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Diagnosis of Cushing’s Syndrome

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.

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Diagnosis of Cushing’s Syndrome

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

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

  3. Cushing’s Syndrome Ddx • Exogenous Corticosteroids • Oral • Inhaled/Topical – hi potency • Surreptitious 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

  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 95-100%) • 248-840 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 74-100% • Obsolete test!

  19. 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

  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) 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

  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 > 35% @ 15/30 min (mean) from baseline or • ↑ cortisol > 20% @ 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 57-100%

  24. Biochemical Localization: ACTH Dependent *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 > 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?)

  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 StimTest positive but no definitive lesion on MRI and surgeon requires laterlization

  31. 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 1.1-2.2pM ACTH Independent CT abdo 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 • Ectopic ACTH • CT thorax, abdo • Thyroid U/S • Octreotide Scan Pituitary MRI 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

  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 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

  33. 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

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