pituitary and adrenal “perioperative”...
TRANSCRIPT
Maria Fleseriu, MD, FACE
Professor , Director Northwest Pituitary Center
Oregon Health Science University
Pituitary and Adrenal “Perioperative” Endocrinology
Disclosure
• Chiasma,Cortendo,Novartis,Pfizer
– Principal investigator: Research
funding to OHSU
– Scientific consulting fee
Do endocrinologists need to be consulted preoperatively
for pituitary and adrenal tumors?
Pituitary
Does the patient need surgery from an endocrine standpoint?
How long should patients be monitored/ kept inpatient?
How and when do we re-evaluate the patient post operatively?
Do we have any data (randomized trials) for how to best manage patients?
Adrenal
• Is this a secretory tumor?
• When do we need to find out if it is-inpatient or outpatient?
• Will need removal from an endocrine point of view?
4
Case
CC: 54 y old with headache + altered mental status
HPI:
• Missed work which was unusual for him.
• He was called into work where he became increasingly
confused and disoriented while also complaining of a
headache.
• As part of his work up in ED, a CT revealed a large sellar
and suprasellar mass and he was transferred to our
hospital for further workup and management.
ROS: Headache, confusion, somnolence, vision loss?
5
Case continued
BP 118/65 | Pulse 64 | Temp 36.8 °C (98.2 °F) | RR 12 | Ht 1.803 m (5' 11") | Wt 94.5 kg (208 lb 5.4 oz) | SpO2 96% | BMI 29.07 kg/(m^2)
General Appearance: Obese male, lying in bed, awakens to voice briefly holding bridge of nose with eyes closed.
HEENT: MMM, mild conjunctival injection, no moon facies, no facial plethora.
Neck: +dorso-cervical fat pad enlargement, no supraclavicular fat pad enlargement.
Abdominal: soft, NT, +BS, no violaceous striae.
Skin: no acne, skin not oily, did not have multiple skin tags.
Neurologic: bilateral eyelid apraxia, upgaze deficit, no facial droop, able to move all 4 extremities spontaneously against gravity, somnolent, oriented to self and year.
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MRI with contrast homogenously 5.8 x 3.4 x 2.5 cm sellar, supra sellar massextending into the third ventricle and interpeduncular cistern causingsecondary obstructive hydrocephalus. The right cavernous carotid is
encased.
Imaging
7
Hormonal work-up
• TSH 0.64 mLU/l
• Free T4: 0.7 (0.6-1.2)
• Prolactin: 99*
• ACTH: 22
• Cortisol: 9.4 ug/dL
• FSH<1, LH<1
• Testosterone: 22
• IGF-1 152 ng/ML (68-245ng/ML)
8
What is next?
• Patient underwent transphenoidal pituitary surgery
• Pathology
– Sections show fragments of anterior pituitary tissue with disrupted acinar
architecture (highlighted by reticulin stain) and involvement by sheets of
relatively monomorphic adenoma cells which strongly express prolactin.
– Adrenocorticotropic Hormone Negative
Human Growth Hormone Negative
Prolactin Positive
Cyto-Keratin CAM 5.2 Positive focal
Somatostatin Receptor 2A Positive
KI67 % Positive 5%
p53 Negative
Negative control slide for IHC stain Negative
SF-1 Positive focal
9
What Now?
What is the diagnosis?
Reminder:
PRL 99 with dilution
SF-1 positive
10
Cell Lineage
specific
transcription
factors
Pit-1
T-pit
SF-1
ER
TPit
11
Initial evaluation for large tumors
• Imaging- ideally pituitary dedicated MRI
• Visual field testing (if mass abuts/compresses optic nerve)
• Evaluate HPA axis
• Check for clinical and biochemical signs of hormone
excess
12
Evaluate for hormonal secretion
• If prolactinoma-
medical therapy >
surgical therapy.
• Acromegaly and
Cushing's disease at
increased risk for
cardiovascular
complications.
