1. Diagnosis of Cushing’s Syndrome
William Harper, MD, FRCPC
Endocrinology & Metabolism
Assistant Professor of Medicine
McMaster University

2. Nomenclature Cushing’s Syndrome Cushing’s Disease
Hypercortisolism of any cause
Cushing’s Disease
Corticotropin (ACTH) secreting pituitary adenoma

3. Cushing’s Syndrome Ddx
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

4. 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

5. Management of Cushing's Syndrome
When to clinically suspect Cushing’s syndrome?
Rare: overall prevalence 1/100,000
Establish hypercortisolism (Cushing’s syndrome)
Screening Tests
Confirmatory Tests
Biochemical Localization
Imaging
Pituitary Incidentaloma 10%
Adrenal Incidentaloma 1-9%
IPSS (if necessary)
Treatment

6. When to clinically suspect Cushing’s syndrome?

7. 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

8. Facial Plethora & Centripetal Obesity

9. Centripetal Obesity

10. Proximal Muscle Atrophy

11. Wide (>1cm) Purple Striae

12. Spontaneous Ecchymoses

13. Management of Cushing's Syndrome
When to clinically suspect Cushing’s syndrome?
Rare: overall prevalence 1/100,000
Establish hypercortisolism (Cushing’s syndrome)
Screening Tests
Confirmatory Tests
Biochemical Localization
Imaging
Pituitary Incidentaloma 10%
Adrenal Incidentaloma 1-9%
IPSS (if necessary)
Treatment

14. 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 %)
nM/d Equivocal
> 840 nM/d consistent with Cushing’s Syndrome (SPEC 98%)

15. 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)

16. 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%)

17. Management of Cushing's Syndrome
When to clinically suspect Cushing’s syndrome?
Rare: overall prevalence 1/100,000
Establish hypercortisolism (Cushing’s syndrome)
Screening Tests
Confirmatory Tests
Biochemical Localization
Imaging
Pituitary Incidentaloma 10%
Adrenal Incidentaloma 1-9%
IPSS (if necessary)
Treatment

18. 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 %
Obsolete test!

19. Establish hypercortisolism (Cushing’s syndrome)
CRH/DXM test
Nieman et al, JAMA, 269: , 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 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

20. Management of Cushing's Syndrome
When to clinically suspect Cushing’s syndrome?
Rare: overall prevalence 1/100,000
Establish hypercortisolism (Cushing’s syndrome)
Screening Tests
Confirmatory Tests
Biochemical Localization
Imaging
Pituitary Incidentaloma 10%
Adrenal Incidentaloma 1-9%
IPSS (if necessary)
Treatment

21. Biochemical Localization
Plasma ACTH:
< 1.1 pM ACTH Independent (adrenal source)
pM Equivocal
> 2.2 pM ACTH Dependent
> 110 pM Suggests ectopic ACTH source
If Equivocal ( pM) do CRH Stimulation test
No stimulation  ACTH independent
Stimulation  ACTH dependent

22. 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 > 15/30 min (mean) from baseline or
↑ cortisol > 30/45 min (mean) from baseline
SEN 88-93% SPEC 100%

23. 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 %

24. Biochemical Localization: ACTH Dependent
CRH Test
Stimulates
No Stimulation
HDDST or
8 mg O/N DST
Suppresses
Only 1/153 ectopic
(Do MRI)
*Probably Pituitary
No suppression
*Probably pituitary
1/3 Pituitary
2/3 Ectopic
(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

25. Management of Cushing's Syndrome
When to clinically suspect Cushing’s syndrome?
Rare: overall prevalence 1/100,000
Establish hypercortisolism (Cushing’s syndrome)
Screening Tests
Confirmatory Tests
Biochemical Localization
Imaging
Pituitary Incidentaloma 10%
Adrenal Incidentaloma 1-9%
IPSS (if necessary)
Treatment

26. Imaging Choice of test dependent on biochemical work-up Pituitary MRI
Definitive lesion > 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?)

27. Management of Cushing's Syndrome
When to clinically suspect Cushing’s syndrome?
Rare: overall prevalence 1/100,000
Establish hypercortisolism (Cushing’s syndrome)
Screening Tests
Confirmatory Tests
Biochemical Localization
Imaging
Pituitary Incidentaloma 10%
Adrenal Incidentaloma 1-9%
IPSS (if necessary)
Treatment

28. 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

29. 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

30. 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

31. Confirmatory Testing:
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
Independent
CT abdo pM
ACTH dependent
1st 8mg O/N DST or HDDST
2nd CRH Test if above test negative
CRH Test
No Stim
Positive
Stim
No CRH stim
No DXM suppression
Stim by CRH or
DXM suppresses
Adrenal Surgery
Pituitary
MRI
Ectopic ACTH
CT thorax, abdo
Thyroid U/S
Octreotide Scan
Conclusive
(> cm)
Inconclusive
IPSS
>2 basal
>3 CRH
<1.5 basal
<2 CRH
Conclusive
Pituitary Surgery
Continue search for ectopic source
Remove ectopic source

32. 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 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

33. Treatment of Cushing’s
TSS: Incomplete Resection
Repeat surgery if no initial biochemical cure
Hypercortisolism recalcitrant to surgery:
XRT: 2nd line (max benefit 3-12 mos)
Medical (adrenal enzyme inhibitors)
Ketoconazole
Metyrapone
Aminoglutethimide
Etomidate
Adrenelectomy
Surgical versus Medical (Mitotane)
Nelson’s Syndrome