Theodore C. Friedman, M.D., Ph.D.
Professor of Medicine-UCLA
Chairman, Department of Internal Medicine
Charles R. Drew University
Dr. Friedman’s Endocrinology Clinic
Nuances of Cushing’s Syndrome
MAGIC Adult Convention
Las Vegas, NV
April 21, 2013
Do Magic Convention Cushing’s Patients
Know More Than Many Endocrinologists?
•
•
•
•
I think so!
I will show the conventional statement.
You will give an answer.
No cheating by looking at the handouts.
Is Cushing’s Syndrome Rare?
• Probably not
•
•
•
•
•
•
Catargi et al. JCEM 2003, 88:5808-200 consecutive overweight patients with
type 2 diabetes, but no other stigmata of hypercortisolism. 4 (2%) patients were
found to have Cushing’s syndrome and another 7 are being evaluated.
Reimondo et al. Clin. Endo 2007,67:225-229 found that 5% of diabetic patients
failed to suppress to dexamethasone.
Kadioglu et al. Endo Society 2004 86: P2-455- 100 consecutive obese patients.
Cushing’s syndrome was diagnosed in 11%.
Nishikawa et al. Endo Society 2004 86: P3-437- 1020 patients with hypertension.
11 had Cushing’s syndrome and 10 had subclinical Cushing’s syndrome (2%).
These studies may have missed mild Cushing’s syndrome and may actually be
low.
Maybe Cushing’s syndrome is not so rare
Do patients with Cushing’s need to have all
the signs and symptoms listed in textbooks?
• No
• Textbooks show severe cases.
• Most patients have some but not all signs and symptoms of
Cushing's
• Patients are being diagnosed earlier and patients with mild
Cushing’s may only have some of the signs and symptoms
Common symptoms I see
• Wired at night
• Trouble sleeping-trouble falling asleep or frequent
awakenings
• Severe fatigue-new onset
• Abrupt weight gain-without other cause such as decreased
activity or depression
• Decreased ability to exercise
• Menstrual abnormalities
• Cognitive changes- “brain fog”
• Decreased libido
• Symptoms of adrenal insufficiency-joint pains, can’t get
out of bed, nausea and vomiting
• Depression, anxiety, mood-swings
All patients with Cushing’s are
obese
• Patients who really watch caloric intake and
exercise (often hard), do not gain much
weight
• If you start thin, you probably will not
become obese
All children with Cushing’s are short
• If a child gets Cushing’s before 10, most
likely their growth rate will decrease.
• But if they start tall, they will end up tall
• Obesity leads to increased estradiol which
accelerates growth rate
• Boys slow down growth rate around 14 and
girls around 12.
• An older child with Cushing’s is unlikely to
be short
Periodic Cushing’s is very rare and may not
exist
• Friedman, T.C., Ghods, D.E., Zachery, L., Shayesteh, N.,
Seasholtz, S., Zuckerbraun, E., Shahinian, H.K., Lee, M.L.,
McCutcheon, I.E. (2010) High Prevalence of Normal Tests
Assessing Hypercortisolism in Subjects with Mild and Episodic
Cushing’s Syndrome Suggests that the Paradigm for Diagnosis
and Exclusion of Cushing’s Syndrome Requires Multiple
Testing. Hormone and Metabolic Research. 42: 874-881.
• We found that 65 of the 66 patients with Cushing’s syndrome
had at least one normal test of cortisol status and most patients
had several normal tests.
• The probability of having Cushing’s syndrome when one test
was negative was 92% for 2300 h salivary cortisol, 88% for 24-h
UFC, 86% for 24-h 17OHS and 54% for night-time plasma
cortisol.
Periodic Cushing’s is very rare and may not
exist
• These results demonstrated that episodic hypercortisolism is
highly prevalent in subjects with mild Cushing’s syndrome and
no single test was effective in conclusively diagnosing or
excluding the condition.
• Rather, the paradigm for the diagnosis should be a careful history
and physical examination and in those patients in whom mild
Cushing’s syndrome/disease is strongly suspected, multiple tests
assessing hypercortisolism should be performed on subsequent
occasions, especially when the patient is experiencing signs and
symptoms of short-term hypercortisolism.
One normal test excludes the diagnosis of
Cushing’s syndrome
• Our paper on episodic Cushing’s syndrome showed that
most patients with confirmed Cushing’s syndrome are
episodic with one or more normal values.
• Thus one normal value does not exclude Cushing’s.
