Cushing Syndrome

Question 1

Categories of Causes

Answer 1

• ACTH Dep
  
  • ACTH secreting pituitary adenoma = Cushing Disease (peaks at 25-45 and more common in women)
  • Can also be ectopic CRH or ACTH production
• ACTH Indep
  
  • Adrenal adenoma or carcinoma
  • Bilateral ACTH Indep Macro-nodular adrenal hyperplasia (abberent receptors on adrenal tissue respond to other stimulators –> inc cortisol) OR primary pigmented nodular adrenal disease (both very rare)

Question 2

Common Cushing Presentation

Answer 2

• Central obesity (moon face), hyperlipidemia, diabetes, glucose intolerance, HTN, osteopenia
• Erythrocytosis and proteolysis that thins skin –> red complexion
• Buffalo hump (emphasis of fat around neck and upper back); esp if out of proportion to rest of obesity
• Menstrual irregularities, female balding, acne, hirsutism
• Inc risk infections contributes to mortality
• High specificity = facial plethora, proximal myopathy, easy bruising, wide violet striae

Question 3

Cushing Physiology (Ca, blood, CNS, Muscle, Sex, cardio)

Answer 3

• Cortisol inhibits Vit D effect on intestinal Ca absorption, inc Ca excretion in urine and dec bone formation (osteoporosis, pathological fractures, nephrolithiasis)
• Heme/immuno - dec lymphocytes, cytokines, antibodies ALSO dec clotting factors and platelets (prone to thromboembolic events); inc PMNs (de-margination and BM stimulation)
  
  • Inc infections, mycoses, impaired wound healing
• CNS - dec seizure threshold, emotional lability, insomnia (no diurnal dec cortisol at night), worsens underlying psych problems
• Muscle - inc proteolysis so wasting of muscle mass (weaker)
• Sex - inhibits LH, FSG (amenorrhea) and inc DHEAS (more androgens –> acne, hirsutism and balding)
• HTN - inc sensitivity to catecholamines and high levels of cortisol act on MR receptors –> inc water retention

Question 4

When should you screen for Cushing?

Answer 4

• If unusual features for age (HTN, osteoporosis in young)
• Multiple progressive features (esp easy bruising, plethora, muscle weakness - specific)
• Kids falling off growth charts for ht while inc wt
• Incidental adenoma w/ no overt Cushing’s symptoms
• DO NOT screen everyone w/ DM, obesity and depression

Question 5

3 Screening Tests

Answer 5

• 1- Overnight Dexamethasone Suppression Test (low dose)
  
  • Give dexa at midnight then measure cortisol in AM; in normal person dexa should suppress cortisol
  • False pos - stress, depression, alcohol, drugs that alter dexa metabolism
• 2- 24 hr Urinary Free Cortisol (over-production of cortisol)
  
  • Not influenced by cortisol binding globulin so okay if on estrogen
  • False pos - stress, depression, alcohol, high urine output (overwhelms kidney enzyme that converts cortisol to cortisone)
  • False neg - chronic renal failure (check GFR too)
  • Repeat in case cyclic Cushing’s give pos result
• 3- Late Night Salivary Cortisol (loss of normal circadian cortisol pattern)
  
  • Easy
  • Repeat in case cyclic Cushing’s give pos result
  • Do not use if circadian rhythm is off
  • False pos - topical or inhaled steroids, chewing tobacco or licorice (inhibits HSD11beta2), smokers, vigorous brushing or gum bleeding contaminates specimen
  • Good if renal failure or if on drugs that mess up dex test

If 1 is pos do another; if 2 pos then find source

Question 6

Test to Differentiate Cushing and Pseudo Cushing

Answer 6

• 2 day overnight dex suppression test

- Give dex every 6 hrs for 2 days then meas on morning after 2nd day

Question 7

Tests to Determine Source of Cushings

Answer 7

**ACTH Level (twice in morning)

• If high or normal ACTH –> do pituitary MRI
  - If neg MRI … do high dose dexa suppression test (if pituitary source then still under some control and >50% cortisol suppression v. ectopic and adrenal tumors under NO control so <50% cortisol suppression)
  
  • petrosal - sinus sampling w/ CRH (done to differentiate b/n ectopic and pituitary adenoma)
  • Give CRH then simultaneously collect samples of ACTH and cortisol; if gradient of ACTH from central petrosal sinuses is 3x greater than ACTH in periphery then confirms pituitary adenoma as source
  • If suspect ectopic - chest CT or MRI (bronchial or thymus carcinoid tumor most common); can also do abdomen, pelvis, neck CT for other tumors
• If suppressed ACTH level - adrenal CT for adenoma or carcinoma (neg feedback on ACTH level)
  * *Must support adrenal tumor w/ biochemical test b/f surgery…

Question 8

Pseudo Cushing Syndrome

Answer 8

• Some or all clinical features that resemble true Cushing’s and evidence of hyper-cortisol (pos screen) BUT if resolve underlying cause then signs go away
• Ex) alcoholism (actually inc stress –> inc CRH –> inc ACTH and cortisol) but when ceases drinking for 4-6 wks the screen is negative

Question 9

Tx of Pituitary Adenoma, Adrenal Mass or Ectopic Tumor

Answer 9

• If pituitary adenoma then transphenoidal resection –> leads to suppression of HPA axis for 1-2 yrs (endogenous cortisol was suppressing HPA - needs to recover)
  - In meantime give stress doses of hydrocortisone
  - If not cured by surgery, re-operate or give ketoconazole, pituitary gamma knife, bilateral adrenalectomy (last resort)
• If adrenal source - adrenalectomy is 100% curative
• Surgical removal of ectopic tumor