Cushing’s Syndrome A Clinical Approach Stavroula Christopoulos, MD, FRCPC

Cushing’s Syndrome Outline Definitions Clinical features Differential diagnosis Diagnostic approach Treatment Applied knowledge: a case presentation

Cushing’s Syndrome 1932: Harvey Cushing described a series of seven pts with basophilic adenomas of the pituitary --- CD

Cushing’s Syndrome Definitions Cushing’s disease Pseudo-Cushing’s syndrome

Cushing’s Syndrome Clinical features

Cushing’s Syndrome Clinical features

Cushing’s Syndrome Clinical features

Cushing’s Syndrome Clinical features 63y.o M admitted on 7W with L/E muscle weakness and a T6 sensory level Diagnosis?

Cushing’s Syndrome Clinical features General Central obesity Proximal muscle weakness HTN Headaches Dermatologic Wide purple striae Spontaneous ecchymoses Facial plethora Hyperpigmentation Acne, hirsutism Fungal skin infections Endocrine/Metabolic Hypokalemic alkalosis Hypokalemia Osteopenia Hypogonadism Glucose intolerance Hyperlipidemia Hyperhomocysteinemia Kidney stones Polyuria Hypercoagulability Neuropsychiatric Insomnia Depression, frank psychosis Impaired cognition and short-term memory Depr us/ agitated

Post-operative Eucortisolism Reversibility of Anatomic, Neuropsychological, and Metabolic Brain Disturbances Following Treatment of Endogenous Cushing’s Syndrome: A 3-Year Prospective Study 23 patients with endogenous CS Post-operative Eucortisolism Curative Surgery Baseline 6 months 12 months 24 months 36 months MRI MRI MRI MRI MRI Psych Psych Psych Psych 1H-MRS 1H-MRS 1H-MRS

Results Pre-operative MRI MRI 36 mo post eucortisolism

Results Anatomic Evaluation: Subjective Grading of Cerebral Atrophy * Grade 3 Grade 2 Grade 1 Controls Baseline 6 mo 12 mo 24 mo 36 mo *p value versus preceding value <0.05 *p value versus controls <0.05

Discussion Excess GC enter the brain and act on MR and GR Dendritic atrophy Decreased cell excitability Cell membrane dysfunction Pathophysiologic Mechanisms The pathophysiology of the reversibility is largely unknown and may be related to the reversibility of 1 or many of the above pathophysiologic mechanisms. Neuronal cell death Measurable Clinical Parameters Brain volume loss on MRI Neuropsychological and Cognitive Dysfunction Neurometabolic Abnormalities on 1H MRS

Cushing’s Syndrome Clinical features Most reliable differentiating signs from obesity are those of protein wasting: Thin skin Easy bruising Proximal weakness

Cushing’s Syndrome Etiology

Cushing’s Syndrome Etiology ACTH-dependent (Pseudo-CS) Pituitary (CD) (70%) Microadenomas (95%) Macroadenomas (5%) Ectopic ACTH or CRH (10%) Small cell lung ca Carcinoids: lung, pancreas, thymus ACTH-independent (Factitious) Unilateral Adrenal adenoma (10%) Adrenal carcinoma (5%) Bilateral Macronodular Hyperplasia (AIMAH) (<2%) Primary pigmented Micronodular Adrenal disease (PPNAD) (<2%) McCune Albright Syndrome (<2%)

Cushing’s Syndrome AIMAH Adrenal cortisol hypersecretion with radiological evidence of massive adrenal macronodules “ACTH-independent macronodular adrenal hyperplasia” “Massive macronodular adrecortical disease” “Autonomous macronodular adrenal hyperplasia” “Macronodular adrenal hyperplasia”

Cushing’s Syndrome AIMAH Presents 5th-6th decade Radiological features Bilateral adrenal masses measuring up to 5 cm of soft tissue density Pathological features Combined adrenal weight >60 g200g Cut section: nodules yellow (high lipid content) Inter-nodular hyperplasia

Cushing’s Syndrome AIMAH Lacroix et al. NEJM 1992 First description of a patient with post-prandial hypercortisolism Cortisol levels were correlated post-prandially with GIP levels The presence of ectopic GIP receptors on the adrenal gland was further supported by adrenal imaging following the injection of [123I] GIP Shown to be ectopically expressed at the cell membrane in a non-mutated form Transfection of bovine adrenal cells with the GIP receptor leads to hyperplastic adrenals and hypercortisolism

Cushing’s Syndrome AIMAH Lacroix et al. NEJM 1999 Patient with AIMAH who had transient CS during pregnancy and persistent CS following menopause Cortisol secretion was stimulated by the exogenous administration of GnRH, h CG, or LH. Treated succesfully with GnRH agonist

