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in Endocrinologia Clinica

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AGGIORNAMENTI su PATOLOGIA SURRENALICA Lino Furlani

•  Ipercortisolismo –  Approccio clinico – screening di laboratorio

–  Cenni di terapia farmacologica

•  Ipertensione resistente –  Approccio clinico e screening di laboratorio

nell’Iperaldosteronismo Primitivo

Di cosa parleremo ?

and relatively young women and men, and patients with

hypertension resistant to treatment [5–7]. As such, theEuropean Society of Endocrinology recommends investi-

gation for Cushing’s disease in patients presenting these

features at an unusual (young) age [8].The heterogeneity of Cushing’s disease, the overlapping

of signs and symptoms with those of other disorders, the

need for differential diagnosis, the variety of biochemicaltests and imaging techniques available for diagnosis, and

questions surrounding how to better define response andremission all contribute to the challenges physicians face in

optimizing patient management, despite ongoing advances

in diagnosis and treatment. Thus, a multidisciplinary teamof neurosurgeons, endocrinologists, and radiation oncolo-

gists, as well as an individualized patient approach, is

recommended for the management of Cushing’s disease[9–19].

The first-line treatment for Cushing’s disease is trans-

sphenoidal surgery (TSS) to remove the adenoma, butinitial surgery frequently fails [2, 13]. Although radio-

therapy is an option if initial TSS is unsuccessful, the

effects of radiotherapy may only become apparent aftermany years [20] and the intervention may be followed by

side effects, such as pituitary deficiency or failure, as well

as damage to the optic nerve because of the frequent needof traditional approaches [21, 22]. Medical therapy can also

be useful in cases of surgical failure, but some of the drugs

in use have limited effects or are not approved for use intreating Cushing’s disease [13, 23]. Pasireotide (Signifor!;

Novartis AG, Basel, Switzerland), the first pituitary-direc-

ted medical therapy, was recently approved in the Euro-pean Union and in the US for treating adult patients with

Cushing’s disease for whom surgery is not an option or for

whom surgery has failed. Its long-term effectiveness intreating the symptoms of Cushing’s disease has been

shown in phase III trials [24, 25]. This state-of-the-art

review aims to provide an overview of the most recentscientific research and clinical information regarding

Cushing’s syndrome, with an overall focus on Cushing’s

disease.

Pathophysiology and etiology of Cushing’s disease

Corticotrophic adenomas secreting ACTH are the most

common cause of endogenous Cushing’s syndrome,accounting for approximately 70 % of cases [2]. The

increased ACTH secreted by the tumor acts on the adrenal

glands to stimulate increased cortisol production, which inturn leads to the variety of signs and symptoms of Cush-

ing’s disease (Fig. 1). In most cases, the tumors are benign

and slow growing. Microadenomas (B10 mm in diameter)are found in [90 % of cases, whereas macroadenomas

([10 mm in diameter) are less common (\10 % of cases).As discussed below, the size of the tumor can influence

treatment outcomes.

The biochemical relationships involved in the hypo-thalamus—pituitary—adrenal axis are such that hypercor-

tisolism leading to Cushing’s syndrome can also be caused

by extrapituitary tumors that secrete ACTH or CRH,adrenal adenomas or carcinomas, and adrenal hyperplasia

or dysplasia [2]. Furthermore, several genetic alterations

have also been identified as contributing to sporadic cor-ticotropinoma formation, including alterations to

PRKAR1A (encoding a cAMP-dependent protein kinase A

subunit), PDE11A (encoding a cyclic nucleotide signaltransducer), and PDE8B (encoding a cyclic nucleotide

phosphodiesterase) [26, 27]. Finally, aberrant stimulation

of steroidogenesis in ACTH-independent macronodularadrenal hyperplasia and in some unilateral adenomas can

be driven by ectopic receptors such as those for glucose-

dependent insulinotropic peptide or gastric inhibitorypolypeptide, b-adrenergic receptors, serotonin, and proba-

bly angiotensin II receptor. However, it can also result

Fig. 1 Signs and symptoms of Cushing’s disease

Endocrine

123

•  A chi proporre accertamenti ?

•  Quali ?

•  Cenni di Terapia Farmacologica

Caso clinico

Daniela, di anni 48 AP: familiarità per ICTUS CEREBRI ed IPERTENSIONE ARTERIOSA; IPERTESA da 8 anni. IPERCOLESTEROLEMIA. DIABETE tipo 2. OBESA 1 grado. Terapia: ACEI + DIURETICO; IPOCOLESTEROLEMIZZANTE; ANTIAGGREGANTE; DIETA + METFORMINA Negli ultimi 10 anni aumenta di peso con accentuazione negli ultimi due anni; adotta una dieta ipocalorica che riesce a farLe perdere significativamente peso Nell’ultimo anno per controllare efficacemente la PA associa all’ACE Inibitore anche il diuretico. ECOCOLORDOPPLER TSA (2013): note diffuse di ateromasia di parete; bilateralmente, al bulbo e all’origine della C.I., placca realizzante stenosi del 30% a destra e del 40% a sinistra

Caso clinico

Es. Obiettivo:

-  PA 130/85 con fc 68 bpm, regolare;

-  peso 70,5 Kg, altezza 150 cm, BMI 31,3 Kg/m2

-  Facies «piena», non striae rubrae, non gibbosità, non

ecchimosi, non segni di iperandrogenismo.

In una paziente con queste caratteristiche

avreste avviato uno screening per Cushing ?

Screening negli obesi?

9

CLINICS 2010;65(1):9-13

CLINICAL SCIENCE

Division of Endocrinology and Metabolism, Department of Internal Medicine, Cerrahpasa Medical Faculty - Sivas, Turkey.Email: [email protected]: 90 216 4623114Received for publication on September 11, 2009 Accepted for publication on October 08, 2009

SCREENING FOR CUSHING’S SYNDROME IN OBESE PATIENTS

Ozay Tiryakioglu, Serdal Ugurlu, Serap Yalin, Sibel Yirmibescik, Erkan Caglar, Demet Ozgil Yetkin, Pinar Kadioglu

doi: 10.1590/S1807-59322010000100003

Tiryakioglu O, Ugurlu S, Yalin S, Yirmibescik S, Caglar E, Yetkin DO et al. Screening for Cushing’s Syndrome in obese patients. Clinics. 2010;65(1):9-13.

OBJECTIVES: The aim of this study was to examine the frequency of Cushing’s syndrome (CS) in obese patients devoid of specific clinical symptoms of Cushing’s syndrome. METHODS: A total of 150 obese patients (129 female, 21 male; mean age 44.41 ± 13.34 yr; mean BMI 35.76 ± 7.13) were in-cluded in the study. As a first screening step, we measured 24-h urinary free cortisol (UFC). An overnight 1-mg dexamethasone suppression test was also performed on all patients. Urinary free cortisol levels above 100 µg/24 h were considered to be abnormal. Suppression of serum cortisol <1.8 µg/dL after administration of 1 mg dexamethasone was the cut-off point for normal suppression. The suppression of the serum cortisol levels failed in all of the patients. RESULTS: Measured laboratory values were as follows: ACTH, median level 28 pg/ml, interquartile range (IQR) 14-59 pg/ml; fasting glucose, 100 (91-113) mg/dL; insulin, 15.7 (7.57-24.45) mU/ml; fT4, 1.17 (1.05-1.4) ng/dL; TSH, 1.70 (0.91-2.90) mIU/L; total cholesterol, 209 (170.5-250) mg/dL; LDL-c, 136 (97.7-163) mg/dL; HDL-c, 44 (37.25-50.75) mg/dL; VLDL-c, 24 (17-36) mg/dL; triglycerides, 120.5 (86-165) mg/dL. The median UFC level of the patients was 30 µg/24 h (IQR 16-103). High levels of UFC (>100 µg/24 h) were recorded in 37 patients (24%). Cushing’s syndrome was diagnosed in 14 of the 150 patients (9.33%). Etiologic reasons for Cushing’s syndrome were pituitary microadenoma (9 patients), adrenocortical adenoma (3 patients), and adrenocortical carcinoma (1 patient). CONCLUSION: A significant proportion (9.33%) of patients with simple obesity were found to have Cushing’s syndrome. These findings argue that obese patients should be routinely screened for Cushing’s syndrome.

KEYWORDS: Cushing’s syndrome. Obesity. Screening. Cortisol. Adrenocorticorticotropic hormone.

INTRODUCTION

Obesity is the most common metabolic problem in industrialized countries. In the USA, 32% of adults are classified as overweight, and 22.5% of these individuals are obese.1 Both overweight and obese subjects are at an increased risk for cardiovascular diseases,2 some types of cancer,3 diabetes4, and even premature death.5 Obesity is often accompanied by other chronic disorders including

hypertension, osteoarthritis, bile stones, and dyslipidemia.6-12 In addition to these physical disorders, obesity is commonly associated with psychological and psycho-social problems.10

Obesity can coexist with diverse physical disorders, and physicians should first focus on the differential diagnosis of possible underlying disorders before initiating any management procedure. Obesity is a prominent feature of endocrine diseases including hypothyroidism, insulin-excess syndromes, polycystic ovary syndrome (PCOS), hypogonadism, hypothalamic disease/injury, growth hormone deficiency, leptin deficiency or leptin receptor defects, pseudohypoparathyroidism, and Cushing’s syndrome (CS).11,12

Diagnosis of CS is primarily based on the signs and 9

CLINICS 2010;65(1):9-13

CLINICAL SCIENCE




doi: 10.1590/S1807-59322010000100003




INTRODUCTION




Diagnosis of CS is primarily based on the signs and

9

CL

INIC

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nter

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edic

ine,

C

erra

hpas

a M

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acul

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urke

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US

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RO

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BE

SE

PA

TIE

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Oza

y T

irya

kiog

lu, S

erda

l Ugu

rlu,

Ser

ap Y

alin

, Sib

el Y

irm

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Tiry

akio

glu

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gurl

u S,

Yal

in S

, Yir

mib

esci

k S,

Cag

lar

E, Y

etki

n D

O e

t al.

Scre

enin

g fo

r C

ushi

ng’s

Syn

drom

e in

obe

se

patie

nts.

Clin

ics.

201

0;65

(1):

9-13

.

OB

JEC

TIV

ES:

The

aim

of

this

stu

dy w

as t

o ex

amin

e th

e fr

eque

ncy

of C

ushi

ng’s

syn

drom

e (C

S) i

n ob

ese

patie

nts

devo

id o

f sp

ecifi

c cl

inic

al s

ympt

oms

of C

ushi

ng’s

syn

drom

e.

ME

TH

OD

S: A

tota

l of

150

obes

e pa

tient

s (1

29 f

emal

e, 2

1 m

ale;

mea

n ag

e 44

.41

± 13

.34

yr; m

ean

BM

I 35

.76

± 7.

13)

wer

e in

-cl

uded

in th

e st

udy.

As

a fir

st s

cree

ning

ste

p, w

e m

easu

red

24-h

uri

nary

fre

e co

rtis

ol (

UFC

). A

n ov

erni

ght 1

-mg

dexa

met

haso

ne

supp

ress

ion

test

was

als

o pe

rfor

med

on

all p

atie

nts.

Uri

nary

free

cor

tisol

leve

ls a

bove

100

µg/

24 h

wer

e co

nsid

ered

to b

e ab

norm

al.

Supp

ress

ion

of se

rum

cor

tisol

<1.

8 µg

/dL

aft

er a

dmin

istr

atio

n of

1 m

g de

xam

etha

sone

was

the

cut-

off p

oint

for n

orm

al su

ppre

ssio

n.

The

sup

pres

sion

of t

he s

erum

cor

tisol

leve

ls fa

iled

in a

ll of

the

patie

nts.

R

ESU

LTS:

Mea

sure

d la

bora

tory

val

ues

wer

e as

fol

low

s: A

CT

H, m

edia

n le

vel 2

8 pg

/ml,

inte

rqua

rtile

ran

ge (

IQR

) 14

-59

pg/m

l; fa

stin

g gl

ucos

e, 1

00 (9

1-11

3) m

g/dL

; ins

ulin

, 15.

7 (7

.57-

24.4

5) m

U/m

l; fT

4, 1.

17 (1

.05-

1.4)

ng/

dL; T

SH, 1

.70

(0.9

1-2.

90) m

IU/L

; to

tal c

hole

ster

ol, 2

09 (

170.

5-25

0) m

g/dL

; LD

L-c

, 136

(97

.7-1

63)

mg/

dL; H

DL

-c, 4

4 (3

7.25

-50.

75)

mg/

dL; V

LD

L-c

, 24

(17-

36)

mg/

dL; t

rigl

ycer

ides

, 120

.5 (

86-1

65)

mg/

dL. T

he m

edia

n U

FC le

vel o

f th

e pa

tient

s w

as 3

0 µg

/24

h (I

QR

16-

103)

. Hig

h le

vels

of

UFC

(>1

00 µ

g/24

h)

wer

e re

cord

ed in

37

patie

nts

(24%

). C

ushi

ng’s

syn

drom

e w

as d

iagn

osed

in 1

4 of

the

150

patie

nts

(9.3

3%).

Etio

logi

c re

ason

s fo

r C

ushi

ng’s

syn

drom

e w

ere

pitu

itary

mic

road

enom

a (9

pat

ient

s),

adre

noco

rtic

al a

deno

ma

(3 p

atie

nts)

, an

d ad

reno

cort

ical

car

cino

ma

(1 p

atie

nt).

CO

NC

LU

SIO

N: A

sig

nific

ant p

ropo

rtio

n (9

.33%

) of p

atie

nts

with

sim

ple

obes

ity w

ere

foun

d to

hav

e C

ushi

ng’s

syn

drom

e. T

hese

fin

ding

s ar

gue

that

obe

se p

atie

nts

shou

ld b

e ro

utin

ely

scre

ened

for C

ushi

ng’s

syn

drom

e.

KE

YW

OR

DS:

Cus

hing

’s s

yndr

ome.

Obe

sity

. Scr

eeni

ng. C

ortis

ol. A

dren

ocor

ticor

ticot

ropi

c ho

rmon

e.

INT

RO

DU

CT

ION

Obe

sity

is

the

mos

t co

mm

on m

etab

olic

pro

blem

in

indu

stri

aliz

ed c

ount

ries

. In

the

USA

, 32

% o

f ad

ults

are

cl

assi

fied

as o

verw

eigh

t, an

d 22

.5%

of

thes

e in

divi

dual

s ar

e ob

ese.

