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

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 General %

• Obesity 90
• Hypertension 85

 Skin

• Plethora 70
• Hirsutism/hair loss 75
• Striae

50

• Acne 35
• Bruising/thinning 35

 Musculoskeletal

• Osteopenia/porosis

80

• Weakness 65

➢ Neuropsych

%

• Lability,euphoria,insomnia,

depression,psychosis 85

 Gonadal sx

• Abnormal menses 70
• Decreased libido/

impotence 85

 Metabolic

• Glucose intolerance 75
• Diabetes 20
• Hyperlidemia

70

• 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

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 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

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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

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 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

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 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%

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 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

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 DEX 1mg at 2300H  Serum cortisol at 0800H  Normal response-AM cortisol < 1.8mcg/dl

(50 nmol/L)

 Sens---97-100%  Spec---80-100%

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 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%

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 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

4/14/2018 19 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

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 Choose conditions/assay  Perform ONDST(1MG) or LNSC or Ucort  If normal CS very unlikely  If abnormal confirm with 2nd 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

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 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

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 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

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Oldfield et al 1985

Cavernous/Inferior Petrosal Sinus Sampling IPSS Right Left Left CS IPS peripheral Cushing’s Disease Central/peripheral ACTH ratio ≥ 2 Or ≥ 3 after CRH

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 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)

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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

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 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

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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

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 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

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%

 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

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Dose(mg/wk) U Cort normal

 Study #1* 1-7(median 3.5) 8/20(40%)

24 months

 Study #2** 0.5-6(mean 2.1) 9/30(30%)

12-60 months (mean 37) *JCEM 94:223,2009 **Eur J Endocrinol 136:709,2010

600 mcg* 900 mcg* All pts

 U Cort normal

• At 6 mos

12/82 21/80 33/162 (15%) (26%) (20%)

• At 12 mos

5/39 10/39 15/78 (13%) (26%) (19%)

 Adverse effects-diarrhea 58%, nausea 52%,

DM/hyperglycemia 73%, new diabetic DX 46% *600 or 900 mcg SQ BID

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10-30mg** 30-40mg** All pts

 U Cort normal 26/75 19/76 45/150

at 12 mos (35%) (25%) (30%)

 Adverse effects-diarrhea 39%,

hyperglycemia 48%, diabetes 21% *Lancet Diabetes Endocrinol 6:17,2018 **10-30mg or 30-40mg IM monthly for12 mos

Dose U Cort normal (mean:mg/day)

 Pre Surgery 755+284 19/39(49%)

(4.1+4.1 mos)

 Post TSS or XRT 780+292 78/158(49%)

(24.8+33.6 mos)

 Long term 33/51(65%)

(24-135 mos)

 Adverse effects-intolerance 21%,elevated LFT’s

16%,markedly elevated LFT’s 3%, AI 5%

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 Glucocorticoid antagonist-can’t follow cortisol  50 pts treated for 6 mos(dose 732+366 mg/day)  C-DM--decreased aucGTT >25% 15/25(60%)  C-HT---decreased DBP >5mm HG 8/21(38%)  WT decreased 5.7+7.4 %  Adverse effects—Nausea 48%,fatigue 48%,

headache 44%,hypokalemia 34%,HTN 24%. Arthralgia,vomiting,edema,dizziness,anorexia in 20-30%. AI-N=2

UCORT normal

 Cabergoline/ketoconazole 25/32 (78%)  Pasireotide/cabergoline/

ketoconazole 13/17 (76%)

 Ketoconazole/octreotide

3/4 (75%) *Pituitary 18:253,2015

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 Consider in

• Young pts
• Those who fail TSS, XRT and medical RX



Advantages

• Rapidly corrects hypercortisolism with low

morbidity/mortality

• Should reverse excess mortality
• Low recurrence rate

 Disadvantages

• Permanent AI
• Risk of Nelson’s syndrome

 Transphenoidal surgery is the procedure of

choice, however, there are no clear guideline as to how to proceed when patients fail TSS as primary therapy

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 Small cell lung cancer(50%)  Carcinoid tumors (LUNG,

mediastinum/thymus, abdomen,pancreas

 Pancreatic neuroendocrine tumors  Medullary thyroid cancer  Pheochromocytoma/paraganglioma  Neuroendocrine tumors of unknown origin  Misc

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From Aniszewski et al, World J Surg 32:659, 2001

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 Exclude CD by negative IPSS  CT and MRI equally accurate  Utility of newer imaging procedures unclear

EAS:LOCALIZATION SERIES PIT MRI IPSS BODY CT/ SRS OCCULT ABN (-) MRI(+) (+) 1* -

• 65% -

2** 26% 100% 74% 49% 19% *BARTS(1969-2001,N=40) JCEM 91:371,2006 **NIH(1984-2004,N=90) JCEM 90:4955,2005

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 RX primary tumor  Inhibit ACTH or cortisol secretion  Laparoscopic adrenalectomy

