4/14/2018 1 4/14/2018 2 4/14/2018 General - PDF document

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4/14/2018  General % ➢ Neuropsych % ◦ Obesity 90 ◦ Lability,euphoria,insomnia, ◦ Hypertension 85 depression,psychosis 85  Skin  Gonadal sx ◦ Plethora 70 ◦ Abnormal menses 70 ◦ Hirsutism/hair loss 75 ◦ Decreased libido/ ◦ Striae 50 impotence 85 ◦ Acne 35  Metabolic ◦ Bruising/thinning 35 ◦ Glucose intolerance 75  Musculoskeletal ◦ Diabetes 20 ◦ Osteopenia/porosis 80 ◦ Hyperlidemia 70 ◦ Weakness 65 ◦ Polyuria 30 ◦ Kidney stones 15  Cushing’s disease(CD): 20 -40 yo woman with gradual progression and modest androgen excess  Ectopic ACTH syndrome(EAS) ◦ Benign: frequently cushingoid, hyperpigmented and hypokalemic. The tumor may be occult ◦ Malignant: Older male smoker with lung cancer and absent cushingoid features. Weight loss, weakness, HTN, hypokalemia, pigmentation and anemia are common  Adrenal adenoma: mild to moderate cushingoid features and absent androgen excess  Adrenal carcinoma(ACC):rapidly progressive features of cortisol, androgen and/or mineralocorticoid excess 3

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4/14/2018  DIAGNOSIS  DDX OF ACTH-INDEPENDENT AND ACTH- DEPENDENT CAUSES  DDX OF PITUITARY (CD) AND ECTOPIC CAUSES OF ACTH-DEPENDENT CS  Choose your conditions  Choose your test  Choose your cortisol assay (LC/MS/MS)  Keep it simple 11

4/14/2018 DO NOT USE Tests which are not useful  Any test beginning with “17” • AM, 4PM, 8 PM, or random serum cortisol • Tests which are not practical  Midnight serum cortisol • Six day DST •  Tests for DDX  Localizing procedures  Late night salivary cortisol (LNSC)  Overnight DEX suppression (ONDST 1 mg)  24h urine cortisol 12

4/14/2018  False + ( Pseudocushing’s syn) ◦ Acute illness/hospitalization ◦ Severe stress ◦ Morbid obesity ◦ Sleep apnea ◦ Depression/Anxiety ◦ Alcohol excess ◦ Anorexia nervosa * Regardless of test used  False negative responses ◦ Mild Cushing’s ◦ Episodic /Cyclic Cushing’s (rare) *Regardless of test used 13

4/14/2018  Collect 2 samples at 2300H on consecutive days  Normal values at 2300H ◦ ELISA/EIA---<4.3 nmol/l ◦ LC/MS/MS---<0.09 mcg/dL  Sensitivity---92%  Specificity---96% 14

4/14/2018  Advantages ◦ Ease of collection/multiple specimens ◦ Many pts with pseudocushing’s maintain normal diurnal variation ◦ Two normal values exclude Cushing’s  Disadvantages(false+) ◦ Pseudocushing’s ◦ Altered sleep/wake cycles ◦ A WORD OF CAUTION  Liu et al * ◦ Male veterans with DM2 ◦ LNSC SPEC(%)  All subjects 80  DM/HTN/AGE>60 60  Baid et al ** ◦ Obese subjects ◦ LNSC  By RIA 84  By LC/MS/MS 92 * Clin Endocrinol 63:642,2005 ** JCEM 94:3857,2009 15

4/14/2018  DEX 1mg at 2300H  Serum cortisol at 0800H  Normal response-AM cortisol < 1.8mcg/dl (50 nmol/L)  Sens---97-100%  Spec---80-100% 16

4/14/2018  Advantages ◦ A normal response excludes CS with 97-98% accuracy  Disadvantages (false +) ◦ Pseudocushing’s ◦ Estrogen/tamoxifen increase CBG ◦ Accelerated DEX metabolism- phenytoin,phenobarb,rifampin,carbamazapine ◦ Renal failure  Disadvantages (false-) ◦ Delayed DEX metabolism (<1%)  Collect two 24H urines  Assay by RIA or LC/MS/MS  Normal range 4-50 mcg/24H(LC/MS/MS)  Sens---76-100%  Spec---81-100% 17

4/14/2018  Advantages ◦ Estimates 24H excretion ◦ Not increased in moderate obesity  Disadvantages ◦ Requires 24H collection ◦ Many patients with pseudocushing’s have mild to moderate increases in UC ◦ False + with high urine volume ◦ False - in renal failure 18

4/14/2018 Sens Spec LR- LR+ • DST 1mg <50** 100 91.9 12.4 <138** 86.8 96.7 0.14 28.7 • LNSC <14.5** 84.2 88.9 0.18 7.6 • UCORT <170*** 97.4 90.9 0.03 10.8 **nmol/L ***nmol/24h Note: For cortisol nmol/Ldivided by 27.6=mcg/dl  Two day low-dose DST ◦ DEX 0.5mg Q6H x 48H (OR 1.0 mg Q12H) ◦ Collect serum cortisol at 48H ◦ Normal response — serum cortisol <1.8mcg/dl ◦ Useful in pts with mildly abnormal results of other tests 19

