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Master Professor Rounds Master Professor: Madup Naim, MD Division of Endocrinology Presenter: S. Marty Pantz, MD Date Case Presentation ID/CC: HPI: Case Presentation (cont’d) PMH: HTN x 25 yrs DM x 18 yrs Hypothyroidism x 18 yrs Hospitalizations x 2 Depression Dyslipidemia Arthritis 1. January 2006—nausea/vomiting, given IVF and discharged later that day 2. January 2006—atypical chest pain, scheduled for outpatient ischemic work-up h/o L CVA in January, with residual R-sided facial paresthesias Menstrual/OB Hx: postmenopausal x 9 yrs, not on HRT h/o regular menses, G1P1 Allergies: NKDA Case Presentation (cont’d) Meds: Lexapro 10 mcg daily Norvasc 10 mg daily Synthroid 75 mcg daily Metformin 500 mg BID ASA 81 mg daily Spironolactone 25 mg daily Metoprolol 50 mg BID Benazepril 40 mg daily Zocor 40 mg qHS Family Hx: mother deceased from heart disease (+) DM Social Hx: (+) tobacco use — 5 cigarettes/day x 10 yrs denies EtOH, IVDA from Mexico Physical Exam Vital Signs: T 98.2 BP 139/74 HR 78 RR 20 0/10 pain General: WDWN, dark in appearance, (+) truncal obesity, NAD, AAO x 3, slow to respond to questions, at times inattentive HEENT: NC/AT, (+) moon facies, (+) hirsutism, PERRL, EOMI, mmm, no thyromegaly, no LAD, (+) dorsal fat pad Chest: CTAB, no c/w/r CV: RRR, nl S1S2, no S3/S4, no m/c/r/g Ab: (+) BS, S/NT/ND, no HSM GU: no clitoromegaly Skin/Extremities: (+) abdominal striae, (+) ecchymotic areas over abdomen and antecubital fossa, (+) thinning of skin, decreased subcutaneous fat, (+) bilateral muscle wasting, 1+ edema BLE Neuro: AAO x 3, proximal muscle weakness, 2+ DTR Differential Diagnosis Differential Diagnosis • Cushing’s Syndrome – ACTH-dependent vs. ACTH-independent • • • • • • Pseudo-Cushing’s Syndrome PCOS Uncontrolled Hypothyroidism Rheumatoid Arthritis Polymyalgia Rheumatica Myopathy How would you approach this patient? Studies Labs: • BMP • CBC w/diff • TSH/free T4 • Additional Tests • Screening Tests I • Screening Tests II Imaging studies: • CXR • MRI brain Next Basic Metabolic Panel 135 101 17 4.0 22 0.6 236 Return to Menu CBC w/differential 12.7 322 7.7 37.5 N80 L14 M6 Return to Menu TSH/Free T4 TSH 1.81 uIU/ml Free T4 1.34 ng/dl Return to Menu Additional Tests • random cortisol 37.8 mcg/dl (10:40) 26.5 mcg/dl (21:20) (normal AM: 5-25 mcg/dl, normal PM: 3-13 mcg/dl) • ACTH 69 pg/ml (21:20) (normal 5-27 pg/ml) • Estradiol 25 pg/ml • DHEA-S 227 μg/dl • FSH 1.0 U/L • Testosterone 47 pg/dl • LH < 1.0 U/L • Prolactin 15.8 ng/ml Return to Menu Initial Screening Tests 24 hour urinary free cortisol 457 μg (4-50 μg) Low dose Dexamethasone Suppression Test 5/25 21:25 5/31 23:00 6/01 08:01 ACTH ACTH 69 pg/ml Dexamethasone 56 pg/ml Cortisol 1 mg Cortisol 26.5 mcg/dl 14.1 mcg/dl Return to Menu High Dose Dexamethasone Suppression Test 7/12 10:46 ACTH 61 pg/ml Cortisol 21.6 mcg/dl 7/12 PM 7/13 07:34 ACTH Dexamethasone 9 pg/ml 8 mg Cortisol 3.1 mcg/dl Return to Menu CXR atherosclerotic vascular disease Return to Menu MRI Brain MRI MRI MRI Brain no identifiable masses chronic nonspecific white matter changes Return to Menu Working Diagnosis Cushing’s Syndrome ACTH-dependent most likely pituitary in origin A Quick Synopsis on Cushing’s Syndrome • rare condition that results from chronic exposure to glucocorticoids, characterized by abnormally high levels of cortisol • more common in females than male, although ectopic causes occur more frequently in males • two broad categories – ACTH-dependent (includes Cushing’s disease, ectopic ACTH syndrome, and ectopic CRH syndrome) – ACTH-independent (adrenal adenoma, adrenal carcinoma, micronodular hyperplasia, macronodular hyperplasia) ACTH-Dependent Cushing’s Syndrome • characterized by high cortisol associated with normal/high ACTH levels with dexamethasone suppression • Cushing’s disease (70% of cases) – pituitary source of excess ACTH production – females > males • Ectopic ACTH syndrome (15%) – usually from small cell cancer or other ACTH-producing tumors – males > females • Ectopic CRH syndrome – very rare ACTH-Independent Cushing’s Syndrome • high