesis of cortisol early in the pathway.
  3.  Biolateral adrenalectomy
Term
Apart from surgical risk, what disadvantages does bilateral adrenalectomy have?
Definition
  1. Requiring lifelong replacement of both glucocorticoid and mineralocorticoid hormones.
  2. Concern that it increases the risk of Nelson's syndrome ( which is malignant growth of residual ACTH-secreting adenoma due to lack of cortisol feedback inhibition). 
Term
What is Nelson's Syndrome and what predisposes to its developement?
Definition
Malignang growth of residual ACTH-secreting adenoma due to lack of cortisol feedback inhibition.  This occurs as a complication of bilateral adrenalectomy.
Term
What are the top 3 sites for development of an ectopic ACTH secreting tumor?
Definition

Small cell carcinoma of the lung.

Bronchial carcinoid tumor.

Thymic carcinoid tumor. 

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