• A series of normal values does make Cushing’s unlikely at
the current time
• I usually like to see at least two separate high values for
testing
You would have died from Cushing’s
syndrome if you had it for this long
Cushing’s Disease Is Not Necessarily a Progressive and Fatal Disease
A Case of Documented Cushing’s Disease Untreated for 26 Years
(Patel, et al. 2005, Endocrinologist 15:343-344.
1983
1996
2000
1977-Hospitalized for severe hypertension
1977-Overnight dex-8 AM cortisol=33 µg/dL
2003-Elevated 17-OHS X3
2003-4 mm pituitary tumor
Only severe Cushing’s patients should
undergo testing and treatment
• Patients with “mild” Cushing’s syndrome have a low
quality of life.
• Quality of life does not correlate well with cortisol
measurements
• All patients with Cushing’s deserve to be diagnosed and
cured
Imaging should only be performed after the
diagnosis of Cushing’s is made
• Most of the patients I see have pituitary Cushing’s
disease.
• 3T MRIs are high quality; most pituitary tumors
are seen on MRI.
• Patients can have incidentalomas, so a tumor
doesn’t make the diagnosis of Cushing’s, but does
give an important piece of information.
• A negative MRI in a patient that has a normal or
mildly elevated ACTH pretty much excludes
Cushing’s (low ACTH=adrenal Cushing’s, high
ACTH=ectopic)
Pituitary MRI
• In literature approximately 50% of patients with Cushing disease have
a visible tumor on MRI (older, non-dynamic, lower power MRIs).
• 10% of normal volunteers have MRIs consistent with a pituitary
adenoma (Hall et al. Ann. Intern. Med., 1994, 120:817-820).
• Now 3 Tesla dynamic MRIs can pick up small tumors are done.
• Patients without Cushing's syndrome or with adrenal/ectopic Cushing's
can have a pituitary incidentaloma.
• Friedman, T.C., Zuckerbraun, E., Lee, M.L., Kabil, M.S., Shahinian,
H.K. (2007) Dynamic Pituitary MRI Has High Sensitivity and
Specificity for the Diagnosis of Mild Cushing's Syndrome and Should
be Part of the Initial Workup. Hormone and Metabolic Research
39:451-456.
23 of 24 patients had had a MRI consistent with a pituitary lesion
Pituitary MRI
12
Tumor size (mm)
10
8
6
4
2
0
Pt #
50% of patients with Cushing’s disease have
normal MRIs
• I found that 90% of patients with Cushing’s disease had a visible
tumor on MRI and 95% have an abnormal MRI
• Friedman, T.C., Zuckerbraun, E., Lee, M.L., Kabil, M.S., Shahinian,
H.K. (2007) Dynamic Pituitary MRI Has High Sensitivity and
Specificity for the Diagnosis of Mild Cushing's Syndrome and Should
be Part of the Initial Workup. Hormone and Metabolic Research
39:451-456.
Make the diagnosis of Cushing’s syndrome
before figuring out which type.
• ACTH is helpful to get early
• Imaging is helpful to get early
• A negative MRI in a patient that has a normal or mildly elevated ACTH
pretty much excludes Cushing’s
70% of patients with Cushing’s have
Cushing’s disease, 20% adrenal and 10%
ectopic
•
•
•
•
•
My experience is that 95% are pituitary
5% adrenals
< 1% ectopic
I probably have a selection bias.
Pituitary patients are the hardest to distinguish between normals; ectopics
and adrenal patients often have higher cortisol and may be easier to
diagnose and stay local
You need a UFC greater than 3 times normal
to have Cushing’s syndrome
• Only 4/66 patients in our study with
confirmed Cushing’s had a UFC > 3X
normal
• Most of my patients had UFCs between 1X
and 2X
17-hydroxysteroids are an old
test and should not be performed
• Mengden et al. (Clin Inv, 1992) showed that UFC was
better able to distinguish Cushing’s syndrome from normal
individuals than could 17OHS.
• The subjects in that study, however, had sustained and
substantial hypercortisolism.
• We suspect that in high cortisol production states, the UFC
assay would be a better assay to distinguish patients with
Cushing’s syndrome from those without Cushing’s
syndrome.
17-hydroxysteroids are an old test
and should not be performed (2)
• However, at lower cortisol production rates, the 17OHS
assay may be able to detect mild hypercortisolism in some
patients with normal 24-h UFC levels.