1 B

oth

over

wei

ght

and

obes

e su

bjec

ts a

re a

t an

in

crea

sed

risk

for

car

diov

ascu

lar

dise

ases

,2 so

me

type

s of

ca

ncer

,3 di

abet

es4 ,

and

even

pre

mat

ure

deat

h.5

Obe

sity

is

ofte

n ac

com

pani

ed b

y ot

her

chro

nic

diso

rder

s in

clud

ing

hype

rten

sion

, ost

eoar

thri

tis, b

ile s

tone

s, a

nd d

yslip

idem

ia.6-

12

In a

dditi

on to

thes

e ph

ysic

al d

isor

ders

, obe

sity

is c

omm

only

as

soci

ated

with

psy

chol

ogic

al a

nd p

sych

o-so

cial

pro

blem

s.10

Obe

sity

can

coe

xist

wit

h di

vers

e ph

ysic

al d

isor

ders

, an

d ph

ysic

ians

sho

uld

firs

t fo

cus

on t

he d

iffe

rent

ial

diag

nosi

s of

pos

sibl

e un

derl

ying

dis

orde

rs b

efor

e in

itiat

ing

any

man

agem

ent

proc

edur

e. O

besi

ty i

s a

prom

inen

t fe

atur

e of

end

ocri

ne d

isea

ses

incl

udin

g hy

poth

yroi

dism

, in

suli

n-ex

cess

syn

drom

es,

poly

cyst

ic o

vary

syn

drom

e (P

CO

S),

hyp

ogon

adis

m,

hypo

thal

amic

dis

ease

/inj

ury,

gr

owth

hor

mon

e de

fici

ency

, le

ptin

def

icie

ncy

or l

epti

n re

cept

or d

efec

ts, p

seud

ohyp

opar

athy

roid

ism

, and

Cus

hing

’s

synd

rom

e (C

S).11

,12

Dia

gnos

is o

f C

S is

pri

mar

ily b

ased

on

the

sign

s an

d

11

CLINICS 2010;65(1):9-13 Screening Cushing’s Syndrome in Obesity Tiryakioglu O et al.

Table 2 - Laboratory findings in the study patients

Simple obesity

Cushing’s syndrome

p

ACTH (pg/ml) 25.7 [15-51]

35 [13.5-94.5]

0.43

Cortisol (µg/dL) 10.2 [7.8-14.8]

9.4 [8.1-13.5]

0.88

Glucose (mg/dL) 99 [91-113]

100 [93.5-114]

0.91

Insulin (mU/ml) 14.7 [7.4-24.2]

18.9 [14.9-28.5]

0.07

f T4 (ng/dL) 1.2 [1.07-1.4]

1.1 [1.04-1.63]

0.56

TSH (mIU/L) 1.64 [0.9-2.8]

1.78 [1.6-4.2]

0.25

Cholesterol (mg/dL) 203 [172-249]

238.5[178.-264]

0.24

LDL-c (mg/dL) 129 [97-159]

168 [122-168]

0.15

HDL-c (mg/dL) 44 [37.5-50.5]

46 [29-66]

0.72

VLDL-c (mg/dL) 24 [17-33]

38 [16.2-50]

0.2

Triglyceride (mg/dL) 120 [86-161]

208[89.8-251]

0.15

Urine cortisol (µg/24 h) 28 [15-92.5]

74 [27-133]

0.02

DMST cortisol (µg/dL) 0.88 [0.7-1.15]

3.35 [2.5-6.5]

< 0.0001

HOMA-R(mg/dl x mU/ml)

4.02[1.91-6.59]

4.66[4.38-9.08]

0.06

Values are medians and interquartile ranges.DMST: 1-mg dexamethasone suppression test

Table 3 - Etiologies of the 14 patients diagnosed with Cush-ing’s syndrome

N %

Pituitary adenoma 9 64.28

Surrenal cortex adenoma 3 21.42

Surrenal cortex carcinoma 1 7.15

Declined further evaluation 1 7.15

Figure 1 - Twenty-four-hour free cortisol levels in patients with Cushing’s syndrome and simple obesity

Figure 2 - The comparison of the 1-mg dexamethasone suppression test results for both groups

We compared the group of 14 obese patients with CS to the remaining group of 136 patients with simple obesity. There was no significant difference in levels of ACTH (p=0.43) or basal cortisol (p=0.88) between the CS group and the group of simple obese patients without CS. However, 24-h UFC excretion (Figure 1) and morning cortisol levels following administration of 1 mg DMS (Figure 2) were significantly more elevated in obese patients with CS than in simple obese patients without CS.

There were no significant differences between the groups

in mean values for serum lipids, glucose, BMI, systolic blood pressure, or waist-to-hip ratio. Diastolic pressure was higher in patients with CS (p=0.02). Although higher HOMA-R values were recorded in patients with CS (median, 4.66 mg/dL x mU/ml; IQR, 1.38-9.08) compared to simple obese patients (median, 4.02 mg/dL x mU/ml; IQR, 1.91-6.59), the difference between the two groups narrowly failed to achieve statistical significance (p=0.06).

DISCUSSION

Here, we report on 150 obese patients screened for CS. A diagnosis of CS was established in 14 patients (9.33%). This finding confirms the need to evaluate patients with simple obesity for CS despite the absence of other signs or symptoms of the disorder.

This conclusion is supported by several previous studies. Obesity is a frequent clinical sign of CS, and adipose tissues in CS patients typically have a central distribution. Obese patients with CS may live without any evident metabolic disorder associated with CS. However,

11



Simple obesity


p

ACTH (pg/ml) 25.7 [15-51]

35 [13.5-94.5]

0.43

Cortisol (µg/dL) 10.2 [7.8-14.8]

9.4 [8.1-13.5]

0.88


100 [93.5-114]

0.91

Insulin (mU/ml) 14.7 [7.4-24.2]

18.9 [14.9-28.5]

0.07

f T4 (ng/dL) 1.2 [1.07-1.4]

1.1 [1.04-1.63]

0.56

TSH (mIU/L) 1.64 [0.9-2.8]

1.78 [1.6-4.2]

0.25


238.5[178.-264]

0.24

LDL-c (mg/dL) 129 [97-159]

168 [122-168]

0.15

HDL-c (mg/dL) 44 [37.5-50.5]

46 [29-66]

0.72

VLDL-c (mg/dL) 24 [17-33]

38 [16.2-50]

0.2


208[89.8-251]

0.15


74 [27-133]

0.02


3.35 [2.5-6.5]

< 0.0001


4.02[1.91-6.59]

4.66[4.38-9.08]

0.06



N %










DISCUSSION



11



Simple obesity


p

ACTH (pg/ml) 25.7 [15-51]

35 [13.5-94.5]

0.43

Cortisol (µg/dL) 10.2 [7.8-14.8]

9.4 [8.1-13.5]

0.88


100 [93.5-114]

0.91

Insulin (mU/ml) 14.7 [7.4-24.2]

18.9 [14.9-28.5]

0.07

f T4 (ng/dL) 1.2 [1.07-1.4]

1.1 [1.04-1.63]

0.56

TSH (mIU/L) 1.64 [0.9-2.8]

1.78 [1.6-4.2]

0.25


238.5[178.-264]

0.24

LDL-c (mg/dL) 129 [97-159]

168 [122-168]

0.15

HDL-c (mg/dL) 44 [37.5-50.5]

46 [29-66]

0.72

VLDL-c (mg/dL) 24 [17-33]

38 [16.2-50]

0.2


208[89.8-251]

0.15


74 [27-133]

0.02


3.35 [2.5-6.5]

< 0.0001


4.02[1.91-6.59]

4.66[4.38-9.08]

0.06



N %










DISCUSSION



11



Simple obesity


p

ACTH (pg/ml) 25.7 [15-51]

35 [13.5-94.5]

0.43

Cortisol (µg/dL) 10.2 [7.8-14.8]

9.4 [8.1-13.5]

0.88


100 [93.5-114]

0.91

Insulin (mU/ml) 14.7 [7.4-24.2]

18.9 [14.9-28.5]

0.07

f T4 (ng/dL) 1.2 [1.07-1.4]

1.1 [1.04-1.63]

0.56

TSH (mIU/L) 1.64 [0.9-2.8]

1.78 [1.6-4.2]

0.25


238.5[178.-264]

0.24

LDL-c (mg/dL) 129 [97-159]

168 [122-168]

0.15

HDL-c (mg/dL) 44 [37.5-50.5]

46 [29-66]

0.72

VLDL-c (mg/dL) 24 [17-33]

38 [16.2-50]

0.2


208[89.8-251]

0.15


74 [27-133]

0.02


3.35 [2.5-6.5]

< 0.0001


4.02[1.91-6.59]

4.66[4.38-9.08]

0.06



N %










DISCUSSION



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INTRODUCTION





DSMZ 1 mg CLU

10

CLINICS 2010;65(1):9-13Screening Cushing’s Syndrome in Obesity Tiryakioglu O et al.

symptoms of the disorder. Nevertheless, a significant number of CS patients present only with simple obesity13-14 or with type 2 diabetes mellitus and poor glycemic control.15-17 Metabolic syndrome may also indicate the presence of CS. Patients without specific clinical features of CS have been referred to as sub-clinical Cushing’s syndrome (SCS)15 patients, and the diagnosis of SCS affords a considerable challenge to the physician.

We accordingly set out to determine the frequency of CS in patients presenting with simple obesity in the absence of other specific signs or symptoms indicative of CS.

PATIENTS AND METHODS

This study included 150 consecutive simple obese patients (129 female, 21 male, mean age: 44.41 ± 13.34 yr, body mass index (BMI) > 25 kg/m2) who were followed and treated at the Endocrinology Metabolism outpatient clinic at Cerrahpasa Medical Faculty between June 2003 and June 2004. Written informed consent was obtained from all patients before commencement of the study. Review of patient medical history was used to exclude subjects in which the dexamethasone suppression test could be biased either by medication (including exogenous glucocorticoid intake) or by other factors known to influence the test (including drug use, alcoholism, obvious depression, or pregnancy). None of the patients had nephropathy (creatinine clearance <30 ml/min), acute illness, or sleep disorders.

All patients in our study had simple obesity; none of them had diabetes mellitus. Since the patients had simple obesity, careful examinations did not reveal hirsutism, buffalo hump, easy bruising, or any other manifestations suggestive of CS suggestive manifestations.

Clinical characteristics recorded included BMI and anthropometric measurements. Morning blood samples following fasting (12 h) were drawn from an antecubital vein for determination of the concentrations of adrenocorticorticotropic hormone (ACTH) (N: 0-46 pg/ml), cortisol (N: 5-28 µg/dL), glucose, insulin (N: 0-20 µIU/L), serum lipids (total cholesterol, LDL, HDL, VLDL-cholesterol, and triglyceride), free thyroxin (fT4) (N: 0.93-1.77 ng/dL), and thyrotropin (TSH) (N: 0.15-3.7 IU/ml). Urine (24 h) was collected from each subject in order to perform urinary free cortisol (UFC) measurements. Patients whose 24-h UFC excretion exceeded 100µg/dL were defined as abnormal. All patients subsequently underwent a 1-mg overnight dexamethasone suppression test (DMS). Suppression of serum cortisol to <1.8 µg/dL after dexamethasone administration was the cut-off point for normal suppression without consideration of 24-h UFC. Measurement of serum ACTH levels and an 8-mg DMS

were performed as second-step investigations in all patients who failed to achieve serum cortisol suppression <1.8 µg/dL after administration of 1 mg DMS. Complementary imaging studies, magnetic resonance imaging (MRI) of the sella, cavernous sinus sampling, and abdominal computed tomography (CT) were performed when the results of the second-step evaluations were consistent with ACTH-dependent or ACT-independent CS.

Insulin, cortisol, fT4, TSH, and ACTH were assessed by radioimmunoassay (RIA) using a Packard Riastar gamma counter (Perkin-Elmer, Waltham, MA, USA) and commercial assay kits. Other biochemical laboratory tests were measured with an Olympus AU 600 autoanalyser (Olympus, Tokyo, Japan). Insulin resistance was assessed using the homeostasis model assessment ratio (HOMA-R) formula (18).

Calculations were done with SPSS software (version 10; SPSS Inc, Chicago, IL, USA), and differences in the values of the variables between the groups were evaluated by the Mann-Whitney U test. The degree of the correlation between parameters was evaluated by regression analysis. A value of p<0.05 was considered to be statistically significant.

RESULTS

We analyzed a series of patients presenting with simple obesity for the presence of sub-clinical CS. The clinical characteristics and laboratory findings for these patients are summarized in Tables 1 and 2.

In 37 patients (24%), 24-h UFC excretion exceeded the cut-off point (median, 30; interquartile range (IQR), 16-103 µg/24 h). Fourteen patients had unsuppressed cortisol levels as indicated by the 1-mg dexamethasone suppression test. Complementary imaging studies were performed on these 14 CS patients, which revealed pituitary microadenoma in 9 patients, adrenal adenoma in 3 patients, and adrenal carcinoma in 1 patient. Histological diagnosis was obtained in 13 patients; one patient declined to undergo surgical intervention for definitive diagnosis (Table 3).

Table 1 - Summary of physical examination findings in the patient group

(Mean ± SD) (n=150)

BMI (kg/m2) 35.76 ± 7.13

Waist (cm) 104.07 ± 15.77

Waist-to-hip ratio 0.98 ± 0.92

Systolic blood pressure (mm/Hg) 135.13 ± 20.49

Diastolic blood pressure (mm/Hg) 87.23 ± 13.03

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INTRODUCTION





150 sogge)

Hindawi Publishing CorporationISRN EndocrinologyVolume 2013, Article ID 321063, 4 pageshttp://dx.doi.org/10.1155/2013/321063

Clinical StudyRoutine Screening for Cushing’s Syndrome Is NotRequired in Patients Presenting with Obesity

Serap Baydur Sahin,1 Hacer Sezgin,2 Teslime Ayaz,3 Emine Uslu Gur,3 and Kadir Ilkkilic3

1 Department of Endocrinology and Metabolism Disease, Recep Tayyip Erdogan University Medical School, 53020 Rize, Turkey2Department of Family Medicine, Recep Tayyip Erdogan University Medical School, Rize, Turkey3Department of Internal Medicine, Recep Tayyip Erdogan University Medical School, Rize, Turkey

Correspondence should be addressed to Hacer Sezgin; [email protected]

Received 7May 2013; Accepted 2 June 2013

Academic Editors: C.-H. Anderwald, C. Bizzarri, C. N. Mowa, and G. F. Wagner

Copyright © 2013 Serap Baydur Sahin et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Background. Cushing’s syndrome (CS) is a relatively unusual condition that resembles many of the phenotypic features of obesity.Our aimwas to evaluate the frequency of CS in obese patients.Materials andMethods.This study included 354 consecutive patients(87.9% female, age 37.8 ± 13.4 years) who presented with simple obesity. All the patients were evaluated for the clinical signs of CS.Lipid parameters, fasting glucose (FPG) and insulin, 75 gr oral glucose tolerance test, basal cortisol and ACTHweremeasured. 1mgovernight DST was performed. Results.The mean weight of the patients was 102.4 ± 20.1 kg and BMI 40 ± 7.35 kg/m2. 34.5% of thepatients were hypertensive. 36.2% of the patients had central obesity, 72% dorsocervical fat accumulation, 28.8% abdominal striaeand 23.2% acne. 49.4% of the women had hirsutism. 46.5% had prediabetes and 12.0% had type 2 diabetes, 72.6% had dyslipidemia.The mean cortisol and ACTH levels were as follows: 9.28 ± 3.53 !g/dL and 17.02 ± 10.43 pg/mL. Seven patients failed to suppressplasma cortisol to less than 1.8 !g/dL. Biochemical confirmation testswere performed in these patients and 2of themwere diagnosedglucocorticoid-secreting adrenal adenoma. Conclusions. Routine screening for CS in obese patients is not required.

