Differential Diagnosis of Cushing s Syndrome
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1 Differential Diagnosis of Cushing s Syndrome Cushing s the Diagnostic Challenge Julia Kharlip, MD and Caitlin White, MD Endocrinology, Diabetes and Metabolism Perelman School of Medicine at the University of Pennsylvania Penn Pituitary Center 1
2 Disclosures Consultant, Chiasma 2
3 if you have never missed the diagnosis of ACTH-dependent Cushing syndrome, and you have never been fooled attempting to establish its cause, you should refer your patients with suspected hypercortisolism to somebody who has. 3 Findling J JCEM 2006
4 Overview Case of mild Cushing s disease: 1. Longitudinal observation with repetitive testing as means of achieving greater diagnostic certainty 2. Review testing for diagnosis versus localization. Exogenous Cushings and a role synthetic glucocorticoid serum testing to document occult systemic exposure 4
5 Cushing s Syndrome: Epidemiology Disorder of chronic excess of cortisol in endogenous Cushing s and synthetic glucocorticoid in exogenous Endogenous disease is rare: Incidence: 1-10 patients per million per year Cushingoid states due to exogenous steroid use are highly prevalent Difficulty and delay in diagnosis CD: 6 month to 10 years Bolland Clin Endocrinol 2011; Flitsch J Exp Clin Endocrinol Diabetes 2000; Psaras Exp Clin Endocrinol Diabetes 2011; Biller JCEM 2008; Clayton JCEM
6 Diagnostic Challenges Epidemiology: rarity Intra-individual variability related to severity of disease, duration and pre-morbid state Lack of a sensitive and specific diagnostic tests to follow the paradigm of: 1. Sensitive Screening Test 2. Specific Confirmatory Test 3. Reliable Localization Test for ACTH dependent Cushing s: Pituitary vs. Ectopic Source
7 Clinical Case #1: 32 yo F with Weight Gain Likelihood MOD LOW LOW-MOD Clinical Findings Physical Findings 40 lb weight gain; new pre- HTN menorrhagia, fatigue No DM, osteoporosis, easy bruising, muscle weakness Round face No centripetal adiposity No wide violaceous striae, no hirsutism No supraclavicular, dorsocervical fat pad 7
8 Clinical Case #1: 32 yo F with e Likelihood MOD Clinical Findings 40 lb weight gain; new pre- HTN menorrhagia, fatigue No DM, osteoporosis, easy bruising LOW LOW-MOD Physical Findings Round face No centripetal adiposity No wide violaceous striae, no hirsutism No supraclavicular, dorsocervical fat pad Biochem AM Cort: 12.2 ug/dl (6-19) ACTH: 50, 27 pg/ml (6-58) 24 UFC: 50 mcg/24 hr (< 50) 8
9 Initial Testing JCEM
10 Clinical Case #1: 32 yo F with e Likelihood MOD Clinical Findings 40 lb weight gain; New pre- HTN Irregular menses, fatigue No DM, osteoporosis LOW LOW-MOD Physical Findings Round face No centripetal adiposity No violaceous striae, no hirsutism No supraclavicular, dorsocervical fat pad Biochem AM Cort: 12.2 ug/dl (6-19) ACTH: 50, 27 pg/ml (6-58) 24 UFC: 59, 50 mcg/24 hr (< 50) LNSC 0.10, 0.09, 0.27 mcg/dl (<0.09) DST: Normal 10
11 Use of Repetitive Measurements To Overcome High Variability UFC and LNSC are highly variable within an individual patient Patients with Cushing s Disease: LNSC 35% (95% CI, 27-44%) 24 UFC 31% (95% CI, 24-39%) Obese: for LNSC 39% (95% CI, 26-57%); UFC: 48% (95% CI, 36-61%) Need at least 2 samples for LNSC and 24 UFC 11 Guttenberg et al in press ; Cost 1994; Elias JCEM 2014
12 Sensitivity and Specificity of Available Tests 12 Elamin JCEM 2014
13 Patient 1 Longitudinal Course 2013: Started acupuncture, herbal remedies, yoga therapy, calorie counting and exercise. Lost 20 lb, hypertension resolved, menstruation normalized. She felt better. 6 mos 1 yr 2 yrs 3 yrs 13
14 Subsequent Testing JCEM
15 Patient 1 Longitudinal Course Declined intervention 6 mos 1 yr 2 yrs 3 yrs 15
16 Patient 1 Longitudinal Course 2014: Gained 15 pounds, hypertension returned. Did not want surgery. Started on cabergoline 0.5 mg twice weekly 6 mos 1 yr 2 yrs 3 yrs 16