• UFC measurements will increase only mildly until a point
of saturation of cortisol binding to CBG is exceeded
• 17OHS measurements which are not dependent on cortisol
exceeding the threshold of binding to CBG are more likely
to be linear with cortisol production.
17-hydroxysteroids are an old test
and should not be performed (3)
UFC/17OHS
350
UFC/17-OHS X10
300
250
200
UFC
17OHS X10
150
100
50
0
1
2
3
Blood draws raise your cortisol and should
not be used to assess cortisol
• Meeran et al. (Br J Clin Pract 1993; 47: 246-247 )
found that serum cortisol did not rise until 4 min
after a venipuncture in volunteers subjects awaken
from sleep who had blood drawn by venipuncture.
• Serum cortisol is not affected by venipuncture,
unless multiple unsuccessful attempt have been
done.
A pic-line is the best way to
measure cortisol
• Cortisol is not raised by venipuncture
• In my mouse studies, cortisol was raised by having a line
placed.
• Most important is the midnight cortisol, other times are not
that helpful.
• Avoid pic-lines
• Have to correct for time zone differences
Morning cortisols are helpful for making the
diagnosis of Cushing’s
• Friedman, T.C. and Yanovski, J.A. (1995) Morning
Plasma Free Cortisol: Inability to Distinguish Patients with
Mild Cushing Syndrome from Patients with PseudoCushing States. J. Endocrinol. Invest. 18:696-701.
• Cushing’s syndrome is a disease of high cortisol at night.
• Morning samples are not helpful for diagnosing Cushing’s
4 PM cortisols are helpful for making the
diagnosis of Cushing’s
• 4 PM cortisols are probably a little higher in Cushing’s
patients compared to patients suspected of Cushing’s, but
too much overlap
• No literature on cut-offs
• Only use night-time cortisols
You need to do a 24 hr (and not shorter durations)
urine for UFC to assess cortisol status
• 24 hr UFC are one of the main tests for the diagnosis of
Cushing’s syndrome.
• Many patients with Cushing’s have high cortisol during the
night and low cortisol during the day, so the 24 hr UFC is
cancelled out
• I have patients collect a 10 hr sample from 10 PM (discard
first void) to 8 AM
• A value > 16 ug/mg Cr is consistent with Cushing’s
syndrome
• I have not published this yet, but it works well.
Testing for Cushing’s can be done at any
time-whether having symptoms or not
• Most patients with Cushing's are episodic.
• Need to do testing when in a high.
• Record symptoms in a diary, so they can go back to see
their symptoms when they get a high.
Testing for Cushing’s can be done at any
time-whether having symptoms or not
•
•
•
•
•
•
•
•
•
Wired at night
Weight gain
Acne
Anxiety increase/mood swings/irritability
Euphoria/more energy than usual
Very few aches and pains
Insomnia/inability to stay or fall asleep.
Energy levels that “perk up” after sunset.
“Speed talking” – mind is going faster than your brain can
process the thoughts to speak them.
• Water weight gain – edema
• High blood pressure
• High blood sugar if diabetic
Patients who suppress to overnight
dexamethasone do not have Cushing’s syndrome
• Friedman, T.C. (2006) Experimental and Clinical
Endocrinology and Diabetes 216: 356-360.
• 14/17 patients with proven Cushing’s suppressed to
dexamethasone with a cortisol < 5
• Conclusion: test not helpful for excluding Cushing's
syndrome.
• If someone has a high value after dexamethasone, may
help with the diagnosis of Cushing's syndrome, but those
patients usually are severe and can be diagnosed anyway
• If patient suppresses to overnight dexamethasone, adrenal
adenoma or ectopic is unlikely.
Overnight dexamethasone test
14
0800 h cortisol (g/dL)
12
10
8
6
4
2
0
1
2
3
4
5
6
7
8
9
10
Patient #
11
12
13
14
15
16
17
Dex-CRH test is the gold standard test for
diagnosing mild Cushing’s syndrome
• Dex-CRH test was only tested in those with severe,
sustained Cushing's.
• Many of my patients with confirmed Cushing's had a low
cortisol in the dex-CRH test.
• CRH is currently not available
Petrosal Sinus Sampling can be used to make
the diagnosis of Cushing’s disease
• Petrosal sinus sampling (IPSS) samples blood draining the
pituitary.
• NIH study in the 90s showed that normal volunteers,
patients with pseudoCushing's and patients with Cushing's
had similar petrosal sinus sampling results.