1. Introduction

Cushing’s syndrome (CS) is considered a contributing factorto the development of obesity. On the other hand, obesityitself might share the symptoms and signs of CS such as hir-sutism, menstrual abnormalities, acne, dorsocervical fat pad(buffalo hump), supraclavicular fullness, glucose intolerance,and hypertension. Physicians may be called upon to excludeCS in obese patients, who are increasingly present in the gen-eral population. Early recognition of CS can reduce the mor-bidity and mortality [1].

The diagnosis of CS is often a challenge for clinicians dueto the variable pattern and the nonspecificity of clinical man-ifestations.The diagnosis can be difficult particularly in statesof mild or cyclical or periodical hypercortisolism [2–4]. Thesuspicion of CS arises in the presence of concomitant recentweight gain, impaired glucose tolerance, and high blood pres-sure [3]. Several studies reported a 1–5% prevalence of unsus-pected CS in patients with poorly controlled type 2 diabetes

and/or hypertension [5–8]. However, there are only few stud-ies on the prevalence of CS in obese patients [9–13].We there-fore aimed to evaluate the frequency of CS in patients whopresent with obesity.

The 1mg overnight dexamethasone-suppression test(DST) is the most frequently used screening tool for CS [14].Because it is easy to perform and has low cost it is used as afirst-line screening test in outpatient screening. However, thelack of suppression after 1mg overnight DST may be seen in2–8%of the obese individuals [10, 11, 14]. Our second aimwasto reevaluate the validity of the 1mg overnight dexametha-sone suppression test as a CS screening test in obese patients.

2. Patients and Methods

This study included 354 consecutive patients with a bodymass index (BMI) >30 kg/m2 who were admitted to ourendocrine outpatient because of simple obesity betweenNovember 2012 and May 2013. Patients were excluded from

Hindawi Publishing CorporationISRN EndocrinologyVolume 2013, Article ID 321063, 4 pageshttp://dx.doi.org/10.1155/2013/321063

Clinical StudyRoutine Screening for Cushing’s Syndrome Is NotRequired in Patients Presenting with Obesity

Serap Baydur Sahin,1 Hacer Sezgin,2 Teslime Ayaz,3 Emine Uslu Gur,3 and Kadir Ilkkilic3

1 Department of Endocrinology and Metabolism Disease, Recep Tayyip Erdogan University Medical School, 53020 Rize, Turkey2Department of Family Medicine, Recep Tayyip Erdogan University Medical School, Rize, Turkey3Department of Internal Medicine, Recep Tayyip Erdogan University Medical School, Rize, Turkey

Correspondence should be addressed to Hacer Sezgin; [email protected]

Received 7May 2013; Accepted 2 June 2013

Academic Editors: C.-H. Anderwald, C. Bizzarri, C. N. Mowa, and G. F. Wagner

Copyright © 2013 Serap Baydur Sahin et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Background. Cushing’s syndrome (CS) is a relatively unusual condition that resembles many of the phenotypic features of obesity.Our aimwas to evaluate the frequency of CS in obese patients.Materials andMethods.This study included 354 consecutive patients(87.9% female, age 37.8 ± 13.4 years) who presented with simple obesity. All the patients were evaluated for the clinical signs of CS.Lipid parameters, fasting glucose (FPG) and insulin, 75 gr oral glucose tolerance test, basal cortisol and ACTHweremeasured. 1mgovernight DST was performed. Results.The mean weight of the patients was 102.4 ± 20.1 kg and BMI 40 ± 7.35 kg/m2. 34.5% of thepatients were hypertensive. 36.2% of the patients had central obesity, 72% dorsocervical fat accumulation, 28.8% abdominal striaeand 23.2% acne. 49.4% of the women had hirsutism. 46.5% had prediabetes and 12.0% had type 2 diabetes, 72.6% had dyslipidemia.The mean cortisol and ACTH levels were as follows: 9.28 ± 3.53 !g/dL and 17.02 ± 10.43 pg/mL. Seven patients failed to suppressplasma cortisol to less than 1.8 !g/dL. Biochemical confirmation testswere performed in these patients and 2of themwere diagnosedglucocorticoid-secreting adrenal adenoma. Conclusions. Routine screening for CS in obese patients is not required.

1. Introduction

Cushing’s syndrome (CS) is considered a contributing factorto the development of obesity. On the other hand, obesityitself might share the symptoms and signs of CS such as hir-sutism, menstrual abnormalities, acne, dorsocervical fat pad(buffalo hump), supraclavicular fullness, glucose intolerance,and hypertension. Physicians may be called upon to excludeCS in obese patients, who are increasingly present in the gen-eral population. Early recognition of CS can reduce the mor-bidity and mortality [1].

The diagnosis of CS is often a challenge for clinicians dueto the variable pattern and the nonspecificity of clinical man-ifestations.The diagnosis can be difficult particularly in statesof mild or cyclical or periodical hypercortisolism [2–4]. Thesuspicion of CS arises in the presence of concomitant recentweight gain, impaired glucose tolerance, and high blood pres-sure [3]. Several studies reported a 1–5% prevalence of unsus-pected CS in patients with poorly controlled type 2 diabetes

and/or hypertension [5–8]. However, there are only few stud-ies on the prevalence of CS in obese patients [9–13].We there-fore aimed to evaluate the frequency of CS in patients whopresent with obesity.

The 1mg overnight dexamethasone-suppression test(DST) is the most frequently used screening tool for CS [14].Because it is easy to perform and has low cost it is used as afirst-line screening test in outpatient screening. However, thelack of suppression after 1mg overnight DST may be seen in2–8%of the obese individuals [10, 11, 14]. Our second aimwasto reevaluate the validity of the 1mg overnight dexametha-sone suppression test as a CS screening test in obese patients.

2. Patients and Methods

This study included 354 consecutive patients with a bodymass index (BMI) >30 kg/m2 who were admitted to ourendocrine outpatient because of simple obesity betweenNovember 2012 and May 2013. Patients were excluded from

N° Sogge) 354 Test DST 1 mg (> 1,8 mcg/dl) 7 (2%) Test DST 2 mg in 2 gg (> 1,8 mcg/dl) 2 (0,6%) Nei 2 sogge): -‐ UFC nella norma -‐ ACTH < 5 pg/ml -‐ “elevated midnight CorPsol”

DIAGNOSI: Adenoma Surrenalico

ISRN Endocrinology 3

24-hour urinary free cortisol levels were in normal range.One of the patients was a 39-year-old woman and physicalexamination revealed central obesity (BMI = 40 kg/m2), abuffalo hump, moon facies, and supraclavicular fullness. Shehad no muscle weakness, no facial plethora, and abdominalstriae. She had menstrual irregularities and prediabetes.Computed tomography (CT) scanning of the adrenals identi-fied the cortical adenomameasuring 38mmon the right side.She underwent a right laparoscopic adrenalectomy.The otherpatient was a 76-year-old, postmenopausal woman who hadcentral obesity (BMI = 35 kg/m2), a 15-year history of type2 diabetes mellitus, and a 20-year history of hypertension.The patient was being treated with insulin (glycosylatedhemoglobin [HbA1c] was 7%), and her hypertension wasbeing controlled with an angiotensin-converting enzymeinhibitor. Computed tomography (CT) scan of the abdomendetected a low-density adrenal mass measuring 3 cm on theright side. She declined to undergo surgical intervention.

4. Discussion

Among 354 people who were obese, two patients (0.5%) werediagnosed with Cushing’s syndrome. The false positive ratefor the 1mg overnight dexamethasone-suppression test was1.4%, even when using a cut-off serum cortisol of 1.8!g/dL.

The suspicion of CS depends largely on individual clinicaljudgment and personal practice. The patients do not alwayspresent a clear Cushing phenotype. They can have only themild signs of hypercortisolism, such as facial fullness and cen-tral obesity. It may be difficult to decide whether these signsmay be attributable to an underlying occult hypercortisolismor are manifestations of the obesity. In our study, the symp-toms or signs for CS, such as facial fullness, dorsocervical fataccumulation, and hirsutism were present in a major propor-tion of the population.

Screening for Cushing’s syndrome is recommended inpatients with multiple and progressive clinical features (facialplethora, easy bruising, striae, and proximal myopathy),patients with unusual features for age (e.g., osteoporosis,hypertension, and type 2 diabetes), and patients with adrenalincidentaloma by the Endocrine Society guidelines [16].Early recognition of patients with CS, particularly those withmilder forms, is important to prevent the long-term physicalconsequences and increased mortality that may occur whenthe disease is left untreated [17]. Therefore we screened theobese patients for CS who have not a clear Cushing pheno-type. In our study population, which includesmorbidly obesepatients in major proportion, mean age of the patients wasyoung and also the prevalence of glucose intolerance and hy-pertension was high.

The reported prevalence of CS among the obese patientsvaries widely between the different studies, ranging from0.6% to 9.4% [10, 11, 13, 14].This heterogeneity may be due tothe different inclusion criteria as well as the different cut-offvalues to define cortisol suppression after the 1mgDST. Jank-ovic et al. screened 433 morbidly obese patients and foundthe prevalence of CS below 0.6% [13]. They used the 1mg-DST for screening CS, but defined the cut-off value as 3 !g/dL

differently from our study. In the other three studies, CS wasscreened in a small number of patients [10, 11, 14]. Tiryakiogluet al. demonstrated a high prevalence of CS in the obese pop-ulation despite the absence of other signs or symptoms of thedisorder (9.4%). The cutoff value for the 1mg DST was1.8 !g/dL [10].

Some studies evaluated the prevalence of occult CS inoverweight and obese patients with uncontrolled diabetesand it was found to be 0–9.4% indifferent studies [5, 15, 18, 19].In all the studies, the first screening step was performed withthe 1mgDST, but the cutoff values for the suppression of cor-tisol were different (from 1.8 to 5!g/dL).

The 1mg overnight dexamethasone suppression test isproved to be a simple, sensitive, and highly specific screeningtest for Cushing’s syndrome. Serum cortisol after overnight1mgDST above 50 nmol/L (18 ng/mL or 1.8mg/dL) is consid-ered to be suggestive of Cushing’s syndrome [16]. 24 h urinecortisol, 1mgovernightDST andmidnight cortisol, and com-bined strategies based on these tests have similar accuracy [16,20]. 2mg 48 h dexamethasone suppression test is considereda second-line test because it is not often simple to carry out inan outpatient [16].

The lack of suppression after 1mg overnight DST may beseen in the obese individuals.The ratio of false positive 1mgDST results in obese populationwas as follows in the differentstudies: 8%[11] and 2.3%[12]. In our study, this ratiowas 1.4%.Our results suggest that even in the obese population, 1mgovernight DST is a sensitive and specific screening test forCushing’s syndrome.

In conclusion, the present data do not supportwidespreadscreening of obese patients for Cushing’s syndrome. Wesuggest that examination for hypercortisolism should only beperformed in obese patients with a cushingoid appearanceand hypertension or glucose intolerance or dyslipidaemia.

References

[1] J. Etxabe and J. A. Vazquez, “Morbidity and mortality in Cush-ing’s disease: an epidemiological approach,”Clinical Endocrinol-ogy, vol. 40, no. 4, pp. 479–484, 1994.

[2] A. B. Atkinson, D. R. McCance, L. Kennedy, and B. Sheridan,“Cyclical Cushing’s syndrome first diagnosed after pituitary sur-gery: a trap for the unwary,” Clinical Endocrinology, vol. 36, no.3, pp. 297–300, 1992.

[3] G. Arnaldi, T. Mancini, B. Kola et al., “Cyclical Cushing’s syn-drome in a patientwith a bronchial neuroendocrine tumor (typ-ical carcinoid) expressing ghrelin and growth hormone secret-agogue receptors,” Journal of Clinical Endocrinology andMetab-olism, vol. 88, no. 12, pp. 5834–5840, 2003.

[4] D. F. Gunther, I. Bourdeau, L. Matyakhina et al., “Cyclical cush-ing syndrome presenting in infancy: an early form of primarypigmented nodular adrenocortical disease, or a new entity?”Journal of Clinical Endocrinology and Metabolism, vol. 89, no.7, pp. 3173–3182, 2004.

[5] B. Catargi, V. Rigalleau, A. Poussin et al., “Occult Cushing’s syn-drome in type-2 diabetes,” Journal of Clinical Endocrinology andMetabolism, vol. 88, no. 12, pp. 5808–5813, 2003.

[6] G. Reimondo, A. Pia, B. Allasino et al., “Screening of Cushing’ssyndrome in adult patients with newly diagnosed diabetes mel-litus,” Clinical Endocrinology, vol. 67, no. 2, pp. 225–229, 2007.

Screening of Cushing’s Syndrome in Outpatients withType 2 Diabetes: Results of a Prospective MulticentricStudy in Italy

Massimo Terzolo, Giuseppe Reimondo, Iacopo Chiodini, Roberto Castello,Roberta Giordano, Enrica Ciccarelli, Paolo Limone, Claudio Crivellaro,Irma Martinelli, Marcella Montini, Olga Disoteo, Bruno Ambrosi, Roberto Lanzi,Maura Arosio, Sanzio Senni, Antonio Balestrieri, Erica Solaroli, Bruno Madeo,Raffaella De Giovanni, Felice Strollo, Rodolfo Battista, Alessandro Scorsone,Vito A. Giagulli, Daniela Collura, Aldo Scillitani, Renato Cozzi,Marco Faustini-Fustini, Anna Pia, Roberta Rinaldi, Barbara Allasino, Giulia Peraga,Francesco Tassone, Piernicola Garofalo, Enrico Papini, and Giorgio Borretta*

Context: Cushing’s syndrome may remain unrecognized among patients referred for metabolicsyndrome; thus, a proactive screening has been suggested in certain patient populations withfeatures of the disorder. However, conflicting data have been reported on the prevalence ofCushing’s syndrome in patients with type 2 diabetes.

