Cushing syndrome
• Cushing’s Syndrome
– Hypercortisolism of any cause
• Cushing’s Disease
– Corticotropin (ACTH) secreting pituitary
adenoma
Cushing’s Syndrome Ddx
1) ACTH Dependent 80%
Pituitary adenoma (65-75%)
Ectopc ACTH (10-15%) Exogenous Corticosteroids
Carcinoid (usually bronchial) •Oral
Small cell lung cancer •Inhaled/Topical – hi potency
Pheochromocytoma (rare) •Surreptitious
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
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
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 Tests
Confirmatory Tests
3) Biochemical Localization
4) Imaging
Pituitary Incidentaloma 10%
Adrenal Incidentaloma 1-9%
5) IPSS (if necessary)
6) Treatment
When to clinically suspect Cushing’s syndrome?
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
Facial Plethora & Centripetal Obesity
Centripetal Obesity
Proximal Muscle Atrophy
Wide (>1cm) Purple Striae
Spontaneous Ecchymoses
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 Tests
Confirmatory Tests
3) Biochemical Localization
4) Imaging
Pituitary Incidentaloma 10%
Adrenal Incidentaloma 1-9%
5) IPSS (if necessary)
6) Treatment
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
• < 248 nM/d R/O Cushing’s Syndrome (SEN 95-100%)
• 248-840 nM/d Equivocal
• > 840 nM/d consistent with Cushing’s Syndrome (SPEC 98%)
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)
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%)
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 Tests
Confirmatory Tests
3) Biochemical Localization
4) Imaging
Pituitary Incidentaloma 10%
Adrenal Incidentaloma 1-9%
5) IPSS (if necessary)
6) Treatment
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!
Establish hypercortisolism (Cushing’s syndrome)
• CRH/DXM test
• Nieman et al, JAMA, 269:2232-2238, 1993.
• 58 adults with MILD hypercortisolism
• Diagnosis of Cushing’s confirmed at surgery
• Diagnosis of Pseudo-Cushing’s based on extended
f/up (28 mos) without progression
• 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
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 Tests
Confirmatory Tests
3) Biochemical Localization
4) Imaging
Pituitary Incidentaloma 10%
Adrenal Incidentaloma 1-9%
5) IPSS (if necessary)
6) Treatment
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
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%
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%
Biochemical Localization: ACTH Dependent
CRH Test CRH Test
Stimulates No Stimulation
HDDST or Only 1/153 *Probably
8 mg O/N DST ectopic Pituitary
Suppresses (Do MRI) (Do MRI)
HDDST or *Probably 1/3 Pituitary
8 mg O/N DST pituitary 2/3 Ectopic
No suppression (Do MRI) (Do IPSS)
*Probably Pituitary: High pre-test probability (80-90% ACTH dependent
Cushing’s pituitary) combined with at least 1 test pointing to pituitary as source
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 Tests
Confirmatory Tests
3) Biochemical Localization
4) Imaging
Pituitary Incidentaloma 10%
Adrenal Incidentaloma 1-9%
5) IPSS (if necessary)
6) Treatment
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?)
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 Tests
Confirmatory Tests
3) Biochemical Localization
4) Imaging
Pituitary Incidentaloma 10%
Adrenal Incidentaloma 1-9%
5) IPSS (if necessary)
6) Treatment
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
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
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
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
< 1.1pM >2.2pM
ACTH 1.1-2.2pM
Independent ACTH dependent
CT abdo No Stim CRH Test 1st 8mg O/N DST or HDDST
Positive 2nd CRH Test if above test negative
Stim No CRH stim
Stim by CRH or No DXM suppression
Adrenal Surgery DXM suppresses
Pituitary Ectopic ACTH
MRI •CT thorax, abdo
Conclusive Inconclusive •Thyroid U/S
(>0.8-1.0cm) s al IPSS •Octreotide Scan
>2 b a H
R
>3 C <1.5 basal Conclusive
<2 CRH
Pituitary Surgery
Continue search for Remove
ectopic source ectopic source
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
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