Cushing’s Syndrome AIMAH

Cushing’s Syndrome AIMAH 3 days 1st= posture , mixed meal 2: gnrh, trh 3: glucagon, vasopressin, serotonin agonist (metoclopramide) Acth, cortisol at 30-60 min intervals x2-3 hours >50% Source: Christopoulos, Bourdeau, and Lacroix, Horm Research 2005

Cushing’s Syndrome AIMAH Source: Christopoulos, Bourdeau, and Lacroix, Horm Research 2005

Cushing’s Syndrome PPNAD Adrenal CS caused by small nodules that may not be visualized on imaging Adrenal glands contain multiple small cortical black pigmented micronodules (<4 mm) Positive stain synaptophysin

Cushing’s Syndrome PPNAD Sporadic or part of Carney’s complex: pigmented lentigines and blue nevi on the face, neck, trunk and multiple endocrine and non-endocrine tumors (atrial myxomas) Second decade PARADOXICAL increase of cortisol secretion during Liddle test (0.5mg q6 –2mg q6)– 100% increase in UFC at day 6 highly specific – study shown high expression of GR in PPNAD nodules

Cushing’s Syndrome PPNAD

Cushing’s Syndrome Diagnostic approach 1. Establishing the diagnosis of CS 2. Establishing the cause of CS a. ACTH-dependent vs independent b. Identifying the source in ACTH-dependent 3. Imaging

Cushing’s Syndrome Diagnostic approach Key physiological principles Cortisol hypersecretion in most patients with CS is cyclical

Cushing’s Syndrome Diagnostic approach Key physiological principles Loss of circadian rhythm in pts with CS

Cushing’s Syndrome Diagnostic approach Key physiological principles (cont.) Pituitary tumors are partially autonomous—they retain feedback inhibition, but at a higher setpoint than the normal pituitary gland Adrenal and ectopic tumors have autonomous hormone secretion and do NOT (usually) exhibit feedback inhibition

Cushing’s Syndrome Diagnostic approach 1. Establishing the diagnosis of CS 2. Establishing the cause of CS a. ACTH-dependent vs independent b. Identifying the source in ACTH-dependent 3. Imaging

Cushing’s Syndrome Diagnostic approach 1. Establishing the diagnosis of CS 24-hour urinary free cortisol Low-dose dexamethasone suppression tests Midnight plasma cortisol or late-night salivary cortisol

Cushing’s Syndrome Establishing the dx 24-hr urinary free cortisol Direct assessment of circulating free (biologically active) cortisol Up to 3 collections if high suspicion UFC>4X normal -- diagnostic FN rate <6% Assess whether collection is complete with urinary volume and creatinine If GFR<30cc/min, UFC may be falsely low FP rate <4% Recently shown with fluid intake >5L/day Excess circ cortisol saturates the binding proteins and is excreted in the urine as free cortisol

Cushing’s Syndrome Establishing the dx Low-dose DST (Overnight vs 48-hr DST) Am cortisol <50nmol/L (traditionally <138nmol/L) Excellent sensitivity but borderline specificity—false positives Pseudo-Cushing’s Pt’s error in taking medication Decreased dex absorption Drugs accelerating dexa metabolism (eg: dilantin, tegretol, rifampin…) Elevated CBG (pregnancy, OCP) Assay error (interaction with reaction—atarax, librium…) 3-8% of pts with CD will retain sensitivity to low-dose dex 48-hr: slightly more specific

Cushing’s Syndrome Establishing the dx Midnight plasma cortisol Most studies with inpatients, sleeping, and installed venous catheter—VERY impractical and expensive Level <50nmol virtually R/O the dx Level >207 nmol/L virtually rules in the dx Late-night salivary free cortisol Increasing interest in recent years Pts collect saliva by chewing on cotton However, a modified cortisol assay is required so not validated by all labs Excellent sensitivity and specificity—but exact cutoffs not established

Cushing’s Syndrome Establishing the dx Differentiating between pseudo-Cushing’s and CS Very difficult with coexistant depression, alcoholism, obesity Recently discovered and validated test at the NIH: Combined low dose DST-CRH test Cortisol >38nmol/L had 100% sensitivity, specificity, and diagnostic accuracy Recent literature not reproduced these results—midnight cortisol>256

Cushing’s Syndrome Establishing the dx Source: Newell-Price et al. Lancet 2006

Cushing’s Syndrome Diagnostic approach 1. Establishing the diagnosis of CS 2. Establishing the cause of CS a. ACTH-dependent vs independent b. Identifying the source in ACTH-dependent 3. Imaging

Cushing’s Syndrome Establishing the cause of CS Clinical features may provide a clue First step is to measure plasma ACTH to differentiate ACTH-dependent from ACTH-independent CS If ACTH <1 pmol/L---adrenal CS If ACTH >3.3 pmol/L—ACTH-dependent If ACTH 1-3CRH stim

