Diagnosis of Cushing’s Syndrome

William Harper, MD, FRCPC

Endocrinology & Metabolism

Assistant Professor of Medicine

McMaster University

Nomenclature

• 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%) 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

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 TestsConfirmatory Tests

3) Biochemical Localization4) 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 TestsConfirmatory Tests

3) Biochemical Localization4) 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 TestsConfirmatory Tests

3) Biochemical Localization4) 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 TestsConfirmatory Tests

3) Biochemical Localization4) 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

Stimulates

CRH Test

No Stimulation

HDDST or

8 mg O/N DST

Suppresses

Only 1/153 ectopic

(Do MRI)

*Probably Pituitary

(Do MRI)

HDDST or

8 mg O/N DST

No suppression

*Probably pituitary

(Do MRI)

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

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)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 TestsConfirmatory Tests

3) Biochemical Localization4) 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

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

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