Objective: Our aim was to evaluate the prevalence of unsuspected Cushing’s syndrome amongoutpatients with type 2 diabetes.

Design and Setting: This was a cross-sectional prospective study in 24 diabetes clinics across Italy.

Patients: Between June 2006 and April 2008, 813 patients with known type 2 diabetes withoutclinically overt hypercortisolism were evaluated. Follow-up of the study was closed in September2010. Patients were not selected for characteristics conferring a higher pretest probability ofhypercortisolism. Patients underwent a first screening step with the 1-mg overnight dexametha-sone suppression test.

Results: Forty patients failed to suppress serum cortisol less than 5.0 !g/dl (138 nmol/liter) andunderwent a standard 2-d, 2-mg dexamethasone suppression test, after which six patients (0.6%of the overall series) failed to suppress cortisol less than 1.8 !g/dl (50 nmol/liter), receiving adefinitive diagnosis of Cushing’s syndrome that was adrenal dependent in five patients. Fourpatients were cured, being able to discontinue, or reduce, the glucose-lowering agents.

Conclusions: The present data do not support widespread screening of patients with type 2 dia-betes for Cushing’s syndrome; however, the disorder is less rare than previously thought whenconsidering epidemiology of type 2 diabetes. Our results support a case-finding approach in pa-tients with uncontrolled diabetes and hypertension despite appropriate treatment. (J Clin Endo-crinol Metab 97: 3467–3475, 2012)

Subtle clinical presentations of Cushing’s syndrome,characterized by a paucity of signs and symptoms

due to mild cortisol hypersecretion, are increasinglyfound in clinical practice. In parallel, the metabolicsyndrome epidemic is leading to a boost in the numberof patients with a Cushingoid phenotype, who could

be potentially candidate to be tested for hypercortiso-lism (1).

The Endocrine Society guidelines for the diagnosis ofCushing’s syndrome recommended against widespreadtesting for the condition, unless in patients with unusualfeatures for age or multiple and progressive features, par-

ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright © 2012 by The Endocrine Societydoi: 10.1210/jc.2012-1323 Received February 5, 2012. Accepted June 18, 2012.First Published Online July 5, 2012

*Author affiliations are shown at the bottom of the next pageAbbreviations: BMI, Body mass index; CT, computerized tomography; DST, dexametha-sone suppression test; HbA1c, glycosylated hemoglobin; HPA, hypothalamus-pituitary-adrenal; MRI, magnetic resonance imaging.

O R I G I N A L A R T I C L E

E n d o c r i n e C a r e

J Clin Endocrinol Metab, October 2012, 97(10):3467–3475 jcem.endojournals.org 3467

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 March 2014. at 05:28 For personal use only. No other uses without permission. . All rights reserved.

small numbers, we cannot definitively prove thatscreening of Cushing’s syndrome results in a more fa-vorable outcome of the patients who were diagnosedwith the condition. However, it is noteworthy that allthe treated patients were able to discontinue, or reduce,medications for diabetes after remission of hypercorti-solism despite that hypercortisolism was rather mildcompared with that usually observed in patients withadrenal-dependent Cushing. Weight loss after surgerywas key to the improved patient outcome.

In conclusion, the results of the present study do notsupport the application of a wide-scale screening of Cush-ing’s syndrome in patients with type 2 diabetes, unlessmore efficient screening procedures will become available.The frequency of Cushing’s syndrome in an unselectedpatient population was low compared with the number offalse-positive results to make a routine screening strategyapplicable in practice.

Considering the epidemic of type 2 diabetes in the West-ern world, however, the present data suggest that Cushing’ssyndrome is less rare than previously thought (although notfrequent enough to warrant systematic screening). This isplausible because the available epidemiological data tookinto account only diagnoses made in hospitalized patients,thus considering only the most severe and clinically obviouscases (31–34).

Our results may influence clinical practice supporting acase-finding approach in patients selected for uncon-trolled diabetes despite appropriate treatment and resis-tant hypertension. The frequency of definitive Cushing’ssyndrome was indeed of 5.1% among patients withHbA1c greater than 9.0% despite intensive treatment andthe levels of blood pressure not at target despite threedrugs. A diagnosis of type 2 diabetes younger than 50 yrof age is another factor that should raise suspicion, recall-ing the value of features unusual for age to suspect Cushing(2) because type 2 diabetes usually occurs in older patients(35), although age at diagnosis of type 2 diabetes is shiftingamong a younger population (36). In addition, the lack offamily history of diabetes, which was absent in our pa-tients with definitive Cushing, should be considered toselect patients for screening. However, we should ac-knowledge the limit of the small number of patients withdefinitive Cushing to provide clear-cut recommendations.Moreover, we know from the literature that a concomi-tant presence of one or more features among central obe-sity, osteoporosis, or polycystic ovary syndrome furtherincreases the probability of the condition and may promptappropriate work-up (1, 2, 23).

The patients found to have occult Cushing’s syndromeshould be referred to endocrinologists with specific ex-pertise to ensure a prompt treatment of the condition that

may have a beneficial impact on health outcomes. It ispertinent to consider the fact that adrenal adenoma is theleading cause of occult Cushing’s syndrome and the factthat laparoscopic adrenalectomy has become a safe andrelatively inexpensive procedure, causing limited discom-fort to the patient (29, 30, 37), and makes the search forthe condition more attractive. Because patients with occultCushing’s syndrome have a milder clinical phenotype,physicians involved in the management of diabetes shouldraise their level of awareness for the condition. The knowl-edge and experience of the physician is key in this context;thus, the present data suggest that a specific educationalpolicy may lead to an improved care of patients with type2 diabetes.

Acknowledgments

The funding source had no role in the design and conduct of thestudy, collection, management, analysis, and interpretation ofthe data; and preparation, review, or approval of the manuscript.All of the authors had full access to all of the data in the study andtake responsibility for the integrity of the data and the accuracyof the data analysis.

Address all correspondence and requests for reprints to: M.Terzolo, M.D., Medicina Interna I, Azienda Ospedaliera Uni-versitaria San Luigi Gonzaga, Regione Gonzole, 10, 10043Orbassano, Italy. E-mail: [email protected].

This work was supported by a grant from the Piedmont Re-gion, “Progetti di Ricerca Sanitaria Finalizzata-Bando 2008.”

Disclosure Summary: None of the authors has any financialrelationship relevant to the present work.

References

1. Raff H, Findling JW 2003 A physiologic approach to diagnosis of theCushing syndrome. Ann Intern Med 138:980–991

2. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO,Stewart PM, Montori VM 2008 The diagnosis of Cushing’s syn-drome: an Endocrine Society clinical practice guideline. J Clin En-docrinol Metab 93:1526–1540

3. Leibowitz G, Tsur A, Chayen SD, Salameh M, Raz I, Cesari E, GrossDJ 1996 Pre-clinical Cushing’s syndrome: an unexpected frequentcause of poor glycaemic control in obese diabetic patients. Clin En-docrinol 44:717–722

4. Catargi B, Rigalleau V, Poussin A, Ronci-Chaix N, Bex V, VergnotV, Gin H, Roger P, Tabarin A 2003 Occult Cushing’s syndrome intype-2 diabetes. J Clin Endocrinol Metab 88:5808–5813

5. Chiodini I, Torlontano M, Scillitani A, Arosio M, Bacci S, Di LemboS, Epaminonda P, Augello G, Enrini R, Ambrosi B, Adda G, Tris-chitta V 2005 Association of subclinical hypercortisolism with type2 diabetes mellitus: a case-control study in hospitalized patients. EurJ Endocrinol 153:837–844

6. Boscaro M, Barzon L, Fallo F, Sonino N 2001 Cushing’s syndrome.Lancet 357:783–791

7. Chiodini I 2011 Clinical review: diagnosis and treatment of sub-clinical hypercortisolism. J Clin Endocrinol Metab 96:1223–1236

8. Bray GA 2001 An approach to the classification and evaluation of

3474 Terzolo et al. Cushing’s Syndrome and Type 2 Diabetes J Clin Endocrinol Metab, October 2012, 97(10):3467–3475


Materials and protocolsThe study flow chart is outlined in Fig. 1. All subjects under-

went in an outpatient setting a first screening step by using theovernight 1-mg dexamethasone suppression test (DST) (1 mgdexamethasone administered orally at 2300 h and blood sampledrawing on the following morning at 0800 h for determinationof serum cortisol concentration. Patients who failed to suppressserum cortisol less than 5.0 !g/dl (138 nmol/liter) were offereda second-step evaluation by undergoing a standard 2-d, 2-mgDST 3–6 months after baseline evaluation (0.5 mg dexametha-sone administered orally at 0600, 1200, 1800, and 2400 h andblood sample drawing on the following morning at 0800 h forcortisol determination). A cortisol concentration greaterthan 1.8 !g/dl (50 nmol/liter) was considered abnormal andprompted further evaluation to confirm diagnosis of Cushing’ssyndrome and determine its cause according to a standardizedprotocol (11). Briefly, evaluation should include three 24-h urinecollections for urinary free cortisol measurement and blooddrawing at 0800 h for the determination of plasma ACTH con-centration. An ACTH concentration should provide guidancefor radiological evaluation [pituitary magnetic resonance imag-

ing (MRI) or adrenal computerized tomography (CT)]; in doubt-ful cases, with ACTH concentration between 10 and 20 pg/ml(2.2 and 4.4 pmol/liter), the CRH stimulation test should beperformed to ascertain ACTH dependency (12). Specific treat-ment was pursued in the patients with a definitive diagnosis ofCushing’s syndrome who were followed up for at least 24months after surgery. The hormonal variables were determinedin a single reference laboratory for each participating center us-ing commercially available reagents.

Statistical analysisSample size analysis was done based on the results of previous

studies. It was calculated that approximately 381 patients shouldbe studied to provide an 80% chance (beta) of detecting a prev-alence rate of Cushing’s syndrome of 1%, taking 0.05 as the levelof significance (alpha). Rates and proportions were calculatedfor categorical data and means and SD for continuous data. Nor-mality of data was assessed by the Kolmogorov-Smirnov test. Forcontinuous variables, differences were analyzed by means of thetwo-tailed Student’s t test when data were normally distributed

FIG. 1. Flow-chart of the study.



0,7 %

5 %

Long-Term Follow-Up in Adrenal Incidentalomas: AnItalian Multicenter Study

Valentina Morelli, Giuseppe Reimondo, Roberta Giordano, Silvia Della Casa,Caterina Policola, Serena Palmieri, Antonio S. Salcuni, Alessia Dolci,Marco Mendola, Maura Arosio, Bruno Ambrosi, Alfredo Scillitani, Ezio Ghigo,Paolo Beck-Peccoz, Massimo Terzolo, and Iacopo Chiodini

Department of Clinical Sciences and Community Health (V.M., S.P., A.D., M.A., P.B.-P., I.C.), Universityof Milan, 20122 Milan, Italy; Unit of Endocrinology and Diabetology (V.M., S.P., P.B.-P., I.C.),Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, 20122 Milan, Italy; Division of InternalMedicine I (G.R., M.T.), Ospedale San Luigi, 10043 Orbassano, Italy; Department of Biological andClinical Sciences (G.R., R.G., M.T.), University of Turin, 10124 Turin, Italy; Catholic University (S.D.C.,C.P.), Unit of Endocrinology and Metabolism, 00168 Rome, Italy; Unit of Endocrinology (A.S.S., A.S.),Ospedale “Casa Sollievo della Sofferenza,” IRCCS, 71013 San Giovanni Rotondo, Foggia, Italy; Unit ofEndocrine Diseases and Diabetology (A.D., M.A.), Ospedale San Giuseppe, Gruppo Multimedica, 20123Milan, Italy; Department of Biomedical Sciences for Health (M.M., B.A.), University of Milan, Unit ofEndocrinology and Diabetology, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Milan, Italy;and Division of Endocrinology, Diabetology, and Metabolism (E.G.), Department of Medical Sciences,University of Turin, 10124 Turin, Italy

Context: The long-term consequences of subclinical hypercortisolism (SH) in patients with adrenalincidentalomas (AIs) are unknown.

Setting and Patients: In this retrospective multicentric study, 206 AI patients with a !5-year fol-low-up (median, 72.3 mo; range, 60–186 mo) were enrolled.

Intervention and Main Outcome Measures: Adrenocortical function, adenoma size, metabolicchanges, and incident cardiovascular events (CVEs) were assessed. We diagnosed SH in 11.6% ofpatients in the presence of cortisol after a 1 mg-dexamethasone suppression test !5 "g/dL (138nmol/L) or at least two of the following: low ACTH, increased urinary free cortisol, and 1 mg-dexamethasone suppression test !3 "g/dL (83 nmol/L).

Results: At baseline, age and the prevalence of CVEs and type 2 diabetes mellitus were higher inpatients with SH than in patients without SH (62.2 " 11 y vs 58.5 " 10 y; 20.5 vs 6%; and 33.3 vs16.8%, respectively; P # .05). SH and type 2 diabetes mellitus were associated with prevalent CVEs(odds ratio [OR], 3.1; 95% confidence interval [CI], 1.1–9.0; and OR, 2.0; 95% CI, 1.2–3.3, respec-tively), regardless of age. At the end of the follow-up, SH was diagnosed in 15 patients who werewithout SH at baseline. An adenoma size !2.4 cm was associated with the risk of developing SH(sensitivity, 73.3%; specificity, 60.5%; P $ .014). Weight, glycemic, lipidic, and blood pressurecontrol worsened in 26, 25, 13, and 34% of patients, respectively. A new CVE occurred in 22 patients.SH was associated with the worsening of at least two metabolic parameters (OR, 3.32; 95% CI,1.6–6.9) and with incident CVEs (OR, 2.7; 95% CI, 1.0–7.1), regardless of age and follow-up.

Conclusion: SH is associated with the risk of incident CVEs. Besides the clinical follow-up, in patientswith an AI !2.4 cm, a long-term biochemical follow-up is also required because of the risk of SHdevelopment. (J Clin Endocrinol Metab 99: 827–834, 2014)

ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright © 2014 by the Endocrine SocietyReceived September 18, 2013. Accepted December 18, 2013.First Published Online January 7, 2014

Abbreviations: AH, arterial hypertension; AI, adrenal incidentaloma; BMI, body mass index;CI, confidence interval; CT, computed tomography; CVE, cardiovascular event; DL, dys-lipidemia; 1 mg-DST, 1 mg-dexamethasone suppression test; HPA, hypothalamic-pituitary-adrenal; LDL, low-density lipoprotein; OB, obesity; OR, odds ratio; ROC, receiver operatingcharacteristic; SH, subclinical hypercortisolism; SN, sensitivity; SP, specificity; T2DM, type2 diabetes mellitus; UFC, urinary free cortisol; ULN, upper limit of normal.



doi: 10.1210/jc.2013-3527 J Clin Endocrinol Metab, March 2014, 99(3):827–834 jcem.endojournals.org 827

The Endocrine Society. Downloaded from press.endocrine.org by [Lino Furlani] on 16 March 2014. at 12:54 For personal use only. No other uses without permission. . All rights reserved.





