Cushing’s Syndrome Establishing the cause of CS ACTH-dependent CS Distinguishing between pituitary vs non-pituitary sources is a great challenge!! Carcinoids can be clinically undistinguishable from CD and are difficult to identify by imaging 40% of CD will have non-detectable AN on MRI So, biochemical assessment rather than imaging used to differentiate between pituitary and non-pituitary causes

Cushing’s Syndrome Establishing the cause of CS Two biochemical tests in ACTH-dependent CS High dose DST CRH stimulation test

Cushing’s Syndrome Establishing the cause of CS High-dose DST Principle that pituitary tumors are only partially autonomous, retaining feedback inhibition at a higher set point (80% of CD are suppressible) In contrast, adrenal and ectopic tumors are usually autonomous, and cortisol production will normally not be suppressed by dexa Two-day test (2mg q6hrs) with baseline and final cortisol value—suppression >50 % suggestive of CD

Cushing’s Syndrome Establishing the cause of CS CRH stimulation test Principle that pituitary tumors are responsive to an exogenous dose of CRH whereas ectopic and adrenal tumors are not Ovine CRH administered as an IV bolus and ACTH and cortisol drawn at baseline at 30, 60, 90, and 120 min. MC side effect facial flushing (20%) CD: >50% rise in ACTH, >20% rise in cortisol---91% sensitivity and 95% specificity In ectopic CS, levels are usually not altered. However, some reports of ACTH rise but not cortisol

Cushing’s Syndrome Diagnostic approach 1. Establishing the diagnosis of CS 2. Establishing the cause of CS a. ACTH-dependent vs independent b. Identifying the source in ACTH-dependent 3. Imaging

Cushing’s Syndrome Imaging Adrenal CT In cases of ACTH-independent CS 8% of N have incidentalomas and 20% of CD have at least 1 nodule CXR and CT chest In cases suggesting ectopic source If negative, CT abdo, +/-pelvic, +/-neck SS receptor scintigraphy Head MRI In cases suggesting pituitary source >40% of CD have normal MRI (ave size 5mm) 3-27% have pituitary incidentalomas

Cushing’s Syndrome Imaging

Cushing’s Syndrome Establishing the cause of CS So, pituitary or ectopic??? Bilateral inferior petrosal sinus sampling is the most reliable test to differentiate the source of ACTH and should be done in MOST PTS Can be avoided: If a pt has ACTH dep CS with Concordant DST and CRH stimulation test suggestive of CD AND an MRI lesion >6mm At Mass General: only in macroadenomas

Cushing’s Syndrome Inferior Petrosal Sinus Sampling (IPPS) The most direct way of knowing if the pituitary is making excess ACTH is to measure it The inferior petrosal sinuses receive the drainage of the pituitary gland without admixture of blood from other sources Each half of the pituitary drains in the ipsilateral petrosal sinus

Radiologists Catheters are advanced bil from the fem veins to the inf petrosal sinuses Confirm catheter location under fluoro Samples drawn simultaneously from r, l, and peripherally Baseline and 0.2,5,10,20,30 min post crh

Cushing’s Syndrome IPPS INTERPRETATION Localization If pituitary/periphery ratio >2 (>3 with CRH), the pt has CD If pituitary/periphery ratio <1.5 (<2 with CRH), the pt has ectopic CS --- 94% sensitivity and specificity with CRH Lateralization If the higher side/lower side >1.4/1, the tumor is on the side with higher ACTH levels --- accuracy only 70%

Cushing’s Syndrome IPPS Failure to localize Inability to catheterize Incorrect catheter placement Anomalous venous drainage Periodic hormonogenesis Ectopic tumor secreting CRH Failure to lateralize Incorrect catheter placement Sample withdrawal too rapid Midline microadenoma Prior transphenoidal surgery Ectopic tumor secreting CRH

Cushing’s Syndrome IPPS Complications Very infrequent Most common: Hematoma at the groin Transient ear pain Several cases of DVT reported Neurological complications and SAH reported but extremely rare

Cushing’s Syndrome Surgical Treatment Transphenoidal adenomectomy Needs to be done by neurosurgeons who perform pituitary surgery frequently Remission rate of 80-90%--Most common surgical failures with macroadenomas Cure is confirmed by demonstrating profound hypoadrenalism post-op (am cortisol <50 nmol/L) Morbidity extremely low with hypopituitarism and permanent DI very rare with experienced surgeons Period of adrenal insufficiency requiring GC for up to 2 yrs (6-8 mo)