17 The Localization Studies: IPSS and CRH Stimulation Both capitalize on corticotroph adenoma cells retaining sensitivity to CRH Not a diagnostic test!!! Normal corticotroph cells will respond by in increase in ACTH and cortisol IPSS: Central: Peripheral ACTH 262 patients with CD, Ectopic and adrenal CS - IPS:P ratio of 2 in basal sample: Sens-ty 95%, Specificity 100% - IPS:P ratio of 3 in CRH-stim Sensitivity 100%, Specificity 100% 101 patients with CD and 17 patients with ectopic ACTH tumors ACTH inr of 35%: Sensitivity: 70-93%, Specificity 90-99% Cortisol incr of 20%: Sensitivity: 86-88%, Specificity 90-99% Nieman et al JCEM 1993; Oldfield NEJM 1991
18 The Localization Studies: IPSS and CRH Stimulation Both capitalize on corticotroph adenoma cells retaining sensitivity to CRH Not a diagnostic test!!! Normal corticotroph cells will respond by in increase in ACTH and cortisol 262 patients with CD, Ectopic and adrenal CS IPS:P ratio of 2 in basally: Sens 95%, Spec 100% IPS:P ratio of 3 with CRH-stim Sens 100%, Spec 100% CRH: 101 pts with CD and 17 pts with ectopic ACTH ACTH inr of 35%: Sens 70-93%, Spec 90-99% Cortisol incr of 20%: Sens 86-88%, Spec 90-99% 18
19 Patient 1 Localization CRH Stimulation March 20, 2015 ACTH (pg/ml) Cortisol (ug/dl) -15 MIN MIN MIN MIN 98.8 Max ACTH 15 MIN 93.3 Increase 24.5 >500% 30 MIN MIN MIN MIN 18.2 Dx of CD >35% ACTH >20% Cortisol Max Cortisol Increase 150% Nieman et al. JCEM 1993
20 MRI 20
21 Patient 1 Longitudinal Course Agreed to TSS Path: Corticotroph Adenoma Lost 15lb BP and menses nl 6 mos 1 yr 2 yrs 3 yrs 21
22 Use of Repetitive Measurements Longitudinally Cushing s syndrome tends to progress: Accumulation of new features increases probability disease is present Endocrine Society Guidelines: We suggest further evaluation and follow-up for the few patients.. with discordant results, especially if the pretest probability of Cushing's syndrome is high (2 ). Timing of re-evaluation not deliniated
23 My Approach 1. Educate patients about diagnosis as a process 1. Multiple testing data points: 1. LNSC x 3; UFC x 2 2. Longitudinal re-evaluation (every 3-6 months) 3. Active surveillance with supportive clinical interventions Weight management Goal-directed PT aimed at abnormal weight re- -distribution and steroid myopathy Psychological counseling 23
24 24
25 Patient 1 - Conclusions 1. Mild Cushing s presents a diagnostic challenge 2. Cardinal clinical and physical stigmata may be absent 3. Biochemical results are often discrepant and/or minimally abnormal 4. Longitudinal repetitive testing leads to greater diagnostic certainty as the condition persists/evolves 5. In the meantime, supportive therapies can be given 25
26 Clinical Case #2: 36 yo F with fatigue and low cortisol AM Cortisol 2.1 mcg/dl, ACTH <5 pg/l L knee sports injury, s/p L knee replacement 5 months prior: Kenalog 40 mg (triamcinolone acetonide) L knee injection and 2 months before presentation another 80 mg ~400 mg HC Facial swelling & flushing, esophageal erosions, rapidly lost muscle mass collapsed on knee prosthesis within the month of 2 nd injection Physical Examination: Cushingoid appearing CT abdomen: normal adrenal glands 26
27 Triamcinolone Persisted in Circulation Beyond 5 Months Months after 2nd Kenalog injection ACTH pg/ml <2 < Cortisol ug/dl Triamcinolone ug/dl (<0.1) Neg
28 Clinical Case #2: 36 yo F with fatigue and low cortisol Oral estrogen in OCP likely delayed triamcinolone metabolism through p450 and renal clearance Recommendations: 1. Stop OCP or transition to transdermal Estrogen 2. Follow Sick day rules 3. Start physiologic replacement dose of HC 4. Physical Therapy to address steroid myopathy 28
29 HPA Axis Recovered 15 mo. After Last Triamcinolone Injection Hydrocortisone 29
30 Synthetic Glucocorticoid Screen: Send-out to Mayo Labs Ordering synthetic glucocorticoid screens: Test Name: Synthetic Glucocorticoid Screen, Serum Send out at hospital lab: Mayo Test Code: Quest Test Code: 99895, send to Mayo code #81031 Sample Requirement: 10mL red top or SST tube Method: LC-MS/MS 30
31 Patient 2 - Conclusion Use of synthetic glucocorticoid screen can be useful in detecting systemic absorption of glucocorticoids in patients with suppressed or low-normal ACTH, Cushingoid features and non-systemic forms of glucocorticoid use 31
32 Thank you 32
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