4/14/2018  Choose conditions/assay  Perform ONDST(1MG) or LNSC or Ucort  If normal CS very unlikely  If abnormal confirm with 2 nd test  If equivocal consider two day LDDST and/or follow over time  ACTH-dependent Percent ◦ Pituitary (Cushing’s disease) 75 ◦ Ectopic ACTH syndrome 10 ◦ Ectopic CRH <1  ACTH-independent ◦ Adrenal adenoma 10 ◦ Adrenal carcinoma 5 ◦ PPNAD & AIMAH <1 20

4/14/2018  Measure ACTH by IRMA or ICMA assay  These assays reliably detect suppressed levels ie < 5 pg/ml  ACTH <5 pg/ml=ACTH independent (image adrenals)  ACTH >10 pg/ml =ACTH dependent 21

4/14/2018  THE PROBLEM • Pituitary adenomas average 5mm in diameter • Many ACTH-secreting carcinoids are <10mm • Routine MRI positive in 42*-50% of pts with CD  STRATEGY • Do Dynamic MRI--Positive or suspicious in 83%** • If MRI negative, equivocal or if high suspicion for ectopic ACTH syn proceed to inferior petrosal sinus sampling (IPSS). • IPSS:positive for CD if central/peripheral ACTH ratio >2 OR >3 after CRH *NIH-JCEM 98:2285,2013 (501 PATIENTS) **UCSF-J Neurooncol 16:693,2014 22

4/14/2018 Cavernous/Inferior Petrosal Sinus Sampling IPSS Oldfield et al 1985 Cushing’s Disease Left Right Left Central/peripheral ACTH ratio ≥ 2 Or ≥ 3 after CRH CS IPS peripheral 23

4/14/2018  Newell-Price et al* ◦ 21 series, 646 subjects ◦ 96% success in canulating bilateral sinuses ◦ Sensitivity--96% ◦ Specificity--100% ◦ Lateralization (diagnostic accuracy--78%)  UCSF-Liu C et al** ◦ N=95, all with non-diagnostic MRI, sampled CS and IPS with and without CRH ◦ Sensitivity 100% ,specificity 100% ◦ Lateralization (diagnostic accuracy--62%) *Endo Rev 19:647,1998. **Clin Endo 61:478,2004  Overall diagnostic accuracy---62%*-69%**  15/28(54%) cured by hemihypophysectomy based on lateralization data.* *UCSF- Clin Endo 61:478,2004(N=95) **NIH- JCEM 98:2285,2013(N=501) 24

4/14/2018 Caveats  The Dx of ACTH-dependent CS must be established prior to IPSS  Pt must be hypercortisolemic at the time of the procedure  False + results • Normal pts • Pts with pseudo-CS  ACTH dependent hypercortisolism  Positive pituitary MRI (lesion >5mm) OR  Positive central venous sampling 25

4/14/2018  Transsphenoidal surgery(TSS) Remission:70-85% •  Therapy of persisting/recurrent disease Repeat TSS • Radiotherapy • Medical RX • Bilateral adrenalectomy •  MGH (1978-1996)* NO % ◦ Remission 137/161 85** ◦ Recurrence 10/136 7  UCSF (1975-1998)*** ◦ Remission 236/289 82 ◦ Recurrence 13/150 9 *Ann Intern Med 130:821,1999 , ** 28 pts had more than 1 operation. *** JCEM 89:6348,2004 26

4/14/2018 No SMR  MGH ◦ Deaths 6/159 0.98  UCSF ◦ Deaths 29/248 ◦ Remission 1.2 ◦ Persisting disease 2.8  Therapy of persisting or recurrent disease Repeat TSS • Radiotherapy • Medical RX • Bilateral adrenalectomy • 27

4/14/2018  Remission 168/246(68%) (Range 37-87%)  Relapse 22/123(18%) (Range 0-35%) *Can J Neurol Sci 38:12,2011(11 series,246 patients) %  Conventional • Remission 46-84 • Hypopit 10-76 • Tumor control 93-100  Gamma knife(SRS) • Remission 10-83 • Hypopit 5-66 • Tumor control 85-100 *Arq Bras Endocrinol Metab 51:1373,2007 Pituitary 17:60,2014 28

4/14/2018 %  Gamma Knife ◦ Remission at 2 yrs 62 ◦ Remission at 10 yrs 64 ◦ Remission all pts 57 ◦ Recurrence 18 ◦ Hypopit 25 *JCEM 102:4884,2017 (N=278,mean F/U 5.6 years) Inhibit ACTH secretion • Cabergoline  Pasireotide (new somatostatin analog)  Cyproheptadine ,bromocriptine ,older somatostatin  analogs and sodium valproate not effective  Inhibit cortisol secretion • Ketoconazole • Metyrapone • Mitotane • Etomidate (IV only)  Glucocorticoid receptor antagonist • Mefipristone 29