• They had a central to peripheral gradient of ACTH,
lateralization, and response to CRH.
• Thus, petrosal sinus sampling can not be used to
distinguish between normals and those with Cushing's.
• It can be used to distinguish between pituitary and ectopic
Cushing's or pituitary and adrenal Cushing's, but those can
usually be done by other methods.
• It can help with lateralization (which side the tumor is on),
but MRI can usually give that information.
All patients with Cushing’s disease should
undergo petrosal sinus sampling prior to
surgery
•
•
•
•
No, it usually doesn’t add much information
It is invasive and expensive
It can not be used to diagnose Cushing's.
I use it in those with confirmed Cushing’s and an ACTH in
the range of pituitary Cushing's, but negative MRI.
• It usually needs to be done in a high.
• Since episodic patients can not predict when in a high, I
get a UFC or salivary the day/night before to see if in a
high and try to interpret based on that.
Patients with high cortisol need extensive
testing to determine the type of Cushing’s
•
•
•
•
•
In my practice, most patients are pituitary (>95%).
Morning ACTH <10, likely adrenal Cushing’s.
Morning ACTH >100, likely ectopic Cushing’s.
Morning ACTH 20-100, likely pituitary Cushing’s.
Positive pituitary MRI makes pituitary Cushing’s likely,
but can have incidentalomas
• Suppression to overnight or low dose dexamethasone
makes ectopic or adrenal Cushing's unlikely
• I use ACTH and pituitary MRI to make my decision, use
petrosal sinus sampling if unclear.
Any surgeon can operate on a patients with
Cushing’s syndrome
• Its crucial to go to an experience surgeon.
• Someone who has done at least 200 pituitary cases and 50
Cushing’s cases.
• Surgically, Cushing's tumors are the hardest to remove.
• Often multi-lobulated, with out much of a capsule.
• I have a network of experienced surgeons who I work with
and who trust my workup.
All patients cured from Cushing’s syndrome
should have a morning cortisol less than 4
• The traditional approach has been patients with Cushing’s
disease have sustained high cortisol which suppresses the
normal corticotrophs.
• When the tumor is removed, the normal corticotrophs are
quiescent and ACTH and hence cortisol is low.
• Most of my patients are episodic, during normal cortisol
production, corticotrophs continue to secrete ACTH (no
quiescence)
• Most of my cured patients have a morning cortisol between
10-15.
• I am concerned when the morning cortisol is >20 or
morning ACTH > 30.
All patients cured from Cushing’s syndrome
will have an ACTH-staining tumor found on
pathology
• Classic approach is that ACTH-staining tumors are needed
to prove Cushing’s disease.
• My experience is most of the time, cured patients have
equivalent or negative pathology.
• May be the tumor staining for ACTH was removed in the
“sucker” or missed in pathology.
• Or that in patients who are episodic, if the tumor is not in
an active stage, staining will be negative.
• I am trying to set up a study looking at staining for ACTH
precursors, which may be still positive in episodic
Cushing's.
If the post-op cortisol is greater than 10,
cortisol replacement should be stopped
• I find that if cortisol replacement is not given, patients
develop adrenal insufficiency, even with a post-op cortisol
in the 10-15 range.
• Patients may experience lower cortisol later in the day that
gets missed by a morning sample
• Its always prudent to replace, then taper if no signs of
adrenal insufficiency
Cured Cushing’s patients need cortisol
replacement for at least 1 year
• The lower the post-op cortisol, the longer patients need to
stay on Cortef, before tapering.
• Patients with a post-op cortisol between 10 and 15 can
usually taper off in about 3 months.
• I use a morning cortisol and symptoms of adrenal
insufficiency as a guide.
• A few of my patients (especially after a second surgery),
continue to have undetectable cortisol levels and need
lifelong Cortef.
Cured Cushing’s patients should get a
cosyntropin test before stopping cortisol
replacement
• Cosyntropin test works because low ACTH leads to
adrenal atrophy, which then leads to a blunted cosyntropin
response.
• Cosyntropin response lags behind a morning cortisol
(patients can often taper off Cortef with a blunted
cosyntropin test).
• It doesn’t change management; is a person who tapered off
Cortef, has no symptoms of adrenal insufficiency and has a
normal morning cortisol going to resume Cortef because of
a blunted cosyntropin test.
Brand Cortef and generic hydrocortisone are
equivalent
• Like most generics, they have the same active ingredients
as the brand, but different fillers and binders.
• Small differences in absorption of hydrocortisone may
make a big difference.