cortisol, with low ACTH levels on dexamethasone suppression testing • ~15% of cases • usually adrenal in origin Physiologic and Pathophysiologic Features of the Hypothalamic-Pituitary-Adrenal Axis in Normal Subjects and Patients with Cushing's Syndrome (Top Panels) and the Effect of Dexamethasone (Bottom Panels) * ACTH-dependent Cushing’s Syndrome Orth D. N Engl J Med 1995;332:791-803 *Erratum: thick purple lines should be dotted purple lines (denoting suppressed secretion) ACTH-independent Cushing’s Syndrome Clinical Manifestations of Cushing’s Syndrome • • • • • • • • • • • • • central obesity (>80%) facial plethora (>50%) glucose intolerance (>40%) weakness/proximal myopathy* (>75%) hypertension psychological changes easy bruisability* hirsutism oligomenorrhea/amenorrhea impotence acne, oily skin abdominal striae moon facies • ankle edema • backache, vertebral collapse, fracture • polydipsia, polyuria • renal calculi • hyperpigmentation • headache • exophthalmos • fungal infection • abdominal pain • thinning of skin* • weight gain • dorsal/supraclavicular fat pad *features that distinguish Cushing’s syndrome from Pseudo-Cushing’s syndrome An Algorithmic Approach to the Patient with Cushing’s Syndrome Tests Used for Work-Up • 24 hour urine cortisol – used as initial screening to confirm diagnosis of Cushing’s syndrome – most direct way of measuring cortisol secretion – must correlate with urine creatinine levels to confirm adequate sample collection – preferably, should have 2 or 3 elevated values to confirm dx • Low-dose dexamethasone suppression test – helps distinguish ACTH-dependent vs. ACTH-independent – check evening ACTH/cortisol, give 1 mg dexamethasone between 11pm-MN, check ACTH/cortisol at 8am – standard 2-day, 2 mg suppression test is used as initial screening or if overnight test equivocal Tests Used for Work-Up (II) • High-dose dexamethasone suppression test – delineates pituitary vs ectopic sources of ACTH production – same process as for low-dose suppression testing, but 8mg dexamethasone used – alternative test is total 48 mg given over 8 doses (2 mg every 6 hrs), checking ACTH/cortisol 6 hrs after last dose • Octreotide Scan – useful in identifying ectopic ACTH production in tumors with somatostatin receptors • Inferior Petrosal Sinus Sampling (IPSS) – most direct way to identify excess pituitary ACTH production – simultaneous bilateral sinus & venous samples to measure ACTH – CRH or DDAVP given peripherally, with additional samples drawn at 2-3 minutes & at 5-6 minutes – central:peripheral ratio before/after is compared; if >2-3pituitary – gold standard for detecting Cushing’s disease – $$$, invasive Management of Cushing’s Syndrome • depends on source, but surgery is usually first-line tx • Cushing’s disease – transsphenoidal surgery (70-80% cure rate) – pituitary irradiation as second line – consider total bilateral adrenalectomy as last resort • Ectopic ACTH/CRH syndrome – surgical resection of underlying tumor (poor cure rate in malignancy) – adrenal enzyme inhibitors (i.e. ketoconazole) – medical/surgical adrenalectomy • Adrenal tumors – – – – surgical resection if deemed operable (usually bilateral adrenalectomy) mitotane as a palliative measure for recurrent/residual disease surgical resection of recurrent disease adrenal enzyme inhibitors • Exogenous glucocorticoid use – wean off offending agent slowly Summary • 2 elevated random cortisol levels get an ACTH level • if cortisol + ACTH are high and s/sx consistent with possible Cushing’s initial screening tests to confirm dx and distinguish etiology (24 hr urine cortisol & low-dose dexamethasone suppression test) • depending on the ACTH level, work-up accordingly – if low ACTH on suppression think adrenal causes and get a CT A/P – if high/normal ACTH high-dose dexamethasone suppression test to delineate pituitary (suppressed ACTH) & ectopic sources, followed by appropriate imaging studies • surgery is usually first-line therapy, if resectable References Special Thanks to Chief Holman for his invaluable resources and insight during the preparation of this case!