Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s...
-
Upload
hilda-dalton -
Category
Documents
-
view
226 -
download
3
Transcript of Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s...
![Page 1: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/1.jpg)
Cushing’s Syndrome
![Page 2: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/2.jpg)
Nomenclature
• Cushing’s Syndrome– Hypercortisolism of any cause
• Cushing’s Disease– Corticotropin (ACTH) secreting pituitary
adenoma
![Page 3: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/3.jpg)
Cushing's Syndrome
1) When to clinically suspect Cushing’s syndrome?
Rare: overall prevalence 1/100,000
![Page 4: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/4.jpg)
When to clinically suspect Cushing’s syndrome?
Specific S&S:• Centripetal Obesity• Facial plethora• Proximal muscle atrophy/weakness• Wide (>1cm) depressed purple striae• Spontaneous ecchymoses• Hypokalemic alkalosis• Osteopenia
![Page 5: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/5.jpg)
Facial Plethora & Centripetal Obesity
![Page 6: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/6.jpg)
Centripetal Obesity
![Page 7: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/7.jpg)
Proximal Muscle Atrophy
![Page 8: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/8.jpg)
Wide (>1cm) Purple Striae
![Page 9: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/9.jpg)
Spontaneous Ecchymoses
![Page 10: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/10.jpg)
When to clinically suspect Cushing’s syndrome?
![Page 11: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/11.jpg)
Cushing’s Syndrome
1) ACTH Dependent 80%
Pituitary adenoma (65-75%)
Ectopc ACTH (10-15%) Carcinoid (usually bronchial)
Small cell lung cancer
Pheochromocytoma (rare)
Ectopic CRH (<1%)
2) ACTH Independent 20%
Adrenal Adenoma (10%)
Adrenal Carcinoma (10%)
Nodular adrenal hyperplasia Primary pigmented
Massive macronodular
Food dependent (GIP mediated)
3) Pseudo-Cushing’s
Exogenous Corticosteroids•Oral•Inhaled/Topical – hi potency•Surreptitious
![Page 12: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/12.jpg)
Pseudo-Cushing’s
• Drug/alcohol abuse and withdrawal.• Depression/mania• Panic disorder• Anorexia nervosa• Obesity• Malnutrition• Operations, trauma• Chronic exercise• Hypothalmic amenorrhea• Elevated CBG (estrogens, pregnancy, hyperthyroidism).• Glucocorticoid resistance (family history of adrenal insuff).• Complicated DM
![Page 13: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/13.jpg)
Cushing's Syndrome
1) When to clinically suspect Cushing’s syndrome?
Rare: overall prevalence 1/100,000
2) Establish hypercortisolism (Cushing’s syndrome)
Screening TestsConfirmatory Tests
![Page 14: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/14.jpg)
Establish hypercortisolism (Cushing’s syndrome)
• “Screening” tests
• 1 mg O/N DMST• DXM 1 mg po 11PM 8AM plasma cortisol
• < 140 nM R/O Cushing’s Syndrome» SEN 98% SPEC 71-80%
» < 50 nM SEN ~100% SPEC ? (Poor)
• 24 UFC (urinary free cortisol)• < 248 nM/d R/O Cushing’s Syndrome (SEN 95-100%)
• 248-840 nM/d Equivocal
• > 840 nM/d (>3x normal) consistent with Cushing’s Syndrome (SPEC 98%)
![Page 15: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/15.jpg)
Establish hypercortisolism (Cushing’s syndrome)
• Screening test problems!
• 1 mg O/N DMST• False Positive: Pseudo-Cushing’s, elevated CBG (pregnancy,
OCP, hyperthyroid), drugs which induce hepatic metabolism of DXM (dilantin, tegretol, phenobarbitol, rifampin)
• False Negative: Decreased metabolism or clearance of DXM (liver failure, CrCl < 15 mL/min)
• 24 UFC• False positive: Alcoholism (must abstain from alcohol for 1-2
mos prior to test)
![Page 16: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/16.jpg)
Evening Cortisol Measurement
•Measured at Midnight (physiological nadir)•Plasma
•Patient admitted, asleep during blood draw VS outpatient with hep lock• < 207 nM rules out Cushing’s Syndrome (SEN 96% SPEC 100%)• < 50 nM cutoff (SEN 100% SPEC 26%)
•Salivary• < 3.6 nM rules out Cushing’s (SEN 92% SPEC 100%)
![Page 17: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/17.jpg)
Cushing's Syndrome
1) When to clinically suspect Cushing’s syndrome?
