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

Published byHilda Dalton Modified over 8 years ago

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Presentation on theme: "Cushing’s Syndrome. Nomenclature Cushing’s Syndrome –Hypercortisolism of any cause Cushing’s Disease –Corticotropin (ACTH) secreting pituitary adenoma."— Presentation transcript:

1 Cushing’s Syndrome

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

3 Cushing's Syndrome 1)When to clinically suspect Cushing’s syndrome? Rare: overall prevalence 1/100,000

4 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

5 Facial Plethora & Centripetal Obesity

6 Centripetal Obesity

7 Proximal Muscle Atrophy

8 Wide (>1cm) Purple Striae

9 Spontaneous Ecchymoses

10 When to clinically suspect Cushing’s syndrome?

11 Cushing’s Syndrome 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

12 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

13 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

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 (urinary free cortisol) < 248 nM/d R/O Cushing’s Syndrome (SEN 95-100%) 248-840 nM/d Equivocal > 840 nM/d (>3x normal) 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 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

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 2 nd 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 Diagnosis of Pseudo-Cushing’s 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 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

21 Biochemical Localization Plasma ACTH: < 1.1 pMACTH Independent (adrenal source) 1.1-2.2 pMEquivocal > 2.2 pMACTH Dependent > 110 pMSuggests 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 2 nd 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 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%

25 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 1 st Then CT abdomen/pelvis Then Thyroid U/S to R/O MTC Octreotide Scan: Ectopic ACTH or CRH source (80% SEN?)

26 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)

27 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

28 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) BasalPost CRH

29 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

30 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 Independent CT abdo Adrenal Surgery ACTH dependent 1 st 8mg O/N DST or HDDST 2 nd CRH Test if above test negative CRH Test Pituitary MRI 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 Stim Positive Stim Conclusive (>0.8-1.0cm) Inconclusive >2 basal >3 CRH <1.5 basal <2 CRH Conclusive No CRH stim No DXM suppression Stim by CRH or DXM suppresses

31 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

32 Treatment of Cushing’s TSS: Incomplete Resection Repeat surgery if no initial biochemical cure Hypercortisolism recalcitrant to surgery: XRT: 2 nd 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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