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Risultati simili emergono da un recente studio longitudinale di Di Dalmazi et al su 198 pazienti con AI con un follow-up medio di 7.5 anni, che mostra un peggioramento della funzione surrenalica nel 12% dei pazienti durante il follow-up e un aumento del rischio di sviluppo di nuovi eventi cardiovascolari nei pazienti con IS (stabile o peggiorato) rispetto a quelli senza IS stabili nel tempo (HR 3.01, IC95% 1.04-8.7). Inoltre nei pazienti con IS stabile viene riportato un aumento della mortalità per tutte le cause, associata all’età (HR 1.06, IC95% 1.01-1.12, p = 0.06), e ai livelli di cortisolemia dopo 1mg-DST (HR 1.10, IC95% 1.01-1.19, p = 0.04) e una minor sopravvivenza per eventi cardiovascolari (78.4% vs 97.5%, p = 0.02), rispetto ai pazienti senza IS. Non è stata osservata alcuna differenza per mortalità da neoplasia maligna. In conclusione: a. l’IS espone il paziente con AI al rischio di sviluppare nuovi ECV e di aumentata mortalità. Questi fattori

sembrano associati ai livelli di cortisolemia dopo 1mg-DST; b. i pazienti con un adenoma > 2.4 cm mostrano un rischio maggiore di sviluppare IS, per cui è necessario

eseguire oltre al follow-up clinico, atto a valutare la comparsa di fattori di rischio cardiovascolare come DMT2 e ipertensione arteriosa, anche un follow-up biochimico di lunga durata.

Bibliografia 1. Morelli V, Reimondo G, Giordano R, et al. Long-term follow-up in adrenal incidentalomas: an Italian

Multicenter Study. J Clin Endocrinol Metab 2014, DOI: http://dx.doi.org/10.1210/jc.2013-3527. 2. Di Dalmazi G, Vicennati V, Garelli S, et al. Cardiovascular events and mortality in patients with adrenal

incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing's syndrome: a 15-year retrospective study. Lancet Diabetes Endocrinol 2014, doi: 10.1016/S2213-8587(13)70211-0.

3. Reimondo G. Incidentaloma surrenalico e ipercortisolismo subclinico. Endowiki.

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SUMMARY OF RECOMMENDATIONS

3.0. DIAGNOSIS OF CUSHING’S SYNDROME

Who should be tested3.1. We recommend obtaining a thorough drug history toexclude excessive exogenous glucocorticoid exposure leadingto iatrogenic Cushing’s syndrome before conductingbiochemical testing (1| ).

3.2. We recommend testing for Cushing’s syndrome in thefollowing groups:• Patients with unusual features for age (e.g. osteoporosis,

hypertension) (Table 1) (1| )• Patients with multiple and progressive features,

particularly those who are more predictive of Cushing’ssyndrome (Table 1) (1| )

• Children with decreasing height percentile and increasingweight (1| )

• Patients with adrenal incidentaloma compatible withadenoma (1| ).

3.3. We recommend against widespread testing for Cushing’ssyndrome in any other patient group (1| ).

Initial testing3.4. For the initial testing for Cushing’s syndrome, werecommend one of the following tests based on its suitabilityfor a given patient (Fig. 1) (1| ):

3.4.1. Urine free cortisol (UFC; at least two measurements)3.4.2. Late-night salivary cortisol (two measurements)3.4.3. 1-mg overnight dexamethasone suppression test

(DST)3.4.4. Longer low-dose DST (2 mg/d for 48 h)

3.5. We recommend against the use of the following to test forCushing’s syndrome (1| ):• Random serum cortisol or plasma ACTH levels• Urinary 17-ketosteroids• Insulin tolerance test• Loperamide test• Tests designed to determine the cause of Cushing’s

syndrome (e.g. pituitary and adrenal imaging, 8 mg DST).

3.6. In individuals with normal test results in whom thepretest probability is high (patients with clinical featuressuggestive of Cushing’s syndrome and adrenal incidentalomaor suspected cyclic hypercortisolism), we recommend furtherevaluation by an endocrinologist to confirm or exclude thediagnosis (1| ).

3.7. In other individuals with normal test results (in whomCushing’s syndrome is very unlikely), we suggest reevaluationin 6 months if signs or symptoms progress (2| ).

3.8. In individuals with at least one abnormal test result (forwhom the results could be falsely positive or indicateCushing’s syndrome), we recommend further evaluation by anendocrinologist to confirm or exclude the diagnosis(1| ).

Subsequent evaluation3.9. For the subsequent evaluation of abnormal initial testresults, we recommend performing another recommended test(Fig. 1, 1| ).

3.9.1. We suggest the additional use of the dexamethasone-CRH test or the midnight serum cortisol test in specificsituations (Fig. 1, 1| ).

3.9.2. We suggest against the use of the desmopressintest, except in research studies, until additional data validateits utility (2| ).

3.9.3. We recommend against any further testing forCushing’s syndrome in individuals with concordantly negativeresults on two different tests (except in patients suspected ofhaving the very rare case of cyclical disease) (1| ).

3.9.4. We recommend tests to establish the cause ofCushing’s syndrome in patients with concordantly positiveresults from two different tests, provided there is no concernregarding possible non-Cushing’s hypercortisolism (Table 2)(1| ).

3.9.5. We suggest further evaluation and follow-up forthe few patients with concordantly negative results who aresuspected of having cyclical disease and also for patients withdiscordant results, especially if the pretest probability ofCushing’s syndrome is high (2| ).

4.0. SPECIAL POPULATIONS/CONSIDERATIONS

4.1. Pregnancy: We recommend the use of UFC and againstthe use of dexamethasone testing in the initial evaluation ofpregnant women (1| ).

4.2. Epilepsy: We recommend against the use ofdexamethasone testing in patients receiving antiepilepticdrugs known to enhance dexamethasone clearance andrecommend instead measurements of nonsuppressed cortisolin blood, saliva, or urine (1| ).

4.3. Renal failure: We suggest using the 1-mg overnight DSTrather than UFC for initial testing for Cushing’s syndrome inpatients with severe renal failure (2| ).

4.4. Cyclic Cushing’s syndrome: We suggest use of UFC ormidnight salivary cortisol tests rather than DSTs in patientssuspected of having cyclic Cushing’s syndrome (2| ).

4.5. Adrenal incidentaloma: We suggest use of the 1-mg DSTor late-night cortisol test, rather than UFC, in patientssuspected of having mild Cushing’s syndrome (2| ).

The Diagnosis of Cushing’s Syndrome:

An Endocrine Society Clinical Practice Guideline

GUIDELINESCLINICAL T h e E n d o c r i n e S o c i e t y ’ s

Authors: Lynnette K. Nieman, Beverly M. K. Biller, James W. Findling, John Newell-Price, Martin O. Savage,Paul M. Stewart, and Victor M. Montori

Affiliations: Program on Reproductive and Adult Endocrinology (L.K.N.), National Institute of Child Health andHuman Development, National Institutes of Health, Bethesda, Maryland 20892; NeuroendocrineUnit/Massachusetts General Hospital (B.M.K.B.), Boston, Massachusetts 02114; Medical College of Wisconsin(J.W.F.), Milwaukee, Wisconsin 53226; University of Sheffield (J.N.-P.), Sheffield S102JF, United Kingdom;William Harvey Research Institute, Queen Mary, University of London (M.O.S.), London EC1M6BQ, UnitedKingdom; University of Birmingham (P.M.S.), Birmingham B15 2TT, United Kingdom; and Mayo Clinic(V.M.M.), Rochester, Minnesota 55905

Co-Sponsoring Association: European Society of Endocrinology

Disclaimer Statement: Clinical practice guidelines are developed to be of assistance to physicians by providingguidance and recommendations for particular areas of practice. The guidelines should not be considered inclusiveof all proper approaches or methods, or exclusive of others. The guidelines cannot guarantee any specific outcome,nor do they establish a standard of care. The guidelines are not intended to dictate the treatment of a particularpatient. Treatment decisions must be made based on the independent judgment of health care providers and eachpatient's individual circumstances.

The Endocrine Society makes no warranty, express or implied, regarding the guidelines and specificallyexcludes any warranties of merchantability and fitness for a particular use or purpose. The Endocrine Society shallnot be liable for direct, indirect, special, incidental, or consequential damages related to the use of the informationcontained herein.

First published in the Journal of Clinical Endocrinology & Metabolism, May 2008, 93(5):1526–1540

© The Endocrine Society, 2008

Commercial Reprint InformationFor information on reprint requests of more than 101 and commercial reprints contact:

Heather EdwardsReprint Sales SpecialistCadmus Professional Communications

Phone: 410.691.6214Fax: 410.684.2789 Email: [email protected]

Single Reprint InformationFor information on reprints of 100 and fewer, complete the guideline order form and return using one of thefollowing methods:

Mail: The Endocrine Societyc/o Bank of AmericaP.O. Box 630721Baltimore, MD 21263-0736

Fax: 301.941.0257Email: [email protected]

Questions & CorrespondencesThe Endocrine SocietyAttn: Government & Public Affairs Department8401 Connecticut Avenue, Suite 900Chevy Chase, MD 20815

Phone: 301.941.0200Email: [email protected]: www.endo-society.org

For more information on The Endocrine Society’s Clinical Practice Guidelines or to download the completeversion of this guideline, visit http://www.endo-society.org/publications/guidelines/index.cfm.

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but that are also common in the general population,such as obesity, depression, diabetes, hypertension, ormenstrual irregularity. As a result, there is an overlapin the clinical presentation of individuals with andwithout the disorder (Table 1). We encouragecaregivers to consider Cushing’s syndrome as asecondary cause of these conditions, particularly ifadditional features of the disorder are present. (seeWho should be tested below.) If Cushing’s syndrome isnot considered, the diagnosis is all too often delayed.

In addition, overactivity of the hypothalamic-pituitary-adrenal (HPA) axis occurs without true Cushing’s

syndrome, so that there is an overlap betweenphysiological and pathophysiological causes ofhypercortisolism (Table 2). Thus, certain psychiatricdisorders (depression, anxiety disorder, obsessive-compulsive disorder), poorly controlled diabetesmellitus, and alcoholism can be associated with mildhypercortisolism and may produce test results suggestiveof Cushing’s syndrome, including abnormaldexamethasone suppressibility and mildly elevated UFC(9). Circulating cortisol concentrations are usuallynormal (or slightly reduced) in obesity, but severeobesity can raise UFC. It is thought that higher braincenters stimulate CRH release in these conditions, with

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TABLE 1. Overlapping conditions and clinical features of Cushing’s syndromea

Symptoms Signs Overlapping conditions

Features that best discriminate Cushing’s syndrome; most do not have a high sensitivity

Easy bruising

Facial plethora

Proximal myopathy (or proximal muscle weakness)

Striae (especially if reddish purple and >1 cm wide)

In children, weight gain with decreasing growth velocity

Cushing’s syndrome features in the general population that are common and/or less discriminatory

Depression Dorsocervical fat pad (“buffalo hump”) Hypertensionb

Fatigue Facial fullness Incidental adrenal mass

Weight gain Obesity Vertebral osteoporosisb

Back pain Supraclavicular fullness Polycystic ovary syndrome

Changes in appetite Thin skinb Type 2 diabetesb

Decreased concentration Peripheral edema Hypokalemia

Decreased libido Acne Kidney stones

Impaired memory Hirsutism or female balding Unusual infections(especially short term)

Insomnia Poor skin healing

Irritability

Menstrual abnormalities

In children, slow growth In children, abnormal genital virilization

In children, short stature

In children, pseudoprecocious puberty or delayed puberty

a Features are listed in random order.b Cushing’s syndrome is more likely if onset of the feature is at a younger age.

OSPEDALE CLASSIFICATO "SACRO CUORE - DON CALABRIA"37024 - NEGRAR (Verona) - Tel 045/601.3111 - Fax 045/7500480

U.O.S. di ENDOCRINOLOGIA

Responsabile: Dr Lino Furlani

Tel. 601.3712 (Dr Furlani) - 601.3711 (Dr Dellera, Dr Guerriero) - 601.3750 (Day Hospital) - 601.3310 (Degenze)

Fax 045 6013727 e mail: [email protected]

Sig.ra FEZZARDI Laura, n. 01/09/1972

Negrar, 18/11/2005

Test CRH

Tempi ACTH(ng/L)

Cortisolo(nmol/L)

ACTH%

Cortisolo%

Base 51 27615’ 128 384 15130’ 24 572 107

60’ 36 448

Note: ………………………………………………………………………………………………………...

………………………………………………………………………………………………………………..

………………………………………………………………………………………………………………..

………………………………………………………………………………………………………………..

………………………………………………………………………………………………………………..

Basali DST 1 mg DST 2 mg DST 8 mg vn

ACTH h.8 ng/L 53 CORTISOLO h 8:00 nmol/L 574 652 534 399 171-536

CORTISOLO h.18.00 nmol/L 497 64-340

CLU nmol/d 2358 465 150-1100

Caso clinico

Caso clinico

Cateterismo seni petrosi

Quali esami di screening?

body temperature in daylight hours (particularly earlymorning – for example, with vigorous exercise) or de-crease body temperature in the evening (that is, throughenvironmental or pharmacological manipulations).

Clinical studies of young people with major depressivedisordersMonitoring the 24-hour sleep-wake and activity cycleA key aspect of those studies that focus on disruptionsof sleep-wake cycles and circadian rhythms is the cap-acity to integrate a number of new detailed objectivemeasures (Table 2). These complement extended self-report measures of daily fluctuations in sleep, mood, en-ergy or physical activity. They include extended periodsof actigraphy (for example, typically at least two weeks),as well as 24- to 72-hour assays of body temperatureand 24-hour fluctuations in cortisol or melatonin (in-cluding under controlled environmental parameters,such as light exposure). Even though actigraphy mea-sures are indirect and somewhat more variable (at leastin the short term) than other circadian markers, be-cause of other behavioral and homeostatic influences,they have consistently been found to correlate withthe circadian rhythm of endogenous melatonin and bodytemperature [242-249]. Other new technologies, such assmart phone applications, permit home monitoring ofextended periods of sleep-wake cycle behavior andpatterns of physical activity.Within the research environment, the introduction of dir-

ect ecological monitoring systems [250,251] continues toprovide important new insights into the daily patterns ofphysical activity, daytime resting, eating and other key so-cial behaviors, alongside data related to subjective energy ormood levels. These types of studies have the capacity to

reveal important longitudinal associations between daytimeactivity, sleep-wake cycle timing and mood and other psy-chological and neuropsychological variables.