Rare: overall prevalence 1/100,000
2) Establish hypercortisolism (Cushing’s syndrome)
Screening TestsConfirmatory Tests
![Page 18: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/18.jpg)
Establish hypercortisolism (Cushing’s syndrome)
• “Confirmatory Tests”• 24 UFC
• > 840 nM/d Establishes Cushing’s Syndrome on 2 or more collections AND clear clinical findings of Cushing’s makes diagnosis of Cushing’s with SPEC 98%
• Otherwise, need an additional confirmatory test.
• LDDST (Liddle Test)• 2 baseline 24h urine for cortisol and 17-OH steroids• DXM 0.5 mg q6h x 48h• During 2nd day on DXM repeat 24h urine collection• UFC > 100 nM/d or 17OHS > 11 uM/d indicates Cushing’s• Historical gold standard but SEN 56-69%, SPEC 74-100%• Obsolete test!
![Page 19: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/19.jpg)
Establish hypercortisolism (Cushing’s syndrome)
• CRH/DXM test• Diagnosis of Pseudo-Cushing’s• DXM 0.5 mg po q6h start @ noon for total of 8
doses• Last dose 6AM• 8AM: CRH 1ug/kg IV bolus• Plasma cortisol 15 minutes later: > 38 nM confirms
Cushing’s• SEN 100% SPEC 100%• Effectively distinguishes Cushing’s from Pseudo-
Cushing’s
![Page 20: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/20.jpg)
Management of Cushing's Syndrome
1) When to clinically suspect Cushing’s syndrome?
Rare: overall prevalence 1/100,000
2) Establish hypercortisolism (Cushing’s syndrome)
Screening TestsConfirmatory Tests
3) Biochemical Localization
![Page 21: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/21.jpg)
Biochemical Localization
• Plasma ACTH:< 1.1 pM ACTH Independent (adrenal source)
1.1-2.2 pM Equivocal
> 2.2 pM ACTH Dependent
> 110 pM Suggests ectopic ACTH source
• If Equivocal (1.1-2.2 pM) do CRH Stimulation test• No stimulation ACTH independent
• Stimulation ACTH dependent
![Page 22: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/22.jpg)
Biochemical Localization: ACTH Dependent
• CRH Stimulation Test• Pituitary adenoma but not adrenal or ectopic sources
should respond to CRH by increasing ACTH release
• CRH 1 ug/kg IV
• Plasma ACTH & cortisol: -5, -1, 0, 15, 30, 45 min
• Pituitary disease indicated if:– ↑ ACTH > 35% @ 15/30 min (mean) from baseline
or
– ↑ cortisol > 20% @ 30/45 min (mean) from baseline
• SEN 88-93% SPEC 100%
![Page 23: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/23.jpg)
Biochemical Localization: ACTH Dependent
• HDDST• Baseline 24h urine for UFC and 17OHS
• DXM 2mg q6h x 48h, repeat 24h urine on 2nd day
• Suppression of UFC < 10% basal and/or 17OHS < 36% basal indicates pituitary source (Cushing’s Disease)
• SEN 70% SPEC ~100%
• Not 100% SPEC as 10% of ectopic tumors (usually bronchial carcinoids) will suppress on HDDST
• 8 mg O/N DST• Baseline 8AM plasma cortisol, 11PM DXM 8 mg po
• Next day 8AM plasma cortisol suppress > 50% indicates pituitary Cushing’s with SEN 88-92% SPEC 57-100%
![Page 24: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/24.jpg)
Management of Cushing's Syndrome
1) When to clinically suspect Cushing’s syndrome?Rare: overall prevalence 1/100,000
2) Establish hypercortisolism (Cushing’s syndrome)Screening TestsConfirmatory Tests
3) Biochemical Localization4) Imaging
Pituitary Incidentaloma 10%Adrenal Incidentaloma 1-9%
![Page 25: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/25.jpg)
Imaging
• Choice of test dependent on biochemical work-up• Pituitary MRI
• Definitive lesion > 0.8-1.0 cm (otherwise incidentaloma)
• Note: many corticotroph adenomas much smaller than this, some you can’t even see on MRI.
