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

Nomenclature Cushing’s Syndrome Cushing’s Disease 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 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

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 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

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 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

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 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

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 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

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

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 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

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

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 1.1-2.2pM 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 (>0.8-1.0cm) Inconclusive IPSS >2 basal >3 CRH <1.5 basal <2 CRH Conclusive Pituitary Surgery Continue search for ectopic source Remove 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