Markedly delayed sleep phase in young people withdepressionWhen the various sleep-wake technologies are applied inyounger subjects in the early phases of major mood dis-orders, a quite different pattern of sleep and circadianrhythms emerges in comparison to young persons with-out mood disorders or middle-aged subjects with mooddisorders. Our own studies highlight two key aspects inyoung persons with mood disorders, namely: (a) the pre-dominance of delayed sleep phase (that is, not only go-ing to bed later, but also rising later) [123] rather thanthe more characteristic pattern of phase advance thathas traditionally been linked with more severe forms ofdepression in mid and later-life; and, (b) a late dim lightmelatonin onset (DLMO) compared to values classicallyfound in young healthy persons [42,212]. This delayedpattern of the sleep-wake cycle and endogenous circa-dian rhythms is most marked in those with bipolar thanunipolar phenotypes [123,212]. Importantly, longitudinalprospective studies are needed to identify sleep-wakeor circadian predictors of mood disorders early in thecourse of illness. Notably, promising findings in youthhave highlighted the predictive value of sleep problemsand specific polysomnographic (PSG) markers for the fu-ture development of mood disorders [252-255] and thetransition from unipolar to bipolar depression [256].Such technologies can also be applied in older subjects

with late-life depressive or early neurodegenerative dis-orders. Here, our data shows that greater nocturnalwakefulness as measured by actigraphic monitoring

Figure 3 The normal synchronous relationships between sleep and daytime activity and cortisol, melatonin and body temperature.

Hickie et al. BMC Medicine 2013, 11:79 Page 11 of 27http://www.biomedcentral.com/1741-7015/11/79

30 mcg/dl

0 mcg/dl

536

CorPsolo sierico nmol/L

Cortisolo ritmo circadiano

www.associazionemediciendocrinologi.it Breaking news nr. 9 - marzo 2014

PLENADREN PRESCRIVIBILE DA OGGI IN FASCIA H

Responsabile Editoriale Vincenzo Toscano

Commissione Farmaci AME Raffaele Volpe (Coordinatore) ([email protected] ) Agostino Paoletta, Agostino Specchio, Davide De Brasi, Enrica Ciccarelli

A cura di: Renato Cozzi 1/1

Avevamo già comunicato (AME Breaking News n 3/2014) la pubblicazione sulla G.U. del 28/12/2013 n°

303 della determina AIFA su regime di rimborsabilità e prezzo di vendita del medicinale per uso umano

Plenadren (idrocortisone).

Il medicinale era stato inserito (G.U. 18/05/2012 n° 115) nell'elenco dei farmaci erogabili a totale carico

del Servizio Sanitario Nazionale, ai sensi della legge 648/96.

Da oggi, 3 marzo 2014, il farmaco Plenadren è disponibile in Italia per la prescrizione in fascia H.

Indicazioni terapeutiche: trattamento dell'insufficienza surrenalica negli adulti.

Classe di rimborsabilità: H.

Classificazione ai fini della fornitura: medicinale soggetto a prescrizione medica limitativa, vendibile al

pubblico su prescrizione di centri ospedalieri o di specialisti endocrinologi (RRL).

Allegato: testo GU
















Allegato: testo GU
















Allegato: testo GU

www.associazionemediciendocrinologi.it

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Concentrazione media di cortisolo sierico osservata nell’arco delle 24 ore in seguito alla somministrazione di dosi singole e multiple in pazienti con insufficienza surrenalica primaria (n=62) dopo la somministrazione orale di Plenadren, dato una volta al giorno, e di idrocortisone, dato tre volte al giorno (come da scheda tecnica)

In uno studio recentemente pubblicato (Johannsson G, et al. Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation. J Clin Endocrinol Metab 2012, 97: 473-81) è stato paragonato il profilo giornaliero delle concentrazioni circolanti di cortisolo, l’outcome metabolico e la QoL nei pazienti addisoniani trattati con la formulazione a rilascio modificato rispetto a quelli trattati con la formulazione classica. Si è potuto dimostrare che la somministrazione di Plenadren rispetto alla formulazione convenzionale otteneva: x media giornaliera delle concentrazioni di cortisolo più bassa; x livelli di cortisolo dopo la somministrazione mattutina più alti; x riduzione ponderale, miglior compenso pressorio e glicemico, miglioramento degli indici di anabolismo osseo

e miglioramento della QoL. Gli effetti collaterali erano di lieve entità con entrambi i trattamenti. Le dosi sostitutive orali di Plenadren devono essere personalizzate secondo la risposta clinica: x la dose di mantenimento comune è di 20–30 mg/die, somministrata una volta sola al mattino; x nei pazienti in cui si riscontri ancora una produzione endogena di cortisolo potrebbe essere sufficiente una

dose inferiore; x la più alta dose di mantenimento studiata è di 40 mg/die.

0

5

10

15

20

25

30

1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64

CORTISOLO SIERICO h8 -‐ variabilità

cortisolo (µg/dl)

prelievi multipli mattutini

Variabilità individuale 2-13% tra prelievi

Courtesy of Terzolo

7,5 mcg/dl

5 mcg/dl

1,8 mcg/dl

Findling et Raff; JCEM 2006, 91(10):3746 Kidambi et Al; EJE (2007) 157 725–731

0,15 mcg/dl 0,15 – 0,3 mcg/dl > 0,3 mcg/dl

CORTISOLO SALIVARE

Differentiating between Cushing’s diseaseand pseudo-Cushing’s syndrome: comparisonof four testsR A Alwani*, L W Schmit Jongbloed*, F H de Jong, A J van der Lely,

W W de Herder and R A Feelders

Division of Endocrinology, Room H555, Department of Internal Medicine, Erasmus Medical Centre, PO Box 2040,

3000 CA Rotterdam, The Netherlands*(R A Alwani and L W Schmit Jongbloed contributed equally to this work)

Correspondence

should be addressed

to R A Alwani

Email

[email protected]

Abstract

Objective: To evaluate the diagnostic performance of four different tests in order to differentiate between Cushing’s disease

(CD) and pseudo-Cushing’s syndrome (PCS).

Methods: In this prospective study, a total of 73 patients with clinical features of hypercortisolism and insufficient suppression

of serum cortisol after 1 mg overnight dexamethasone and/or an elevated excretion of cortisol in 24-h urine samples were

included. The circadian rhythm of serum cortisol levels as well as midnight serum cortisol (MserC) levels were assessed in all

73 patients. Late-night salivary cortisol (LNSC) concentrations were obtained in 44 patients. The dexamethasone–CRH

(Dex–CRH) test was performed in 54 patients.

Results: Fifty-three patients were diagnosed with CD and subsequently treated. Twenty patients were classified as having

PSC. Serum cortisol circadian rhythm: the diurnal rhythmicity of cortisol secretion was retained in PCS. A cortisol

midnight:morning ratio of O0.67 is highly suggestive of CD (positive predictive value (PPV) 100% and negative predictive

value (NPV) 73%). MserC concentration O243 nmol/l has a PPV of 98% in predicting true CD (NPV 95%). LNSC level

O9.3 nmol/l predicted CD in 94% of patients (NPV 100%). Dex–CRH test: after 2 days of dexamethasone suppression, a

CRH-stimulated cortisol level O87 nmol/l (TZ15 min) resulted in a PPV of 100% and an NPV of 90%.

Conclusion: The Dex–CRH test as well as a single measurement of cortisol in serum or saliva at late (mid-) night demonstrated

high diagnostic accuracy in differentiating PCS from true CD.

European Journal of

Endocrinology

(2014) 170, 477–486

Introduction

Cushing’s disease (CD) is caused by an adrenocortico-

tropin (ACTH)-secreting pituitary adenoma leading to

chronic overproduction of cortisol. This results in a clinical

phenotype with features like a full plethoric face, central

obesity, and muscle and skin atrophy. The diagnosis can

be difficult due to gradual development of symptoms and

due to overlap with features of metabolic syndrome (1).

In addition, it can be challenging to differentiate cases

with mild ACTH-dependent hypercortisolism from

conditions that are accompanied by (physiologic) over-

activity of the hypothalamic–pituitary–adrenal axis

referred to as pseudo-Cushing’s syndrome (PCS). PCS can

present with a similar clinical phenotype and is associated

with chronic alcoholism, psychiatric disorders, severe

obesity, poorly controlled diabetes, and extreme physical

stress. Treatment of these underlying conditions will lead

EuropeanJournalofEndocrinology

Clinical StudyR A Alwani, L W SchmitJongbloed and others

Differentiating CS and PCS 170 :4 477–486

www.eje-online.org ! 2014 European Society of EndocrinologyDOI: 10.1530/EJE-13-0702 Printed in Great Britain

Published by Bioscientifica Ltd.

Laboratory assays

Serum and urinary cortisol and plasma ACTH were

measured using chemiluminescence-based immunoassays

(Immulite 2000, Siemens, Los Angeles, CA, USA; inter- and

intra-assay coefficients of variation, respectively below 15

and 7% for cortisol and below 6.5 and 5.5% for ACTH).

Urinary cortisol was measured without prior solvent

extraction. Although this may be a less accurate method,

the upper limit of normal of this in-house assay was

carefully determined according to cortisol secretion rate in

healthy controls (18). Salivary cortisol was measured using

a commercial kit (Salivary Cortisol ELISA SLV-2930, DRG

Instruments GmbH, Marburg, Germany).

Statistical analysis

Mean and S.E.M. were calculated for continuous data and

presented as meanGS.E.M. Proportions were calculated for

categorical data. We considered a P value of !0.05 to be

statistically significant. The two-tailed Student’s t-test was

usedwhen continuous datawere normally distributed. The

Mann–WhitneyU testwasusedwhencontinuousdatawere

not normally distributed. Sensitivity, specificity, positive

predictive value (PPV), andnegative predictive value (NPV)

were calculated for each test using standard methods. PPV

was defined as the proportion of patients that are correctly

diagnosed with CD. NPV was defined as the proportion of

patients that are correctly diagnosed with PCS. Receiver

operating characteristic (ROC) curves were used for each

test to determine the area under the curve (AUC) and to

define the cut-off value with the best diagnostic per-

formance by minimizing the absolute difference between

the highest PPV and highest NPV (diagnostic accuracy of

the test). The leave-one-out cross validation method was

used to see if a combination of the MserC measurement

with the Dex–CRH test would further increase the

discriminatory power to distinguish patients with true

CD from patients with PCS. Statistical analysis and

graphing were performed with the commercially available

software packages GraphPad Prism, version 3.0 (GraphPad

Software, San Diego, CA, USA) and MedCalc, version 9.64

(MedCalc Software, Ostend, Belgium).

Results

Cortisol circadian rhythm

The dynamics of cortisol secretion in serum were

investigated in 52 patients with CD and in 19 patients

with PCS. Patients with CD had higher mean cortisol

values at all time points compared with patients with PCS.

Also, patients with CD showed a relatively flat cortisol

pattern throughout the day, whereas patients with PCS

retained a diurnal rhythmicity of cortisol secretion

(Table 1 and Fig. 2). ROC curve analysis (Fig. 2) showed

a cortisol midnight:morning ratio of 0.67 to have the

highest discriminating capacity between the diagnoses of

CD and PCS (PPV 100%, NPV 73%, and AUCZ0.969). The

cortisol midnight:morning ratio was O0.67 in 45 patients

with CD (sensitivity 87%), whereas all patients with PCS

noted a ratio of %0.67 (specificity 100%).

The serum cortisol late afternoon:morning ratio

(cortisol 1700 h:cortisol 0900 h) and the analysis of the

circadian rhythm in salivary cortisol and plasma ACTH

did not improve discrimination between groups and are

therefore not shown.

Midnight serum cortisol

MserC concentrations were obtained in 53 patients with

CD and 20 patients with PCS. Mean MserC levels were

significantly higher in patients with CD (577 nmol/lG43)

than in patients with PCS (141 nmol/lG13) (P!0.001).

800

Cortisol midnight:morningratio

100

80

60

40Sen

sitiv

ity

20

0

100

80

60

40Sen

sitiv

ity

20

0

0 20 40100-Specificity

Midnight serum cortisol

60 80 100

0 20 40100-Specificity

60 80 100

CD

PCS

600h 1200h 1800h 2400h

700

600

500

400

300

Cor

tisol

(nm

ol/l)

200

100

0

Figure 2

(Left) Mean cortisol levels in serum throughout the day of

52 patients with Cushing’s disease (CD) and 19 patients with

pseudo-Cushing’s syndrome (PCS). (Right, top) Receiver

operating characteristic (ROC) curve of the cortisol midnight:

morning ratio in serum. Optimal cut-off valueZ0.67. Area

under ROC curve (AUC)Z0.969 (sensitivity 87%, specificity

100%, positive predictive value (PPV) 100%, and negative

predictive value (NPV) 73%). (Right, bottom) ROC curve of the

midnight serum cortisol concentration. Optimal cut-off

valueZ243 nmol/l. AUCZ0.994 (sensitivity 98%, specificity

95%, PPV 98%, and NPV 95%).

European

JournalofEndocrinology

Clinical Study R A Alwani, L W SchmitJongbloed and others

Differentiating CS and PCS 170 :4 480

www.eje-online.org

lower diagnostic performance of the test (PPV 80–86%

and NPV 92–100%) and proposed different threshold

values for the 15-min post-CRH cortisol concentration

(44–110 nmol/l) (13, 14, 15, 17). These findings are

confirmed in the present survey, as we found an optimal

threshold value of 87 nmol/l for serum cortisol 15 min

after CRH administration (PPV 100% and NPV 90%). The

2-day DST (2 days of dexamethasone suppression without

CRH stimulation) also performed reasonably well (cut-off

50 nmol/l; PPV 92% and NPV 89%), but both its PPV as

well as its NPV further increased after adding CRH

stimulation, although these results are based on a

relatively small sample size. In contrast, a study conducted

by Martin et al. showed no improvement in the diagnostic

accuracy of the 2-day DST when CRH was administered

additionally. However, compared with our survey, there

was a significant difference in the inclusion of patients

with Cushing’s syndrome (pituitary and adrenal vs

pituitary only) and the number of dexamethasone doses

(nine vs eight) (15).

Differences in reliability of the Dex–CRH test in the

above-mentioned studies can possibly be explained by the

use of different protocols for the Dex–CRH test, adminis-

tration of different CRH preparations (ovine or human),

differences in CRH dosage (1 mg/kg or 100 mg), variation

in cortisol and ACTH assays, in particular with respect

to measurements in the low range, and absence of

uniform criteria to define PCS. Despite the fact that the

test is relatively expensive and impractical (hospital admis-

sion is required), the Dex–CRH test, based on its relatively

high diagnostic accuracy, can still be a valuable tool in cases

with indeterminate results of first-line screening tests.