• If biochemical w/up points towards ectopic source• CT Thorax 1st
• Then CT abdomen/pelvis
• Then Thyroid U/S to R/O MTC
• Octreotide Scan: Ectopic ACTH or CRH source (80% SEN?)
![Page 26: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/26.jpg)
Management of Cushing's Syndrome
1) When to clinically suspect Cushing’s syndrome?Rare: overall prevalence 1/100,000
2) Establish hypercortisolism (Cushing’s syndrome)Screening TestsConfirmatory Tests
3) Biochemical Localization4) Imaging
Pituitary Incidentaloma 10%Adrenal Incidentaloma 1-9%
5) IPSS (if necessary)
![Page 27: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/27.jpg)
IPSS• Bilateral catheterization of petrosal venous sinuses via
femoral veins
• Invasive but complication risk low in experienced hands:• CVA 0.2%, Cavernous sinus thrombosis
• Inguinal hematoma, transient tachyarrythmia
![Page 28: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/28.jpg)
IPSS• Measure Central:Peripheral ACTH ratios before & after CRH
stimulation• Pituitary: basal > 2 post CRH > 3• Ectopic: basal < 1.5 post CRH < 2• SEN 95% SPEC 100% (basal)• SEN 100% SPEC 100% (post CRH)
Basal Post CRH
![Page 29: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/29.jpg)
IPSS: Indications
• ACTH dependent Cushing’s with both HDDST and CRH Stim Test negative
• One or both of HDDST and CRH Stim Test positive but no definitive lesion on MRI and surgeon requires laterlization
![Page 30: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/30.jpg)
Clinical Suspicion
Screen Test: 24 UFC or 1mg O/N DST (+/- evening plasma/salivary cortisol)
Confirmatory Testing:Repeat 24 UFC +/- CRH/DXM Test (+/- evening plasma/salivary cortisol)
ACTH
ACTHIndependentCT abdo
Adrenal Surgery
ACTH dependent1st 8mg O/N DST or HDDST2nd CRH Test if above test negative
CRH Test
PituitaryMRI
Pituitary Surgery
IPSS
Ectopic ACTH•CT thorax, abdo•Thyroid U/S•Octreotide Scan
Continue search for ectopic source
Remove ectopic source
< 1.1pM >2.2pM
1.1-2.2pM
No StimPositiveStim
Conclusive(>0.8-1.0cm)
Inconclusive
>2 basal
>3 CRH <1.5 basal<2 CRH
Conclusive
No CRH stimNo DXM suppressionStim by CRH or
DXM suppresses
![Page 31: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/31.jpg)
Treatment of Cushing’s• 1˚ Rx is Surgery
• Pituitary– TSS, adenectomy (if possible), hemihypophysectomy (want
fertility), subtotal resection (85-90%) of anterior pituitary (fertility not an issue).
– Initial cure rate: microadenoma 70-80%
macroadenoma < 60%
– Permanent cure rate: microadenoma 60-70%
– Assessment of Cure Post-op:
» 8AM Plasma cortisol 28-56 nM (undetectable)
» 8AM ACTH < 1-2 pM (undetectable)
» 24h UFC < 28 nM/d
» Persistantly detectable plasma cortisol post-op, even if it is DXM suppressible probably means incomplete resection and almost certain recurrence
• Non-pituitary:Resection of adrenal or ectopic source
![Page 32: Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma.](https://reader035.fdocuments.net/reader035/viewer/2022070413/5697bfe41a28abf838cb5a13/html5/thumbnails/32.jpg)
Treatment of Cushing’s• TSS: Incomplete Resection
• Repeat surgery if no initial biochemical cure
• Hypercortisolism recalcitrant to surgery:• XRT: 2nd line (max benefit achieved @ 3-12 mos)• Medical (adrenal enzyme inhibitors)
– Ketoconazole– Metyrapone– Aminoglutethimide– Etomidate
• Adrenelectomy– Surgical versus Medical (Mitotane)– Nelson’s Syndrome