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Diagnosis of Cushings Syndrome William Harper, MD, FRCPC Endocrinology & Metabolism Assistant Professor of Medicine McMaster University.

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Presentation on theme: "Diagnosis of Cushings Syndrome William Harper, MD, FRCPC Endocrinology & Metabolism Assistant Professor of Medicine McMaster University."— Presentation transcript:

1 Diagnosis of Cushings Syndrome William Harper, MD, FRCPC Endocrinology & Metabolism Assistant Professor of Medicine McMaster University

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

3 Cushings 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-Cushings Exogenous Corticosteroids Oral Inhaled/Topical – hi potency Surreptitious

4 Pseudo-Cushings 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 1)When to clinically suspect Cushings syndrome? Rare: overall prevalence 1/100,000 2)Establish hypercortisolism (Cushings syndrome) Screening Tests Confirmatory Tests 3)Biochemical Localization 4)Imaging Pituitary Incidentaloma 10% Adrenal Incidentaloma 1-9% 5)IPSS (if necessary) 6)Treatment

6 When to clinically suspect Cushings syndrome?

7 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 1)When to clinically suspect Cushings syndrome? Rare: overall prevalence 1/100,000 2)Establish hypercortisolism (Cushings syndrome) Screening Tests Confirmatory Tests 3)Biochemical Localization 4)Imaging Pituitary Incidentaloma 10% Adrenal Incidentaloma 1-9% 5)IPSS (if necessary) 6)Treatment

14 Establish hypercortisolism (Cushings syndrome) Screening tests 1 mg O/N DMST DXM 1 mg po 11PM 8AM plasma cortisol < 140 nM R/O Cushings Syndrome »SEN 98% SPEC 71-80% »< 50 nM SEN ~100% SPEC ? (Poor) 24 UFC < 248 nM/d R/O Cushings Syndrome (SEN %) nM/d Equivocal > 840 nM/d consistent with Cushings Syndrome (SPEC 98%)

15 Establish hypercortisolism (Cushings syndrome) Screening test problems! 1 mg O/N DMST False Positive: Pseudo-Cushings, 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 Cushings Syndrome (SEN 96% SPEC 100%) < 50 nM cutoff (SEN 100% SPEC 26%) Salivary < 3.6 nM rules out Cushings (SEN 92% SPEC 100%)

17 Management of Cushing's Syndrome 1)When to clinically suspect Cushings syndrome? Rare: overall prevalence 1/100,000 2)Establish hypercortisolism (Cushings syndrome) Screening Tests Confirmatory Tests 3)Biochemical Localization 4)Imaging Pituitary Incidentaloma 10% Adrenal Incidentaloma 1-9% 5)IPSS (if necessary) 6)Treatment

18 Establish hypercortisolism (Cushings syndrome) Confirmatory Tests 24 UFC > 840 nM/d Establishes Cushings Syndrome on 2 or more collections AND clear clinical findings of Cushings makes diagnosis of Cushings 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 Cushings Historical gold standard but SEN 56-69%, SPEC % Obsolete test!

19 Establish hypercortisolism (Cushings syndrome) CRH/DXM test Nieman et al, JAMA, 269: , adults with MILD hypercortisolism Diagnosis of Cushings confirmed at surgery Diagnosis of Pseudo-Cushings 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 Cushings SEN 100% SPEC 100% Effectively distinguishes Cushings from Pseudo- Cushings

20 Management of Cushing's Syndrome 1)When to clinically suspect Cushings syndrome? Rare: overall prevalence 1/100,000 2)Establish hypercortisolism (Cushings syndrome) Screening Tests Confirmatory Tests 3)Biochemical Localization 4)Imaging Pituitary Incidentaloma 10% Adrenal Incidentaloma 1-9% 5)IPSS (if necessary) 6)Treatment

21 Biochemical Localization Plasma ACTH: < 1.1 pMACTH Independent (adrenal source) pMEquivocal > 2.2 pMACTH Dependent > 110 pMSuggests 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 2 nd day Suppression of UFC < 10% basal and/or 17OHS < 36% basal indicates pituitary source (Cushings 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 Cushings with SEN 88-92% SPEC %

24 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 Cushings pituitary) combined with at least 1 test pointing to pituitary as source

25 Management of Cushing's Syndrome 1)When to clinically suspect Cushings syndrome? Rare: overall prevalence 1/100,000 2)Establish hypercortisolism (Cushings syndrome) Screening Tests Confirmatory Tests 3)Biochemical Localization 4)Imaging Pituitary Incidentaloma 10% Adrenal Incidentaloma 1-9% 5)IPSS (if necessary) 6)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 cant 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?)

27 Management of Cushing's Syndrome 1)When to clinically suspect Cushings syndrome? Rare: overall prevalence 1/100,000 2)Establish hypercortisolism (Cushings syndrome) Screening Tests Confirmatory Tests 3)Biochemical Localization 4)Imaging Pituitary Incidentaloma 10% Adrenal Incidentaloma 1-9% 5)IPSS (if necessary) 6)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) BasalPost CRH

30 IPSS: Indications ACTH dependent Cushings 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 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 pM No Stim Positive Stim Conclusive (> cm) Inconclusive >2 basal >3 CRH <1.5 basal <2 CRH Conclusive No CRH stim No DXM suppression Stim by CRH or DXM suppresses

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


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