Because it is most difficult to differentiate between CD

and PCS in patients with mild ACTH-dependent hyper-

cortisolism, a clinically relevant observation in our study

is that the diagnostic performance of all evaluated tests

was not different when CD patients with UFC levels within

two times the upper limit of normal were compared with

PCS patients.

Combining second-line tests did not improve diag-

nostic accuracy, possibly due to the relatively small sample

size of the PCS group. As always, whenmore tests are used,

discrepancies between test results can occur. Generally,

within individual patients, the different tests used

indicated the same diagnosis. We found in only four

patients (CDZ3 and PCSZ1) discrepancies between

MserC and post Dex–CRH-stimulated cortisol levels

which were just below or above the cut-off value and

i.e. because they demonstrated a corticotroph adenoma

with positive ACTH staining, these patients cannot be

classified. In the clinical scenario where test results are

discordant in a patient withmild hypercortisolism, follow-

up is recommended for monitoring progression of

symptoms and for repeat testing (1).

ACTH-secreting pituitary adenomas are known to

show overexpression of receptors for CRH and vasopressin

in corticotroph cells. Stimulation with either CRH or

desmopressin, a synthetic vasopressin analog, results in a

direct release of ACTH (40, 41, 42). Tirabassi et al. (43)

reported excellent diagnostic performance as well as

perfect diagnostic agreement for the human CRH test

and the desmopressin test in a study with a small number

of patients with PCS (nZ12), which should be confirmed

by future studies.

The strength of our current survey is its prospective

design and the clear biochemical criteria used to define

PCS (abnormal result in DST and/or elevated UFC on at

least two occasions). The limitations are UFC measure-

ment without solvent extraction, the relatively small

number of PCS patients, no measurement of plasma

dexamethasone levels during DST and Dex–CRH testing

and the fact that not all tests were performed in all

participating patients.

Conclusion

In the present study, the Dex–CRH test as well as

measurement of cortisol in saliva or serum collected at

midnight showed high diagnostic accuracy in distinguish-

ing between true CD and PCS. Results of the different tests

were concordant in most patients and combining tests did

not increase the diagnostic yield. Considering its con-

venience, its high diagnostic accuracy as a first-line

screening test as well as its ability to differentiate between

CD and PCS, the use of midnight salivary cortisol

assessment as a first-choice test seems rational. Depending

on the protocol and assay(s) used, it is important for

diagnostic centers to validate these tests and their

threshold values.

Declaration of interest

A J van der Lely is a consultant for Novartis Pharma, Pfizer International,

and Ipsen Pharma International. WW de Herder is a consultant for Novartis

Pharma and Ipsen Pharma International. R A Feelders is a consultant for

Novartis Pharma. The other authors have nothing to disclose.

Funding

This research did not receive any specific grant from any funding agency in

the public, commercial or not-for-profit sector.

Europea

nJournal

ofEn

docrinology



www.eje-online.org

The ROC curve for MserC is shown in Fig. 2. The optimal

threshold value to detect true CD was 243 nmol/l (PPV

98%, NPV 95%, and AUCZ0.994). All CD patients except

one showed MserC levels in excess of 243 nmol/l

(sensitivity 98%). Nineteen out of 20 patients with PCS

recorded MserC levels of %243 nmol/l (specificity 95%).

Late-night salivary cortisol

Cortisol in saliva wasmeasured in 33 patients with CD and

11 patients with PCS (Fig. 3). Mean LNSC levels were

significantly higher (P!0.001) in the CD group (35.0G

6.4 nmol/l) than in the PCS group (7.7G1.0 nmol/l).

According to the ROC curve (Fig. 3), the cut-off value

yielding the best PPV and NPV was 9.3 nmol/l (AUCZ

0.962). This value corresponds to a sensitivity of 100%,

a specificity of 83%, a PPV of 94%, and an NPV of 100%.

Dex–CRH test

The Dex–CRH test was performed in 35 patients with CD

and 19 patients with PCS. Sixteen out of 19 patients with

PCS had suppressed levels of serum cortisol below

50 nmol/l after 2 days of dexamethasone administration.

The mean cortisol level after dexamethasone suppression

and before CRH administration in the PCS group was

35 nmol/l (G3.0; range 27–78).

Serum cortisol levels were higher than 50 nmol/l in

33/35 patients with CD after 2 days of dexamethasone

suppression. The mean cortisol level after dexamethasone

suppression (before CRH stimulation) in the CD group was

288 nmol/l (G51; range 28–1283). Using a cut-off value

of 50 nmol/l, this 2-day DST (without subsequent CRH

stimulation) demonstrated a sensitivity of 94% and a

specificity of 84% (PPV 92% and NPV 89%).

Additional CRH stimulation (Dex–CRH test) led to a

correct classification of three more patients with PCS

(19/19). This resulted in a further improvement of the

above-mentioned predictive values. The highest diagnos-

tic accuracy of the Dex–CRH test was achieved when the

serum cortisol concentration 15 min after CRH adminis-

tration was used as the criterion. Patients with CD had

significantly higher levels of CRH-stimulated serum

cortisol than patients with PCS: 365G42.9 vs 41G

4.5 nmol/l (P!0.001). Measurement of plasma ACTH or

serum cortisol at other time points did not improve the

performance of the Dex–CRH test (data not shown).

The results of the Dex–CRH test are shown in Fig. 4.

ROC curve analysis showed an optimal cut-off value

of 87 nmol/l for CRH-stimulated serum cortisol at

TZ15 min (sensitivity of 94%, specificity 100%, PPV

100%, and NPV 90%). The AUC provided by the ROC

curve is 0.995 (Fig. 4).

Mild hypercortisolism

The diagnostic value of the described second-line tests did

not significantly differ when only CD patients with mild

hypercortisolism (i.e. UFC within two times the upper

limit of normal; nZ28) were compared with PCS patients

(Table 2).

Combined assessment of second-line tests

Combined assessment of MserC concentration and

Dex–CRH test was performed in 53 patients (35 CD and

18 PCS). The results of the two tests in these patients are

plotted in Fig. 5. Discordant test results were found in four

patients (Table 3).

Owing to the relatively small sample size of the PCS

group in our study, a leave-one-out cross validation

procedure failed to demonstrate any benefit of combining

the results of the two second-line tests; the discriminatory

200100

80

60

40Sen

sitiv

ity

20

00 20 40 60 80 100

100-Specificity

175

150

125

100

75

Cor

tisol

in s

aliv

a (n

mol

/l)

50

25

0CD PCS

9.3 nmol/l

Figure 3

(Left) Dot diagram showing midnight cortisol levels in saliva of

33 patients with Cushing’s disease (CD) and 11 patients with

pseudo-Cushing’s syndrome (PCS). (Right) Receiver operating

characteristic (ROC) curve of the late-night cortisol measure-

ment in saliva (LNSC). A threshold value of 9.3 nmol/l results in a

positive predictive value of 94% to distinguish authentic CD

from PCS (negative predictive value 100%, sensitivity 100%,

specificity 83%, and area under ROC curveZ0.962).

European

JournalofEndocrinology



www.eje-online.org

Differentiating between Cushing’s diseaseand pseudo-Cushing’s syndrome: comparisonof four testsR A Alwani*, L W Schmit Jongbloed*, F H de Jong, A J van der Lely,

W W de Herder and R A Feelders

Division of Endocrinology, Room H555, Department of Internal Medicine, Erasmus Medical Centre, PO Box 2040,

3000 CA Rotterdam, The Netherlands*(R A Alwani and L W Schmit Jongbloed contributed equally to this work)

Correspondence

should be addressed

to R A Alwani

Email

[email protected]

Abstract

Objective: To evaluate the diagnostic performance of four different tests in order to differentiate between Cushing’s disease

(CD) and pseudo-Cushing’s syndrome (PCS).

Methods: In this prospective study, a total of 73 patients with clinical features of hypercortisolism and insufficient suppression

of serum cortisol after 1 mg overnight dexamethasone and/or an elevated excretion of cortisol in 24-h urine samples were

included. The circadian rhythm of serum cortisol levels as well as midnight serum cortisol (MserC) levels were assessed in all

73 patients. Late-night salivary cortisol (LNSC) concentrations were obtained in 44 patients. The dexamethasone–CRH

(Dex–CRH) test was performed in 54 patients.

Results: Fifty-three patients were diagnosed with CD and subsequently treated. Twenty patients were classified as having

PSC. Serum cortisol circadian rhythm: the diurnal rhythmicity of cortisol secretion was retained in PCS. A cortisol

midnight:morning ratio of O0.67 is highly suggestive of CD (positive predictive value (PPV) 100% and negative predictive

value (NPV) 73%). MserC concentration O243 nmol/l has a PPV of 98% in predicting true CD (NPV 95%). LNSC level

O9.3 nmol/l predicted CD in 94% of patients (NPV 100%). Dex–CRH test: after 2 days of dexamethasone suppression, a

CRH-stimulated cortisol level O87 nmol/l (TZ15 min) resulted in a PPV of 100% and an NPV of 90%.

Conclusion: The Dex–CRH test as well as a single measurement of cortisol in serum or saliva at late (mid-) night demonstrated

high diagnostic accuracy in differentiating PCS from true CD.

European Journal of

Endocrinology

(2014) 170, 477–486

Introduction

Cushing’s disease (CD) is caused by an adrenocortico-

tropin (ACTH)-secreting pituitary adenoma leading to

chronic overproduction of cortisol. This results in a clinical

phenotype with features like a full plethoric face, central

obesity, and muscle and skin atrophy. The diagnosis can

be difficult due to gradual development of symptoms and

due to overlap with features of metabolic syndrome (1).

In addition, it can be challenging to differentiate cases

with mild ACTH-dependent hypercortisolism from

conditions that are accompanied by (physiologic) over-

activity of the hypothalamic–pituitary–adrenal axis

referred to as pseudo-Cushing’s syndrome (PCS). PCS can

present with a similar clinical phenotype and is associated

with chronic alcoholism, psychiatric disorders, severe

obesity, poorly controlled diabetes, and extreme physical

stress. Treatment of these underlying conditions will lead

Europea

nJournal

ofEn

docrinology

Clinical StudyR A Alwani, L W SchmitJongbloed and others

Differentiating CS and PCS 170 :4 477–486

www.eje-online.org ! 2014 European Society of EndocrinologyDOI: 10.1530/EJE-13-0702 Printed in Great Britain

Published by Bioscientifica Ltd.

LNSC level 9.3 nmol/l predicted CD in 94% of pt

! Vantaggi •  Buona sensibilità e specificità per la “presentazione moderna” della sindrome

di Cushing

•  Possibilità di campionamenD mulDpli (3 campioni) in ambiente ambulatoriale, non-‐stressato

•  Semplice, poco costoso

! Svantaggi •  Specificità (evening stress, ritmo sonno-‐veglia, uso di liquirizia e tabacco,

contaminazione dei tamponi di raccolta)

•  Interferenza dei sistemi di raccolta (cotone, polieDlene, polistere…)

•  Livelli di riferimento dipendenD dalla metodica: necessità di «costruire» livelli di riferimento locali su larga fascia di popolazione

CORTISOLO SALIVARE

DST 1 mg overnight

and by the Mann-Whitney U test for nonparametric data. Forcategorical variables, differences were analyzed by means of the!2 test and Fisher’s exact test. Levels of statistical significancewere set at P ! 0.05. A multiple regression analysis was per-formed when appropriate. All analyses were performed using theStatistica software package (Microsoft Corp., Tulsa, OK).

Results

A total of 813 consecutive patients with type 2 diabeteswere enrolled. They were 428 men (52.6%) and 385women (47.4%) aged 25–70 yr (median 60 yr) with amedian duration of diabetes of 8 yr (range 1–20 yr). Of thewhole cohort, 17.9% of patients were treated with insulin,62.2% with oral hypoglycemic agents, 13.7% with a com-bined therapy, whereas 6.2% were on diet alone; patientson glitazones were excluded from the study because thesedrugs reportedly interfere with the HPA axis (13). Overall,71.7% of the patients were hypertensive, 56.5% of whomwere treated with two or more drugs, 58.7% had low-

density lipoprotein cholesterol greater than 100 mg/dl,and 79.9% were dyslipidemic, 46.8% of whom were onpharmacological treatment.

All subjects underwent a first screening step for Cush-ing’s syndrome using the overnight 1-mg DST. In a mul-tiple regression analysis including as candidate predictivevariables age, BMI, systolic and diastolic blood pressure,glycosylated hemoglobin (HbA1c), and fasting glucoselevels, post-DST cortisol levels were associated with sys-tolic blood pressure (" " 0.09, P " 0.02) and HbA1cvalues (" " 0.12, P " 0.001). However, the model ac-counted only for 2% (r2) of the total variation (P " 0.007).The patients with HbA1c greater than 7% had post-DSTcortisol levels higher than the remainder [1.73 # 2.28vs. 1.36 # 1.23 #g/dl (48 # 63 vs. 38 # 34 nmol/liter)P " 0.02].

Forty patients (4.9%) failed to suppress cortisol lessthan 5.0 #g/dl (138 nmol/liter) after the 1-mg DST (Fig. 2).They were 21 men and 19 women aged 20–70 yr (median56.5 yr). The patients failing to suppress cortisol wereslightly younger with similar duration of disease and BMI

FIG. 2. Cortisol values after 1-mg DST. FIG. 3. Cortisol values after 2-mg 2-day DST in the 40 non-suppressorpatients.

TABLE 2. Comparison of patients with post-DSTcortisol 5 #g/dl or less (DST suppressors) and post-DSTcortisol greaster than 5 #g/dl (DST nonsuppressors)

DSTsuppressors(n ! 773)

DSTnonsuppressors

(n ! 34)aP

valueAge (yr) 58.6 # 8.8 56.4 # 9.8 NSBMI (kg/m2) 32.1 # 6.1 30.9 # 4.6 NSDuration of

disease (yr)9.8 # 7.9 8.9 # 5.2 NS

Fasting glucose(mg/dl)

172.5 # 65.1 236.8 # 100.8 !0.0001

HbA1c (%) 8.4 # 1.9 9.2 # 2.0 0.01Systolic blood

pressure(mm Hg)

137.9 # 17.2 147.7 # 16.4 0.04

Diastolic bloodpressure(mm Hg)

82.6 # 10.1 80.7 # 10.9 NS

Data are expressed as mean values and SD. NS, Not significant.a Patients with confirmed Cushing’s syndrome have been excluded.