• I recommend brand Cortef for most patients.
Patients who failed pituitary surgery should
get radiation
• Pituitary radiation may take up to 5 years before leading to
normal cortisol levels-my patients don’t want to wait that
long.
• Pituitary radiation may lead to memory loss.
• Pituitary radiation almost always leads to hypopituitarism,
especially growth hormone deficiency.
• A second pituitary surgery or bilateral adrenalectomy are
usually preferred.
• Nelson’s syndrome following bilateral adrenalectomy is
rare in my patients with small, slow growing tumors and
can be treated with surgery if needed.
Pasireotide (Signifor) is the best drug for
Cushing’s disease
• Pasireotide is a recently approved drug for Cushing’s
disease.
• Almost all patients on it get diabetes.
• Its effect on lowering cortisol is mild and variable.
• Its expensive
• Ketoconazole is a better choice.
Ketoconazole is a dangerous drug and should
only be used in those with severe Cushing’s
• Ketoconazole is safe, with the main side effect being
increased liver tests, which usually occur at doses > 1000
mg/day and are reversible.
• It does interact with a lot of drugs, but these interactions
can usually be dealt with by changing the other drug or
watching for side effects
• It has a short-half life so it can be given at night, when
cortisol is inappropriate high in Cushing’s patients.
• I usually give 200 mg at 8 and 10 PM and have patients
take 5-10 mg of Cortef in the AM, if needed.
Ketoconazole should only be used in those
with confirmed Cushing’s
• Ketoconazole can be used diagnostically to determine
which symptoms a patient has are due to high cortisol.
• I use it in patients who Im pretty sure, but not completely
sure has Cushing's and I want them to get symptomatic
relief.
• I’m concerned if someone doesn’t get better on
ketoconazole, if they really have Cushing's.
• I have kept patients on ketoconazole for up to 3 years
without problems.
• I often stop it for a round of testing, or if a patient develops
a tumor on MRI.
Ketoconazole can be given once a day in the
morning
• Cushing's syndrome is a disease of high cortisol at night.
• Ketoconazole has a half-life of 6 hours.
• I give ketoconazole at night in almost all patients.
All patients who fail their first pituitary surgery should
have a second pituitary surgery, especially right away.
• Some patients have a delayed lowering of cortisol and
maybe cured even if its not that apparent.
• I usually reserve a second surgery for those patients with a
visible tumor on MRI.
• This is often not apparent until months after surgery.
Bilateral adrenalectomy is a dangerous procedure and
should be reserved for those who still have high cortisol
after radiation.
• Old data suggested that 10% of patients with bilateral
adrenalectomy died.
• Done laproscopically, bilateral adrenalectomy is quite safe,
with minimal complications.
• It results in an immediate and definitive cure in almost all
patients.
• Patients with one or more failed pituitary surgeries are
good candidates for bilateral adrenalectomy.
• I do like more tests confirming hypercortisolism than I do
for bilateral adrenalectomy.
Bilateral adrenalectomy just replaces one disease
(Cushing's) with another (adrenal insufficiency).
• Cushing’s disease gives the worse quality of life of any
Endocrine diseases
• Cortisol and fludrocortisone replacement is not difficult
with easy monitoring.
• Almost all my patients who had an adrenalectomy are glad
they did.
Patients with bilateral adrenalectomy just need cortisol
replacement
• Fludrocortisone (florinef) is crucial.
• Some patients benefit from DHEA
The best way to monitor fludrocortisone replacement is
by measuring electrolytes
• Electrolytes change late.
• A renin level is the best way to monitor fludrocortisone
replacement.
• A high renin means more fludrocortisone is needed and a
low renin means less fludrocortisone is needed.
• Can be done sitting or standing.
Bilateral adrenalectomy leads to a permanent cure in all
Cushing’s patients
• Remnant tissue (regrowth of adrenal tissue) in the adrenal
bed may occur.
• I have 3 out of about 40 patients who developed it.
• In the great majority, bilateral adrenalectomy does lead to
a permanent cure.
Patients with Cushing's should listen to their doctor’s
advice and not go on the internet.
• The internet is a great source of information for patients.
• Support groups-Cushing’s Help and CSRF are excellent.
• Doctors who state that patients shouldn’t use the internet
are behind the times.
For more information/to schedule an
appointment
• www.goodhormonehealth.com
• mail@goodhormonehealth.com
Who runs the best pituitary patient
conference?
• The Magic Foundation