Cushing’s Syndrome Surgical Treatment Adrenal Surgery Laparoscopic surgery is the treatment of choice for unilateral adrenal adenomas Laparotomy should be done for ACC but poor px Bilateral adrenalectomy is also 2nd line treatment for pts with CD who have not been cured by pituitary surgery +/-radiotx—Pitfalls Permanent need for GC and MC 10-20% risk of Nelson’s syndrome 10% risk of recurrent CS due to remant or ectopic Nelson; locally aggressive pit tumor that secretes high concentration of acth--hyperpigmentation

Cushing’s Syndrome Pituitary Irradiation Conventional irradiation induces remission in only 20-83% of adults Onset of remission: 6mo-5 years Disadvantages: Delayed effectiveness Significant risk of hypopituitarism Risk of neurologic and cognitive damage The role of newer stereotactic radiosurgery remains to be determined

Cushing’s Syndrome Treatment Overview of treatment of CD

Cushing’s Syndrome Medical Therapy Uses of medical therapy Selected cases of CD prior to surgery In cases of CD awaiting the effect of radiotherapy Ectopic CS due to an unresectable tumor Adrenal carcinoma escape

Cushing’s Syndrome Medical Therapy Cortisol synthesis inhibitors Ketoconazole Inhibits 11ß hydroxylase Hepatotoxicity Metyrapone Rapid fall in cortisol, trough at 2 hours Aminoglutethimide Inhibits side-chain cleavage of chol--pregnenolone Mitotane—delayed onset but long-lasting action adrenolytic Inhibits side-chain cleavage and 11ß hydroxylase Etomidate escape

Cushing’s Syndrome Medical Therapy Drugs acting at the hypothalamic-pituitary level PPARγ agonists Dopamine agonists SS analogs Retinoic acid

Case presentation 41 y.o woman referred by her family doctor with fatigue and weight gain PMH significant for DM (1year), hypercholesterolemia, and HTN resistant to 2 medications She was followed for “subclinical hyperthyroidism” Meds: Pravachol, Glucophage, Potassium, Ramipril, Metoprolol, OCP

Case presentation ROS and P/E: Alterations in physical habitus with 50lbs wt gain over 1 year mainly in abdo area Severe insomnia, depression and difficulty concentrating Very evident dorsocervical and supraclavicular fat pads Round, plethoric face Wasted extremities with proximal muscle weakness Abdominal striae and hyperpigmentation Tender thoracic spine to palpation at T12

Case presentation Laboratory data Sodium= 135, K=3.3 BUN, Cr N Glucose=12.4 WBC=10.7 TSH=0.1 (0.3-5) , N FT4

Cushing’s Syndrome Diagnostic approach 1. Establishing the diagnosis of CS 2. Establishing the cause of CS a. ACTH-dependent vs independent b. Identifying the source in ACTH-dependent 3. Imaging

Case presentation Further investigations?? 24hr UFC = 342 nmol/d (28-276) 1mg DST = > 8 am cortisol = 340 nmol/L (N<50) Repeat 24 hr UFC X 2 = 420 nmol/d, 1243 nmol/d D/C OCP X 6-8weeks– 1mg DST => cort = 280 nmol/d Low-dose DEX-CRH test: cortisol = 120 nmol/L (>38 c/w CS)

Cushing’s Syndrome Diagnostic approach 1. Establishing the diagnosis of CS 2. Establishing the cause of CS a. ACTH-dependent vs independent b. Identifying the source in ACTH-dependent 3. Imaging

Case presentation ACTH = 5.7 pmol/L (>3 c/w ACTH-dep) High-dose DST => adequate suppression CRH stimulation test => response c/w CD MRI pit: slight asymmetry with left sided bulge but no definite adenoma visualized CXR, CT chest: normal

Case presentation IPSS Petrosal sinus/periphery = 4.3 (>2) Petrosal sinus/periphery post CRH = 8 (>3) R/L petrosal sinus ratio=2.1 (>1.4)

Case presentation Patient underwent a transphenoidal surgery to resect the right lobe of the pituitary Post-operative transient DI resolved in 3-4 days Pathology: 2 mm corticotroph adenoma Placed on dexamethasone 4mg q 6 hrs and switched to tapering doses of Pred Am cortisol on dex: 25 nmol/L c/w cure

Conclusion Diagnosis and management of CS remains a considerable challenge Our understanding of the pathogenesis has evolved, but mainly with respect to the very rare causes of CS Diagnostic algorithm (biochemical confirmation followed by localisation) should be closely followed to avoid major pitfalls and misdiagnosis Tumour-specific surgery is the mainstay of treatment followed by radiotherapy and/or medical treatment However, treatment of CD remains disappointing and further developments are needed in this area

James Findling, Diagnosis and Differential “Clinicians who have never missed the diagnosis of Cushing’s Syndrome or have never been fooled by attempting to establish its cause should refer their patients with suspected hypercortisolism to someone who has.” James Findling, Diagnosis and Differential Diagnosis of Cushing’s Syndrome. 1991