Transcript Document

So you had your surgery-now
what?
Theodore C. Friedman, M.D., Ph.D.
Professor of Medicine-Charles Drew University
Professor of Medicine-UCLA
Magic Foundation
Symposium on Cushing’s Syndrome
February 22, 2009
Las Vegas, NV
Are you cured?
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Hard to tell
In sustained pre-op hypercortisolism, normal
corticotrope cells are suppressed. Cure used to be
morning cortisol < 4 ug/dL
When tumor is removed, ACTH and cortisol are low
post-op
In episodic Cushing’s, this often doesn’t occur.
I recommend 2 mg of dexamethasone on post-op day 1,
1 mg on post-op day 2, no cortisol replacement on days
3 and 4 and get a 8 am cortisol, ACTH and electrolytes
on day 5, and start cortisol replacement right after blood
draw.
Are you cured?
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The lower the day 5 cortisol the more likely the cure.
Morning cortisol is often in the 10-15 ug/dL range and
patient is still cured.
Cortisol above 20 ug/dL or ACTH above 30 are bad
signs.
Symptoms
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Cortisol levels drop from high to normal, leads to relative
glucocorticoid insufficiency
Joint pains, abdominal pain, weakness, nausea,
vomiting, headache and “hit by a speeding truck” are
signs of relative low cortisol and good signs.
Low sodium is common post-op and also gives
headache and nausea (measure sodium on day 5)
Psychological and psychiatric symptoms (depression,
anxiety) may get worse after surgery due to low brain
CRH levels and patients (and spouses) should be
warned.
Pathology
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Classic Cushing’s patients have clear tumors that stain for
ACTH.
Crooke’s hyaline change occurs with sustained pre-op
hypercortisolism.
Episodic patients may or may not be hypercortisolemic at the
time of surgery, so staining for ACTH may be negative (tumor
off)
Tumors are often tiny and either discarded by suction or
missed by pathologist.
I have never seen Crooke’s hyaline changes in any of my
patients
Most of my patients have unclear or negative pathology in
spite of being cured.
Several patients showed adrenal hyperplasia when they went
for adrenalectomy, yet had normal pituitary pathology.
Pathology-Hyperplasia
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Classic corticotrope hyperplasia was described in Russia and
involves the corticotrope cells in the whole pituitary being
enlarged and suggests an abundance of CRH.
What we see is a small pocket of ACTH-staining cells that are
larger than normal corticotrope cells, but not a clear tumor.
My guess is this is an early tumor.
Often see multiple tumors connected by a barbell or an
octopus with 8 arms.
In some cases, there is a tumor of ACTH-staining cells on one
side and hyperplasia adjacent to it.
Patients with hyperplasia due worse, but can still be cured with
pituitary surgery.
Cortisol replacement
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Cortisol levels go from high to either low or normal.
If no replacement, potential for adrenal insufficiency, even if
cortisol levels are normal.
I replace everyone, but taper off within first 3 months if no
signs of adrenal insufficiency.
Hydrocortisone- generic, cortef- brand, many patients like
hydrocortisone better
Body’s circadian rhythm has high cortisol in AM and low in
afternoon and evening, so want to mimic the body’s on rhythm.
I give 15-20 mg in morning depending on size and 5 mg at
around 2 PM.
I do not see any need for prednisone, dexamethasone or longlasting investigational cortisol preparations in patients on
temporary replacement.
Cortisol replacement (2)
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I monitor 8 AM cortisol levels after holding hydrocortisone for
24 hrs (have patient skip afternoon dose the day before and
take morning dose after blood draw) every 3 months.
Usually an AM cortisol level of > 10-12 ug/dL and no signs of
adrenal insufficiency would lead me to start a taper.
Most cured patients can get off cortisol in 6-12 months.
I taper HC down 2.5 mg to 5 mg every 2 weeks.
I often get a morning cortisol level after taper, but usually don’t
restart if patient is doing well off it.
Cosyntropin test works on adrenal cells atrophying and lags
behind serum cortisol levels- I do not find it more helpful than a
morning cortisol draw.
I have some patients (especially those that had prior surgery)
that have undetectable morning cortisols a year after surgery,
these patients will need lifelong replacement.
Cortisol replacement (3)
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I give subjects a script for solucortef in Act-O-vial 100 mg for
IM injection, but almost never have seen pituitary post-surgery
patients need it
I do not give adrenal bracelets.
Double the dose of hydrocortisone if fever or vomiting.
If can not keep hydrocortisone down, double dose, then give
solucortef shot and go to ER
Most patients do fine
Other pituitary hormones
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Surgery can damage pituitary cells.
High cortisol also suppresses pituitary function-cure
from Cushing’s can improve pituitary function
Order of susceptibility of pituitary cells
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GH
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LH, FSH leading to low estradiol (irregular periods)
and testosterone
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TSH
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ACTH
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AVP
At 3 months, I check IGF1, freet4, free T3, TSH,
testosterone
If low IGF1, especially compared to pre-op, I do GH
stimulation testing- glucagon stimulation test
Other pituitary hormones
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If low free T4 and lowish TSH, I often give
thyroid hormone replacement
I often supplement testosterone with cream
from compounding pharmacy or enroll in my
hypopituitarism study (see end)
If no periods after 1 year, I measure an FSH
and estradiol and replace estradiol with or
without progesterone.
Diabetes Insipidus
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Posterior pituitary makes AVP (also called
ADH)
Regulates free water, low AVP, DI-polyuria and
polydipsia and high serum sodium
High AVP-SIADH, low sodium-headache,
nausea
3 phases of sodium balance-1-3 days post-op:
DI, 5-10 days post-op: SIADH, after 10 days:
DI (rare)
Diabetes Insipidus (2)
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1st phase-in hospital often get DDAVP, 2nd
phase at home-fluid restriction, but gets better
on its own
3rd phase-May need DDAVP-often given at
night to prevent waking up at night to urinate.
Pill or nasal spray.
Sometimes gets better on its own.
Why would you be uncured?
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Part of the tumor left behind- a few cells or one arm of
the octopus
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Multiple tumors and only one removed.
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Incidentaloma removed, ACTH secreting tumor left
behind
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Invasion outside of sella
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Misdiagnosed.
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If uncured, taper of hydrocortisone, re-document
hypercortisolism and consider repeat surgery.
Uncured-what do next
Re-document hypercortisolism
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Reconfirm pituitary source
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Repeat pituitary MRI- “post operative changes” may
mean recurrent tumor
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If visible pituitary tumor, repeat surgery.
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If no visible tumor, consider ketoconazole (see next
lecture) to decrease cortisol synthesis.
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Consider repeat surgery, scrapping the cells at the edge
of the tumor
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Consider adrenalectomy or radiation therapy
On to “Beyond pituitary surgery”
Study
• Recruiting Women with Pituitary Problems
• Ages 18-55
• Location: Los Angeles
• To Receive Testosterone Replacement for 6 Months and Evaluate
Changes in Body Composition, Muscle Strength, Thinking and Sexual
function
• Patients May be Eligible for Growth Hormone
• Patients Will Be Compensated
• Please call Dr. Friedman or Dr. Zuckerbraun at 323-563-9385 or email
[email protected] for more information or to enroll.
• IRB approved