Saturday, April 25, 2015

Testing for Cushing's, Dex

There are actually two types of Dexamethasone Suppression Tests (Dex) used in diagnosing Cushing's, a high dose and a low dose test. There are some differences in procedure, timing, guessed it...dosage.  I'm not going to go in-depth on the procedures of either, but more give a brief overview of what the test is, what they're looking for, and it's downfalls.

These tests are kind of the opposite of a "stim" test in that it isn't meant to stimulate production, but to suppress it.  The point of these tests is to give your body sufficient steroids (Dexamethasone) so that your pituitary's own feedback will stop it's production of ACTH.  In a healthy HPA axis, your body recognizes there is already enough in your system, and thus doesn't produce more.  They give the medication a set number of hours for your pituitary to respond, and then check your cortisol levels to see how much your cortisol has suppressed (or dropped).

Many forms of steroid replacement medication will show up as "cortisol" on lab tests, but in the testing used here, Dex does not.  This makes it a good medication to use for a suppression test, as any cortisol above the expected level (meaning a failure to suppress or failure to suppress enough) can be said to be caused by a process working outside of the normal feedback loop (ie, a tumor).

This is a well-used type of test, and sadly, it is often used to rule out Cushing's when that really isn't what it is good for.  These tests have a statistically high number of false negatives (I've seen published numbers as high as 30%), meaning there is a large chunk of patients who DO suppress on this test who still do go on to be proven to have Cushing's.  And if you throw in the ectopic and cyclic patient groups rarely included in such studies, things really can get muddy.  In my opinion as an educated patient, these tests are great for ruling IN Cushing's, but not for ruling it out.  What I mean by that is that it misses a LARGE number of very ill patients, and some doctors then send them away still suffering, because of these test results (even when other testing comes back routinely diagnostic) so it is not a good test to use to rule out Cushing's as a problem.  But it is good for proof of disease (ruling it in), because if you do not suppress fully on this test, it's pretty obvious there's a problem that needs further investigation and treatment.  (Sadly, patients still get sent on their not-so-merry way...It's often the luck of the draw with doctors, even "specialists" as I explained in the "Testing introduction" post before.)

Something else Dex Suppression tests are good for:  Helping to point towards source.  Adrenal sources do not often suppress, and pituitary ones can.  I honestly don't remember what ectopic sources do!  I would assume they do not suppress either, or at least not much.  But this test alone isn't a sufficient indicator anyway, and more tests and imaging are required to confirm source.  So, really, it's kind of a shot in the dark whether this test is even useful.

*Update:  Another Cushie asked if I would address the Dex-CRH test, and since I don't know too much, I'll just add it here.  I attended the 2014 Magic Convention and heard Dr. Ludlam (Endocrinologist that used to run "Camp Cushie" at Swedish in Seattle but that now works as the endocrinology director at Novartis Pharmaceuticals) speak, and he did discuss the Dex-CRH.  Keep in mind this is year-old memory I'm speaking from, so it's accuracy is suspect.  My impression is that he found it far more accurate than the Dex alone and that he was of the opinion that by using the Dex to suppress normal pituitary function, he could then use CRH (Corticotropic Releasing Hormone) to force an ACTH-producing tumor to produce, and that this resulted in less (or no?) false negatives and far more accurate testing, especially in the episodic and cyclic patient population (he preferred the term "variable").  I have no data to back this up, and it appears I didn't include this in my post of notes last April, so take it for what it is worth.  I've not heard of it being used since (which doesn't mean no one does it, but just that it isn't likely routinely or commonly used) and have not had the test myself.

Here's some info from Dr. Friedman's website:
"Dexamethasone-CRH Test
Another recommended test to distinguish between mild Cushing's syndrome and pseudo-
Cushing's states in those patients with a mildly elevated UFC is the dexamethasone-CRH test. This
test combines two tests, the low-dose dexamethasone suppression test (LDDST) and the CRH test
which individually are good but not great at distinguishing between pseudo-Cushing's states and
Cushing's syndrome. As discussed below, the dexamethasone test takes advantage of the fact that in
patients with Cushing's syndrome, dexamethasone ineffectively suppresses the production of pituitary
ACTH. CRH stimulates the pituitary to secrete ACTH which leads to an increase in cortisol levels.
Patients with Cushing's syndrome have a larger increase in plasma ACTH and cortisol levels than in
normal individuals or those patients with pseudo-Cushing's states. Although these tests individually
are helpful to diagnose Cushing's syndrome, many patients with pseudo-Cushing's states also respond
to them in a similar manner as those with Cushing's syndrome, making them not the ideal test to use
individually. Yanovski et al., (9) elected to combine the two tests and gave 39 patients with Cushing’s
syndrome and 19 patients with pseudo-Cushing’s states dexamethasone (0.5 mg) 4 times a day for 2
days starting at 12 noon (last dose at 6 A.M.). At 8 A.M. on the day of the last dose, the patients
received intravenous ovine CRH (1 μg/kg) and cortisol and ACTH were measured at various times.
All patients with Cushing’s syndrome had mild hypercortisolemia (UFC between 250 and 1000
nmol/d; 90-362 μg/d) so that UFCs between patients with Cushing’s syndrome and pseudo-Cushing’s
states completely overlapped. A plasma cortisol greater than 1.4 μg/dl (38 nmol/L) measured 15
minutes after the CRH injection correctly identified all patients with Cushing’s syndrome, while a
value less than 1.4 μg/d identified all patients with pseudo-Cushing’s states (100% sensitivity and
specificity). In contrast, the low dose dexamethasone test, had a 74% specificity and 69% sensitivity
when 17-OHS was measured on the second day of dexamethasone administration and 100% sensitivity and 56% sensitivity when UFCs were measured. The CRH stimulation test without dexamethasone pretreatment had 100% specificity and 64% sensitivity. This study has the advantage of comparing the dexamethasone-CRH test to other popular tests (LDDST and CRH test) in the same group of patients with mild Cushing’s syndrome and pseudo-Cushing’s states and clearly showed the superiority of the dexamethasone-CRH test in this group of patients. The main drawbacks to this test is that it requires a lot of steps and the drug (CRH), while no longer investigational, is expensive. A subsequent paper (70), found, as expected, that the dexamethasone-CRH test completely distinguished patients with Cushing’s syndrome from normal volunteers." 

Full PDF of article found here.

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