Disorders of Cortisol Secretion Adrenal Insufficiency Cushing’s Syndrome William Harper, MD, FRCPC Endocrinology & Metabolism Assistant Professor of Medicine, McMaster University

Diurnal Rhythm 800 AM: nM 400 PM: nM Midnight: < 140 nM Wide ranges of normal: patients with hypocortisolism or hypercortisolism can easily fall within these ranges

Diagnosis of AI 8AM Plasma Cortisol (Pcortisol at 8AM or during “Stress”): < 83 nM  AI confirmed < 138 nM  suggests AI present (SEN 36%, SPEC~100%) > 552 nM  excludes AI (>552 anytime of day, SEN~100%) [with possible exception of critically-ill patients]

Diagnosis of AI Short Cortrosyn/ACTH test Must be performed within a few days of starting exogenous glucocorticoid Rx or else H-P-A axis will be suppressed by steroid Rx Exogenous glucocorticoid must be dexamethasone (isn’t picked up by the cortisol RIA)

Short Cortrosyn Test High (Standard) Dose: 250 ug IV or IM, measure cortisol t = 0, 30, 60 min Normal: any cortisol > 550 nM (even pre-injection t = 0) Rules out 1˚ AI (SEN 100%) but only 90% SEN for 2˚ AI Low Dose: 1 ug IV (can’t be IM), measure cortisol t = 0, 30 min t = 30 min cortisol > 500 nM rules out 1˚ or 2˚ AI (exception is 2˚ AI of recent onset < 2wk) SEN 95% SPEC 96% ( > 600 nM SEN 100%, SPEC 83%) 1 ug dose stimulates maximal adrenal cortex secretion 30 min after injection and in normal subjects results in a peak plasma ACTH concentration 2X that seen in an ITT

Short Cortrosyn Test (cont’d) Criteria requiring a minimum cortisol increment (i.e. 2x baseline or absolute rise of 250 nM) now considered invalid High basal cortisol due to stress or normal diurnal variation may represent near maximal stimulation with an inability to increase secretion further in upwards of 20% of normal patients Possible exception of critically-ill patients

AI in Critical-Illness Annane et al, JAMA Septic Shock patients Bad prognosticators: Baseline cortisol > 938 nM 250 ug ACTH test: rise in cortisol < 248 nM RCT: ACTH 250 ug, Pcortisol 0, 30, 60 minutes. Nonresponders defined as rise in Pcortisol < 248 nM Hydrocortisone 50 mg IV q6h and fludrocortisone 50 ug via ng od for 7 days. 28d Mort ARR 10% 28d Inotrope dependency ARR 17%

Distinguish 1˚ from Central AI Plasma ACTH Measure with basal cortisol during short ACTH test Primary AI: ACTH > 11 pM Central AI: ACTH < 2.2 pM Must measure BEFORE exogenous glucocorticoid administration as will be suppressed almost immediately 2 phases of steroid feedback suppression on ACTH: Fast Phase (sec-min): membrane stabilizing effect Delayed phase (hrs-days): mediated by glucocorticoid receptor

Distinguish 1˚ from Central AI Long Cortrosyn Test Rarely needed Done if plasma ACTH equivocal ( pM) or result not available (i.e. not sent before the initiation of exogenous glucocorticoids) 250 ug IV infusion over 8h x 3d Plasma cortisols during infusion (0, 4, and 8h) 24h UFC day prior to and on 3 days with infusion 1˚AI: no response Central AI: some response

True tests of H-P-A Axis Cannot be done in acutely ill patients Insulin Tolerance Test (ITT) Insulin induced hypoglycemia stimulates ACTH and cortisol secretion Metyrapone Test Metyrapone = 11  -OHlase inhibitor

Metyrapone 30 mg/kg po midnight 8AM: plasma cortisol < 140 nM (insure adequate 11  inhibition) Normal: Plasma 11-deoxycortisol > 190 nM, ACTH > 22 pM

Determining the Cause of AI Central AI  MRI, coronals through sella 1° AI: Abdominal CT, non-contrast adrenal protocol Large +/- Calcified adrenals: infection (TB, Histo), hemorrhage (anticoagulants), metastases CXR, TB skin test, urine AFB culture Histoplasma serology HIV testing Autoimmune? Exclusion of other causes Anti-adrenal antibodies (anti-21OHlase) Presence of other autoimmune conditions (PGAS)

Polyglandular Autoimmune Syndrome (PGAS) PGAS I AI, Mucocutaneouos candidiasis, hypoparathyroidism PGAS II AI, Thyroid autoimmune disease, T1DM PGAS III (no AI) Thyroid autoimmune disease and T1DM or Thyroid autoimmune disease and one or more of Vitiligo, Alopecia, Hepatic Autoimmune Diseases, Celiac Disease, etc. Therefore, 1° AI should do Calcium profile, TSH, BS, LH, FSH, testosterone (man), estradiol (female)

Treatment of AI Glucocorticoid Replacement Prednisone 5/2.5 mg/d Hydrocortisone 20/10 mg/d Cortisone acetate 25/12.5 mg/d Mineralcorticoid Replacement Won’t need if Central AI or if on Cortisone acetate Florinef mg/d Medic-Alert Bracelet! Sick days: increase dose 2-3X

When to suspect Adrenal Crisis? Acute precipitant: sepsis, surgery, MI, etc. Exogenous corticosteroid use: Current use (suppresses axis within a few days of starting) Replacement dose or greater for over a year »Prednisone 7.5 mg/d or Hydrocortisone 20 mg/d Prednisone > 20 mg/d for > 1mos in past year

Hypercortisolism 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 Tests Confirmatory Tests 3)Biochemical Localization 4)Imaging Pituitary Incidentaloma 10% Adrenal Incidentaloma 1-9% 5)IPSS (if necessary) 6)Treatment

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 Tests Confirmatory Tests 3)Biochemical Localization 4)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 %) 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 Tests Confirmatory Tests 3)Biochemical Localization 4)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 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 % Obsolete test!

Establish hypercortisolism (Cushing’s syndrome) CRH/DXM test Nieman et al, JAMA, 269: , 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 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 Tests Confirmatory Tests 3)Biochemical Localization 4)Imaging Pituitary Incidentaloma 10% Adrenal Incidentaloma 1-9% 5)IPSS (if necessary) 6)Treatment

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

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 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: 2 nd line (max benefit 3-12 mos) Medical (adrenal enzyme inhibitors) –Ketoconazole –Metyrapone –Aminoglutethimide –Etomidate Adrenelectomy –Surgical versus Medical (Mitotane) –Nelson’s Syndrome