• Prolactin
• ACTH/ Cortisol
• IGF-1
• TSH/FT4
• LH/FSH-
estrogen/testoster
one*
13
Evaluate for hormonal deficiencies
Adrenal insufficiency
• Check AM cortisol +/- ACTH
• If results equivocal or clinical suspicion, cosyntropin
stimulation test
• Goal: treatment to prevent adrenal crisis, particularly if
patient is going for surgery
14
TSH
Evaluate for central hypothyroidism & central
hyperthyroidism
• Check Free T4 + TSH
• Central hyperthyroidism very rare
• TSH not reliable even if normal or elevated
• Exact cut- off for repletion varies
– Replacement can prevent hyponatremia, cardiac
complications and postoperative ileus
15
ADH
DI inadequate AVP response to serum osmolality
• More common in suprasellar lesions
– Craniopharyngyomas (81%-96% post op)
Adipsic DI- rare entity
• Craniopharyngiomas accounts for 13-30% of cases
– Particularly in tumors greater than 3.5 cm or causing hydrocephalus
• Other causes include other suprasellar lesions, congenital, infection, aneurism clipping, toluene exposure
• Occurs when patients have inadequate thirst response for rising serum osom
• High morbidity and mortality
– Central sleep apnea
– Excess somnolence
– DVT
– AKI
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GH /LH-FSH axes
• IGF-1 should be checked in all tumors in my opionion
• LH, FSH- can wait if patient will undergo surgery as they
will need re-evaluation post operatively
• No current role for alpha subunit
• Most “silent adenomas” are gonadotroph adenomas
17
Prolactin
• Typically degree of prolactin elevation correlates with
size of tumor
Uptodate
18
Other giant tumor
Fleseriu et a, J Neuroonc, 2006
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Hook effect
• Prolactin levels in giant prolactinomas can be misleading
• Essentially antigen-(prolactin)interferes with assay by preventing complex formation with capture antibody and signal antibody
• Dilution is required to lower
prolactin levels enough to enable
antibody complex formation
• Mild prolactin elevation in range of stalk effect can be misleading in giant adenomas– verifying serial dilutions is key
Smith TP et al. 2007,Nat Clin Pract Endocrinol Metab 3: 279–289, Fleseriu et al, 2006, Neurooncology
20
MRI after surgery and Cabergoline
Fleseriu et a, J Neuroonc, 2006
21
Early postoperative complications
Surgical
• Sellar hematomavisual loss
• Diplopia
• Headache
• CSF leak
• ICA injury
• Hydrocephalus
• Epistaxis
• Infection
– Meningitis
– Sinusitis
– Abscess
Endocrine
DI
SIADH
Adrenal insufficiency
22
Early Postoperative Management
• Serial visual field assessments
• Serial neurologic exams
• Imaging if new neurologic deficit or suspected CSF leak
• Strict ins and outs
• Monitor serum sodium, urine SPG (less than 1.005) or
osm
• UOP > 250 ml/h x 2-3 hours
• DDAVP if indicated?
• AM Cortisol*
• Serum sodium in 5-7 days post op
23
Evaluation of remission in functional adenomas
• Moderately predictive of
early and long term
remission.
POD 1
• Fasting AM GH less
than 1 or 2 ng/ml
• Prolactin level less than
10 ng/mL
• Cortisol *
• CD
– Multiple protocols to
evaluate “cure” Cushing's
– Steroids held and serial
measurements of post op
cortisol
– Particularly important as
they may either need
further treatment or are
adrenally insufficient
24
Prospective study- N=57
• Day 0-14
• 75% of patients had some sodium abnormality
• 38.5% Isolated DI
• 21% isolated Hyponatremia
• 15.7% had combined DI + Hyponatremia
• 8.7% of patients required DDAVP for more than 3 months
• Pituitary manipulation most strongly correlated with risk of
DI
Electrolyte abnormalities following transphenoidal
pituitary surgery
Kristof et al, J Neurosurg. 2009 Sep;111(3):555-62.
25
How long to keep the patient in the hospital?
For DI and SIADH
monitoring ?
Peak incidence DI: 24-48
hours.
Typically do not keep in
hospital to see if they
develop SIADH
To evaluate for remission
Cushing's
- We hold steroids and then
check cortisol q6 hours x 4
Acromegaly
-check am GH POD 1 & 2
26
• Retrospective study comparing outcomes before an after
implementation of a multidisciplinary team and protocol
• N:214, 113 before and 101 after protocol
• Median length of stay decreased from 3 to 2 days (P<0.01)
• No difference in rate of DI or SIADH or other complications
Inpatient multidisciplinary pituitary team
Carminucci AS, Ausiello JC, Page-Wilson G, Lee M, Good L, Bruce JN, Freda PU., Endocr Pract. 2016
27
Glucocorticoids for “non Cushing's” patients
• AM cortisol may be helpful in determining central adrenal
insufficiency post op.
