Determining the type of Cushings syndrome: Not as hard as it seems

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Determining the type of Cushings syndrome Not
as hard as it seems

• Theodore C. Friedman, M.D., Ph.D.
• Professor of Medicine-Charles Drew University
• Professor of Medicine-UCLA
• Magic Foundation
• Symposium on Cushings Syndrome
• February 22, 2009
• Las Vegas, NV

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Types of Cushings

• a. Pituitary Adenoma (Cushings Disease) 80, 95
• b. Ectopic ACTH Syndrome 5, 1
• c. Adrenal adenoma 13, 3
• d. Adrenal carcinoma 2, 1
• Literature-, Friedman
• Men are more likely to have ectopic
• Ectopics are almost always more hypercortisolemic
  and probably easier to pick up.
• Episodic hypercortisolism has not particularly
  been associated with any type of Cushings.

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Determine Hypercortisolism

• Last lecture
• UFC, 17OHS
• Night-time salivary cortisols
• Night-time serum cortisols

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Distinguishing Type of Cushings

• Distinguish between ACTH-independent (adrenal)
  and ACTH-dependent Cushing syndrome (pituitary or
  ectopic) by measuring an 8 AM fasting plasma ACTH
  (remember time zone effect)
• ACTH lt 10 pg/mL-probably adrenal disease
• ACTH gt 100 pg/mL-likely ectopic
• ACTH between 10 pg/mL-100 pg/mL-probably
  pituitary, but there are overlaps
• ACTH needs to be collected in a chilled tube and
  spun immediately.
• Could be in a low
• Get a simultaneous serum cortisol to see if in a
  low.

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Imaging

• Get a pituitary MRI, if not already
• Pituitary tumor makes pituitary Cushings much
  more likely, but could still have pituitary
  incidentaloma and non-pituitary Cushings
• Needs to be confirmed with other test
  (dexamethasone test, ACTH level)
• If low ACTH-get adrenal imaging
• Adrenal MRI and CT are somewhat equivalent,
  usually CT is cheaper, but more radiation exposure

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Imaging (2)

• Patients with pituitary Cushings can have a
  dominant nodule on adrenal imaging, making it
  look like adrenal disease

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Dexamethasone suppression tests

• Classically, non-Cushings patients suppressed to
  overnight (1 mg at midnight) or low dose (0.5 mg
  given every 6 hrs for 2 days) dexamethasone.
• Patients with pituitary Cushings disease did not
  suppress to overnight or low dose dexamethasone,
  but did suppress to high dose dexamethasone (2 mg
  given every 6 hrs for 2 days).
• Patients with adrenal or ectopic Cushings
  suppress to high dose dexamethasone.

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Dexamethasone suppression tests

• I found that most patients with mild pituitary
  Cushings disease do suppress to overnight or low
  dose dexamethasone.
• Thus the overnight or low-dose dexamethasone
  test can be used to distinguish between pituitary
  and adrenal or ectopic Cushings, so patients who
  suppress to low-dose dexamethasone are unlikely
  to have adrenal or ectopic Cushings.
• Isadori et al. (JCEM, 2003, 885299-5306) agreed
  with this approach.
• Still some concern with being periodic.

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Distinguishing Type of Cushings

• oCRH test is also possible as pituitary Cushings
  disease patients respond to oCRH, while adrenal
  or ectopic do not.
• oCRH is expensive
• My approach Patient with ACTH between 10-100
  pg/mL, a pituitary tumor on MRI and suppression
  to overnight or low dose dexamethasone I send to
  pituitary surgery.
• Odds of having pituitary disease are already
  high.

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Distinguishing Type of Cushings

• Patients with an ACTH lt 10 pg/mL, a clean
  pituitary MRI and a tumor on adrenal imaging
  send to adrenal surgery.
• Patients with severe Cushings, edema or low
  potassium, high ACTH and cortisol levels and who
  do not suppress to dexamethasone ectopic
  Cushings IPSS, lung/ thymic imaging, octreotide
  scan

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Inferior Petrosal Sinus Sampling (IPSS)

• IPSS involves sampling the inferior petrosal
  sinuses which drain the pituitary for ACTH.
  Petrosal blood levels of ACTH are compared to
  peripheral levels.
• oCRH is given which usually helps to further
  distinguish between pituitary and ectopic
  sources.
• Test involves catheterization through the femoral
  vein, going through the heart into the carotid
  vein and then to the petrosal sinus.
• But do at an experienced center.
• Safe and not as bad as it sounds
• Cavernous sinus sampling is probably about as
  good.
• Hard to interpret if one petrosal sinus is bigger
  than the other

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Inferior Petrosal Sinus Sampling (IPSS) (2)

• IPSS has been found to be very useful to
  distinguish pituitary Cushing disease from
  ectopic ACTH syndrome. It is also somewhat
  helpful for determining lateralization of the
  pituitary tumor.
• IPSS depends on the suppression of normal
  corticotropes by hypercortisolism.
• It was hypothesized that patients with
  pseudo-Cushing states or normal individuals would
  have lower ACTH concentrations in their petrosal
  sinuses and lower petrosal to peripheral
  gradients than those patients with Cushing
  disease. Additionally, it was expected that
  patients with pseudo-Cushing states or normal
  individuals would have symmetric drainage of ACTH
  into each petrosal sinus.

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Inferior Petrosal Sinus Sampling (IPSS) (3)

• Yanovski et al. (JCEM, 1993, 77503-509)
  performed petrosal sinus sampling in 7
  eucortisolemic volunteers, 8 hypercortisolemic
  patients with pseudo-Cushing states and 40
  patients with Cushing disease.
• All three groups of patients had similar
  petrosal ACTH before and after CRH. There was
  considerable overlap between the three groups
  precluding this test to diagnose Cushing
  syndrome.
• All three groups had elevated petrosal to
  peripheral gradients. Again there was too much
  of an overlap between the three groups to use
  this test to diagnose Cushing syndrome.
• All three groups exhibited significant
  lateralization of ACTH.
• IPSS should not be used to make the diagnosis of
  Cushing syndrome.

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So what is IPSS good for?

• Distinguishing between pituitary or ectopic
  Cushings
• Very good at this, but can usually be done on
  other grounds
• Distinguishing between pituitary and adrenal
• Often can been done on other grounds as well, but
  sometimes needed in hard cases.
• Determining if a questionable spot on MRI
  corresponds to lateralization on IPSS
• If you have a right sided questionable lesion and
  get a right sided lateralization, that would
  support that the pituitary lesion is the source
  of the ACTH and might support the diagnosis of
  Cushings
• If no tumor is seen on pituitary MRI, yet
  pituitary Cushings is expected.
• If ectopic is expected.
• Medical-legal reasons
• I rarely see the need for it

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Do you need to be hypercortisolemic during IPSS?

• Test works on suppression of normal corticotropes
  during high cortisol levels-so technically yes
• In episodic patents, hard to predict when high.
• I get a 24 hr UFC or night-time salivary cortisol
  the day/night before to determine cortisol
  status.
• If clear-cut central to peripheral gradient, then
  its probably interpretable and supports
  pituitary.
• But if low ACTH levels and no central to
  peripheral gradient, then I could be mislead into
  either concluding adrenal or ectopic, then I
  would repeat it.

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On to surgery