EAS: OUTCOME SERIES CURED/ ADRENEX MED SURVIVAL REMISSION RX (F/U) 1* 12% 61% - 40% 2** 30% 30% 70% 38%(5Y) 3*** 47% 37% 69% 79%(2.2Y)

*MAYO(1956-1998,N=106)World J Surg 25:934,2001

**BARTS(1969-2001,N=40) JCEM 91:371,2006 ***NIH(1984-2004,N=90) JCEM 90:4955,2005

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 Adenoma-Unilateral lap adrenalectomy

• Prognosis:cure

 ACC -Lap/open adrenalectomy

• Mitotane
• Inhibit cortisol secretion
• Prognosis:50% mortality in 2 yrs

 PPNAD & AIMAH-Bilateral adrenalectomy

• Cushing’s cured with AI

From Pivonello et al, NEJM, 2005

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26 yo woman with ACTH dependent CS

 MRI

• Rathke’s cyst & ? some focal abnl in

the left wing

Where Is the Source of ACTH? Pituitary vs Ectopic

4/14/2018 41 Right Left Left CS IPS peripheral

86 2270 41 120 4020 346

CRH

53 1014 42 36 36 42

 IPSS confirms CD  Transsphenoidal surgery (TSS)

9/12/2000

 No adenoma was found  Left Hemihypophysectomy

• based on venous sampling + the equivocal focal

abnl in the left lateral wing

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Periop course

 9/12 left hemi  9/13 cortisol 24 ug/dL

• Received HC postop on 9/12

 9/14 cortisol 13ug/dL  9/15 cortisol 1 ug/dL (while on dex)  D/Ced on HC 20/10  9/25 cortisol 13 ug/dL, ACTH 20ng/L  9/28 24h urine 126ug/24 hours  TSS failed her

What Should Be Done to Control Hypercortisolism? A: Repeat surgery B: Radiation C: Medical Therapy D: Surgical Adrenalectomy

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 Repeat surgery was thought not to provide

additional chance for cure

 Bilateral adrenalectomy 12/2000

• 3 months after TSS

 On HC 20/10 mg + Florinef 0.1mg

Postop course 12/2000

 On HC, tapered to 15/5 mg + Florinef

0.1mg

 Weight loss slow, with lots of diet &

exercise

 Oligomenorrhea, last regular cycle

11/1999

• Seen by Repro-endo for infertility
• Found to have anovulation, thought to be weight

related

 Monitored for adrenal remnant stimulation,

cortisol < 1 without HC

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10/2001

• Na 136 mmol/L
• K 4.4 mmol/L
• ACTH ?

432 ng/L on HC 15/5 7/2002

 Received Clomid x2 for fertility  Repeat Na/K/ACTH

ACTH > 1500 ng/L

 ACTH > 1500 ng/L

Does This Concern You? Should Anything Be Done? A: Repeat ACTH B: Increase HC and /or Florinef C: Pituitary MRI D: None of the above

4/14/2018 45 26 yo woman with Cushing’s Disease, s/p adrenalectomy 26 yo with Nelson’s Syndrome

• Endonasal trans-sphenoidal

resection 8/2002

• No evidence of gross invasion
• Complete resection
• ACTH 42 and 50 ng/L postop

4/14/2018 46 26 yo with Nelson’s Syndrome

• 3 uneventful pregnancies

1/2003, 5/2006 and 5/2010

 STRATEGY

• If MRI negative, equivocal or high suspicion for EAS,

proceed to inferior petrosal sampling (IPSS)

• IPSS: Positive for CD if central/peripheral ACTH ratio

> 2 before CRH OR > 3 after CRH

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 Pituitary MRI

• Lesions smaller than 5 mm, especially those <3-4

mm may be artifacts, volume averaging, incidental adenomas or cysts

• Minor degrees of pituitary asymmetry or stalk

deviation in the absence of a discrete lesion are normal variations of pituitary anatomy

• 10% of normals have small adenomas/cysts on MRI

(majority < 5 mm)

 STRATEGY

• Do MRI—if positive (lesion >5mm), proceed to

surgery *

• If MRI negative or high suspicion for ectopic ACTH

syn, proceed to inferior petrosal sinus sampling (IPSS) *caution re: minor abnormalities

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 Dynamic tests ie HDDST ,CRH, desmopressin

and metyrapone are not useful*

 Pituitary MRI is positive in approx. 50% of pts

with CD *Ectopic ACTH syndrome caused by a bronchial carcinoid tumor responsive to dexamethasone ,metyrapone,and corticotropin-releasing factor. Am J Med 84,760,1988

 THE PROBLEM

• Pituitary adenomas average 5mm in diameter
• Many ACTH-secreting carcinoids are < 10mm

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Oldfield et al 1985

Cavernous/Inferior Petrosal Sinus Sampling IPSS

4/14/2018 50 Right Left Left CS IPS peripheral Cushing’s Disease Central/peripheral ACTH ratio ≥ 2 Or ≥ 3 after CRH Right Left Left CS IPS peripheral Cushing’s Disease Central/Peripheral ACTH ≥ 2 Or ≥ 3 after CRH