• CST unreliable for at least two weeks
• Multiple different approaches including
– Empiric stress dose steroids before surgery + discharge on
physiologic replacement, evaluate in 6 weeks
– Steroids if post op am cortisol less than 10-15 mcg/dl
– Steroid sparing: no perioperative steroids and careful post
operative monitoring for AI
28
6 + 12 weeks postoperatively
• Evaluate HPA axis at week 6 + 12
– Cosyntropin stimulation test
• Reevaluation for other pituitary axes
• Initiate repletion for new hormonal deficits if any
• Post operative MRI at week 12 “new baseline”
29
Long term follow up
• Depends on the tumor type
• Periodic MRI (annually for 3-5 years)
• Monitoring for hormone excess
• Periodic HPA axis evaluation (at least annually)
– Recovery is higher than previously thought, especially in
acromegaly patients
Preoperative Hormonal Evaluation:AdrenalProlactinThyroidGHGonadotroph
Replace thyroid and adrenal hormones if insufficiency detected preoperatively
Transsphenoidal SurgeryPerioperative stress dose steroids if indicated
Early Inpatient Monitoring
1 week:General status, sodium, cortisol
6 week:General status, Adrenal, thyroid, GH,
Prolactin
12 week:General status, Adrenal, thyroid, gonad, GH,
Prolactin as clinically indicatedMRI – Baseline post op image
Neurologic status Diabetes insipidus
SIADHEarly outpatient Assessment Long Term Follow up
Hormonal status evaluation annually
or as dictated by clinical state
Assessment for tumor recurrence
Outpatient Follow up
Adapted from; AACE Neuroendocrine and Pituitary Scientific Committee. Endocr Pract. 2015
Assessment for biochemical remission
31
MOC question
• A 29‐year‐old woman is known to have partial
hypopituitarism (on replacement with Hydrocortisone 15
mg daily and Levothyroxine 100 mcg daily) after surgery
for a 2.4 cm pituitary adenoma several years ago.
Residual tumor significantly increased in the last 2 years
and a second pituitary surgery is planned. You see her in
the endocrinology clinic the week of her surgery and give
recommendations to the patient and the on-call
endocrinologist who will manage the patient in the
hospital.
32
Which of the following statements is TRUE?
1. Change her glucocorticoid regimen now from Hydrocortisone to
Prednisone to better prepare her for surgery
2. Increase her daily hydrocortisone from 15 mg to 20 mg daily a
week before surgery to avoid use of stress dose perioperatively
3. Stop levothyroxine in the hospital, it won't get absorbed anyway
and recheck TSH in the first 3-4 weeks after surgery
4. Fixed doses of DDAVP should be prescheduled in the immediate
postoperative period as this is her second pituitary surgery
5. She will need retesting of all pituitary axes starting at 6 weeks after
pituitary surgery and then periodically to monitor the development
or resolution of pituitary deficiencies.
Fleseriu M et al, Hormonal replacement in hypopituitarism in adults: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016; 101: 3888–3921.
Adrenal mass-inpatient
• Is the mass functional?
• Physical signs or symptoms of hyperfunction?
• Biochemical work-up:
– Screen for pheocromocytoma
– Potassium/aldosterone/renin
– Cushing’s
• Is the mass malignant?
• Bilaterality of disease?
• Monitoring for hormone excess after surgery
34
Imaging
35
Imaging
36
Biochemical Workup
• Adrenal Incidentaloma
– Pheochromocytoma: 24 hour urine metanephrines
– Primary Hyperaldosteronism: If hypertensive (with or
without hypokalemia) do PAC/PRA ratio
– Cushing’s Syndrome: Screen for excess cortisol production
If not urgent, preferred work-up as outpatient
Plasma
METANEPHRINES (0.00 - 0.49 nmol/L) 19.10 38x ULN
NORMETANEPHRINES (0.00 - 0.89 nmol/L) >50 56x ULN
EPINEPHRINE CONCENTRATION (10 - 200 pg/mL) 7,180 36xULN
NOREPINEPHRINE(80 - 520 pg/mL) 39,520 76x ULN
DOPAMINE (0 - 20 pg/mL) 1,480 74x ULN
Urine
METANE/CREA RATIO 0 - 300 ug/g CRT 13,488 45x ULN
NORMETANEPHRINE UR 109 - 393 ug/d
NORMETAN/CRE RATIO 0 - 400 ug/g CRT 16,415 41xULN
37
38
Preoperative treatment in pheocromocytoma
39
Pheochromocytoma
Goals for inpatient treatment: Roizen criteria
40
Pheocromocytoma
• ~25-40% of otherwise sporadic PHEO-PGL now
attributed to a known genetic cause.
• Most patients don’t have clinical features to inform
genetic testing, therefore, inclusive (unbiased) gene panels
are reccomended ( for ex whole exome sequencing).
• If VHL, NF1, MEN2 diagnosed on basis of history or
clinical manifestations, direct testing of the suspected gene
is recommended.
Strong consideration for an individualized
surveillance plan- genetic counseling and testing
41
Cushing’s syndrome
• Low Dose DST is best test to assess adrenal autonomy
• 1mg Dexamethasone @ 2300, check cortisol @ 0800
AM Cortisol
Cutoff values
– Endocrine Society: >1.8ug/dL
• Sensitivity >95%
• Specificity 80%
Young, WF. The Incidentally Discovered Adrenal Mass. NEJM 356(6); 2007, 601-610.
42
Low dose Dex
• Consider cortisol-binding globulin
– Estrogen ↑s CBG → false + results if patient is on OCP
– Low albumin (ill patient, nephrotic syndrome) ↓s CBG →
Falsely low cortisol levels
• Consider altered clearance of dexamethasone
– Antiseizure medications, alcohol & rifampicin induce hepatic
clearance of dex
– Renal/liver failure decrease clearance of dex
– Check dexamethasone level at same time as cortisol level
• >5.6nmol/liter (0.22ug/dL) considered appropriate for
suppression
Nieman et al, Endocrine Society Guidelines on Cushing’s Syndrome. 2008.
43Fleseriu. Neurosurg Clinics. 2012, Oct;23(4):653-68
Medical Therapy
Fleseriu. Endo Clinics of North America, 2015
Preoperative medical treatment in severe CS
44
Drug Pros Additional comments Cons
KetoconazoleRapid action
Twice/thrice-daily dosing
May be preferred in women
Side effects: GI, male hypogonadism
New FDA warning LFTs (rare, serious)
Gastric acidity required for absorbtion
Many drug–drug interactions
MetyraponeRapid action
Four-times-daily dosing
Pregnancy? (not approved)
Side effects: GI, hirsutism, hypertension, hypokalemia
‘Escape’ ?
MitotaneBeneficial in adrenal
cancer
Avoid in women desiring pregnancy within 5 years
Side effects: GI, neurologic, teratogenic, adrenolytic
Delayed efficacy
Etomidate Intravenous Intensive ICU monitoring
Nieman L et al, JCEM, 2015, Biller BMK et al. JCEM 2008, Tritos & Biller, Discovery Medicine, 2012, Fleseriu& Petersenn, Pituitary. 2012
Adrenal steroidogenesis inhibitors
45Kamenicky et al. J Clin Endocrinol Metab. 2011 Sep;96(9):2796-804
•11 patients• Mitotane 3.0–5.0 g+ Metyrapone 3.0–4.5 g+ Ketoconazole 400–1200
mg daily dose
•Side effects: GI, rise in cholesterol , γGT
Medical therapy before adrenalectomy in CS
46
Time to recovery adrenal function after curative
surgery for CS
• Retrospective analysis
• 91 patients with CS, 54 with CD
• Mean follow up time 8 years
• Time to recovery– 0.6 years in ectopic Cushing's syndrome
– 1.4 years in Cushing's disease
– 2.5 years in adrenal Cushing's syndrome
• Patients with CD recover adrenal function after surgical “cure” quicker than adrenal CS
• Average recovery of adrenal function in CS in recent study was 11.5 months
Berr, J Clin Endocinol Metab, April 2015
47
Primary hyperaldosteronism and subclinical
Cushing’s syndrome
• Cortisol co-secretion may appear in PA
• First studies: prevalence of subclinical Cushing’s 12-21%
• More studies are needed to evaluate prevalence
• Concern for potential misinterpreting of the adrenal vein
sampling
• Cosecretion of cortisol can raise cortisol levels in the adrenal
vein draining the APA loss of lateralization (and a lost
opportunity to offer potentially curative surgery) or give the
impression that cannulation had failed on the contralateral side
• Risk of adrenal insufficiency after surgery if a diagnosis
of CS is not entertained preop
48
Conclusion
Multidisciplinary teams comprising many specialties are
instrumental in improving outcomes for patients with
pituitary and adrenal tumors.
Future work is needed to create multicenter
databases, especially in US to accumulate long- term data in
rare disorders.
49
Thank you!
References attached
50
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