TABLE 3. Comparison of patients with false -DSTresults and true -positive DST results (confirmedCushing’s syndrome)

False-positiveDST (n ! 34)

True positiveDST (n ! 6)

Pvalue

Age (yr) 56.4 # 9.8 49.7 # 20.8 NSBMI (kg/m2) 30.9 # 4.6 35.9 # 12.6 NSDuration of

disease (yr)8.9 # 5.2 8.0 # 8.2 NS

Fasting glucose(mg/dl)

236.8 # 100.8 232.7 # 28.3 NS

HbA1c (%) 9.2 # 2.0 9.2 # 2.2 NSSystolic blood

pressure(mm Hg)

147.7 # 16.4 145.8 # 19.6 NS

Diastolic bloodpressure(mm Hg)

81.6 # 10.9 78.0 # 11.3 NS

Data are expressed as mean values and SD. NS, Not significant.



Quale cut-‐off?

5 mcg/dl

1,8 mcg/dl

Screening of Cushing’s Syndrome in Outpatients withType 2 Diabetes: Results of a Prospective MulticentricStudy in Italy

Massimo Terzolo, Giuseppe Reimondo, Iacopo Chiodini, Roberto Castello,Roberta Giordano, Enrica Ciccarelli, Paolo Limone, Claudio Crivellaro,Irma Martinelli, Marcella Montini, Olga Disoteo, Bruno Ambrosi, Roberto Lanzi,Maura Arosio, Sanzio Senni, Antonio Balestrieri, Erica Solaroli, Bruno Madeo,Raffaella De Giovanni, Felice Strollo, Rodolfo Battista, Alessandro Scorsone,Vito A. Giagulli, Daniela Collura, Aldo Scillitani, Renato Cozzi,Marco Faustini-Fustini, Anna Pia, Roberta Rinaldi, Barbara Allasino, Giulia Peraga,Francesco Tassone, Piernicola Garofalo, Enrico Papini, and Giorgio Borretta*

Context: Cushing’s syndrome may remain unrecognized among patients referred for metabolicsyndrome; thus, a proactive screening has been suggested in certain patient populations withfeatures of the disorder. However, conflicting data have been reported on the prevalence ofCushing’s syndrome in patients with type 2 diabetes.

Objective: Our aim was to evaluate the prevalence of unsuspected Cushing’s syndrome amongoutpatients with type 2 diabetes.

Design and Setting: This was a cross-sectional prospective study in 24 diabetes clinics across Italy.

Patients: Between June 2006 and April 2008, 813 patients with known type 2 diabetes withoutclinically overt hypercortisolism were evaluated. Follow-up of the study was closed in September2010. Patients were not selected for characteristics conferring a higher pretest probability ofhypercortisolism. Patients underwent a first screening step with the 1-mg overnight dexametha-sone suppression test.

Results: Forty patients failed to suppress serum cortisol less than 5.0 !g/dl (138 nmol/liter) andunderwent a standard 2-d, 2-mg dexamethasone suppression test, after which six patients (0.6%of the overall series) failed to suppress cortisol less than 1.8 !g/dl (50 nmol/liter), receiving adefinitive diagnosis of Cushing’s syndrome that was adrenal dependent in five patients. Fourpatients were cured, being able to discontinue, or reduce, the glucose-lowering agents.

Conclusions: The present data do not support widespread screening of patients with type 2 dia-betes for Cushing’s syndrome; however, the disorder is less rare than previously thought whenconsidering epidemiology of type 2 diabetes. Our results support a case-finding approach in pa-tients with uncontrolled diabetes and hypertension despite appropriate treatment. (J Clin Endo-crinol Metab 97: 3467–3475, 2012)

Subtle clinical presentations of Cushing’s syndrome,characterized by a paucity of signs and symptoms

due to mild cortisol hypersecretion, are increasinglyfound in clinical practice. In parallel, the metabolicsyndrome epidemic is leading to a boost in the numberof patients with a Cushingoid phenotype, who could

be potentially candidate to be tested for hypercortiso-lism (1).

The Endocrine Society guidelines for the diagnosis ofCushing’s syndrome recommended against widespreadtesting for the condition, unless in patients with unusualfeatures for age or multiple and progressive features, par-

ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright © 2012 by The Endocrine Societydoi: 10.1210/jc.2012-1323 Received February 5, 2012. Accepted June 18, 2012.First Published Online July 5, 2012

*Author affiliations are shown at the bottom of the next pageAbbreviations: BMI, Body mass index; CT, computerized tomography; DST, dexametha-sone suppression test; HbA1c, glycosylated hemoglobin; HPA, hypothalamus-pituitary-adrenal; MRI, magnetic resonance imaging.




The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 March 2014. at 05:28 For personal use only. No other uses without permission. . All rights reserved.ticularly those that are more predictive of Cushing’s syn-drome (2). However, unsuspected Cushing’s syndromewas found to be more frequent than previously expectedin different series of diabetic patients submitted to routinescreening (3–5). Thus, a number of patients with Cush-ing’s syndrome may not be recognized while they aremanaged for diabetes, either because of a mild clinicalpresentation or because of insufficient awareness of theirphysicians. Missing a diagnosis of Cushing’s syndromemay have detrimental consequences on patient outcomebecause hypercortisolism is expected to worsen metaboliccontrol and increases the probability of future cardiovas-cular events (6).

The results of the above-mentioned studies may arguein favor of a systematic screening of Cushing’s syn-drome in type 2 diabetes. However, data were mostly gen-erated in academic centers on hospitalized patients, thusraising the possibility of a selection bias toward patients atgreater risk of Cushing’s syndrome than the general dia-betic population (7).

The aim of our study was to screen patients attendingdiabetes clinics in an outpatient setting and in conditionsof standard clinical practice. Cohorts of consecutive pa-tients were enrolled in different Italian diabetes clinicsrather than selecting groups of patients at higher risk forCushing’s, i.e. those who were hypertensive or overweightand who had poor glycemic control.

Patients and Methods

PatientsThe study was conducted under the auspices of the Associa-

zione Medici Endocrinologi (Association of Clinical Endocri-nologists) at 24 diabetes clinics across Italy. Written informedconsent was obtained from all patients, and the institutionalreview board at each center approved the study. Each partici-pating center was requested to recruit consecutively at least 20diabetic patients fulfilling all inclusion criteria and without ex-

clusion criteria, who were attending the center for an ordinaryoutpatient visit from June 2006 to April 2008. Follow-up for thisstudy was closed in September 2010. Patients had to meet thefollowing inclusioncriteria: agebetween18and70yr, bodymassindex (BMI) greater than 25 kg/m2 and known diagnosis of type2 diabetes on active follow-up from at least 1 yr before the study.Exclusion criteria were presence of specific Cushingoid features[easy bruising, facial plethora, proximal myopathy and striae(2)], any severe acute illness, treatment with drugs known toaffect the hypothalamus-pituitary-adrenal (HPA) axis or dexa-methasone metabolism, current or previous history of alcoholabuse or major mood disorders that required psychiatric inter-vention, history of recent surgery or trauma, and pregnancy. Anysubject with a BMI greater than 30 kg/m2 was categorized asobese (8). Any subject with systolic blood pressure greater than140 mm Hg, diastolic blood pressure greater than 90 mm Hg, oron antihypertensive treatment was categorized as hypertensive(9). Dyslipidemia was defined following the Adult TreatmentPanel III criteria as follows: total cholesterol level greater than200 mg/dl, high-density lipoprotein cholesterol levels less than40 mg/dl, serum triglyceride levels greater than 150 mg/dl, andlow-density lipoprotein cholesterol levels greater than 160 mg/dl(10). Patients were also considered dyslipidemic if any specifictreatment was given. The main characteristics of the evaluatedpatients are shown in Table 1.

Medicina Interna I (M.T., G.R., B.Al., G.P.), Dipartimento di Scienze Cliniche e Biologiche, Azienda Ospedaliera Universitaria San Luigi Gonzaga, and Dipartimento di Scienze Cliniche eBiologiche (R.G.), Azienda Ospedaliera Universitaria San Luigi Gonzaga e Endocrinologia, Diabetologia, e Metabolismo, Azienda Ospedaliera Universitaria Molinette, Dipartimento diMedicina Interna, Universita di Torino, 10043 Torino, Italy; Dipartimento di Endocrinologia e Diabetologia (I.C.), Ospedale Maggiore Policlinico Instituto di Ricovero e Cura a CarattereScientifico, Divisione di Endocrinologia e Diabetologia (B.Am.), Dipartimento di Scienze Medico-Chirurgiche, Instituto di Ricovero e Cura a Carattere Scientifico Policlinico San Donato,Divisione di Endocrinologia e Diabetologia (M.A.), Dipartimento di Scienze Mediche, Ospedale San Giuseppe, Universita di Milano, 20122 Milano, Italy; Dipartimento di Medicina Generalee Endocrinologia (R.Ca.), Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy; SS Patologie Endocrine e Metaboliche (E.C.), Ospedale E. Valdese, 10138 Torino, Italy; StrutturaComplessa di Endocrinologia, Diabetologia e Malattie del Metabolismo (P.L.), Azienda Ospedaliera Ordine Mauriziano, 10125 Torino, Italy; Divisione di Endocrinologia, Dipartimento diMedicina Interna (C.C.), Ospedale Centrale di Bolzano, 39100 Bolzano, Italy; Dipartimento di Endocrinologia (I.M.), Ospedale S. Antonio Abate, 21013 Gallarate, Italy; Dipartimento diEndocrinologia (M.M.), Ospedali Riuniti di Bergamo, 24128 Bergamo, Italy; Dipartimento di Diabetologia (O.D.) and Dipartimento di Endocrinologia (R.Co.), Ospedale Niguarda, 20162Milano, Italy; Divisione di Endocrinologia (R.L.), Dipartimento di Medicina Interna e Specialistica, Instituto di Ricovero e Cura a Carattere Scientifico Fondazione Centro San Raffaele delMonte Tabor, 20132 Milano, Italy; Unità Operativa Semplice Endocrinologia (S.S.), AUSL Ravenna, 48100 Ravenna, Italy; Dipartimento di Malattie Metaboliche e Diabetologia (A.B.),Ospedale M. Bufalini, 47023 Cesena, Italy; Dipartimento di Endocrinologia (E.S., M.F.-F.), Ospedale Maggiore Bellaria, Bologna, Italy; Dipartimento di Medicina, Endocrinologia,Metabolismo, e Geriatria (B.M.), Nuovo Ospedale Civile S. Agostino-Estense di Baggiovara, 41100 Modena, Italy; Dipartimento di Medicina Generale (R.D.G.), Ospedale Ceccarini, 47900Riccione, Italy; Unità Operativa di Endocrinologia (F.S.), Istituto Nazionale di Ricovero e Cura per Anziani, Instituto di Ricovero e Cura a Carattere Scientifico, 00164 Roma, Italy; CentroDiabetologico Ospedale Santissima (R.B.), Trinita, Frosinone, Italy; Unità Operative Complessa Diabetologia (A.Sco.), Ospedale Civico Partinico, 90047 Palermo, Italy; Dipartimento diMalattie Metaboliche ed Endocrinologia (V.A.G.), Presidio Ospedaliero Monopoli-Conversano, 70043 Bari, Italy; Centro Catanese di Medicina e Chirurgia (D.C.), 95029 Catania, Italy;Dipartimento di Endocrinologia (A.Sci.), Ospedale “Casa Sollievo della Sofferenza,” Instituto di Ricovero e Cura a Carattere Scientifico, San Giovanni Rotondo, 71013 Italy; Dipartimentodi Endocrinologia (A.P., F.T., G.B.), Azienda Ospedaliera Santa Croce e Carle, 12100 Cuneo, Italy; Dipartimento di Endocrinologia e Malattie Metaboliche (R.R., E.P.), Ospedale ReginaApostolurum, 00041 Albano Laziale, Italy; and Dipartimento di Endocrinologia dell’Eta Evolutiva (P.G.), Ospedale Cervello, 90146 Palermo, Italy

TABLE 1. Main characteristics of the patients

VariableAge (yr) 58.9 ! 8.9BMI (kg/m2) 32.1 ! 6.1Duration of disease (yr) 9.8 ! 7.9Fasting glucose (mg/dl) 174.7 ! 67.7HbA1C (%) 8.4 ! 1.9Systolic blood pressure (mm Hg) 138.2 ! 17.2Diastolic blood pressure (mm Hg) 82.6 ! 10.1Total cholesterol (mg/dl) 186.9 ! 48.7HDL cholesterol (mg/dl) 45.9 ! 23.7LDL cholesterol (mg/dl) 106.9 ! 45.6Triglycerides (mg/dl) 171.2 ! 157.2

Data are expressed as mean values and SD. HDL, High-densitylipoprotein; LDL, low-density l;ipoprotein.



Cushing probabile

Cushing improbabile

Falsi positivi

Falsi negativi

Falsi positivi

Falsi positivi

Arlt et al., 2011

UFC IN PATIENTS WITH CUSHING’S SYNDROME 6000

3500

1000

750

500

250

0

100

Cushing’s Disease n = 288

Adrenal Adenoma n = 80

Adrenal Carcinoma n = 25

Ectopic SecrePon n = 26

(% upper limit) Invitti et al., 1999




















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SUMMARY OF RECOMMENDATIONS

3.0. DIAGNOSIS OF CUSHING’S SYNDROME

Who should be tested3.1. We recommend obtaining a thorough drug history toexclude excessive exogenous glucocorticoid exposure leadingto iatrogenic Cushing’s syndrome before conductingbiochemical testing (1| ).

3.2. We recommend testing for Cushing’s syndrome in thefollowing groups:• Patients with unusual features for age (e.g. osteoporosis,

hypertension) (Table 1) (1| )• Patients with multiple and progressive features,

particularly those who are more predictive of Cushing’ssyndrome (Table 1) (1| )

• Children with decreasing height percentile and increasingweight (1| )

• Patients with adrenal incidentaloma compatible withadenoma (1| ).

3.3. We recommend against widespread testing for Cushing’ssyndrome in any other patient group (1| ).

Initial testing3.4. For the initial testing for Cushing’s syndrome, werecommend one of the following tests based on its suitabilityfor a given patient (Fig. 1) (1| ):

3.4.1. Urine free cortisol (UFC; at least two measurements)3.4.2. Late-night salivary cortisol (two measurements)3.4.3. 1-mg overnight dexamethasone suppression test

(DST)3.4.4. Longer low-dose DST (2 mg/d for 48 h)

3.5. We recommend against the use of the following to test forCushing’s syndrome (1| ):• Random serum cortisol or plasma ACTH levels• Urinary 17-ketosteroids• Insulin tolerance test• Loperamide test• Tests designed to determine the cause of Cushing’s


3.6. In individuals with normal test results in whom thepretest probability is high (patients with clinical featuressuggestive of Cushing’s syndrome and adrenal incidentalomaor suspected cyclic hypercortisolism), we recommend furtherevaluation by an endocrinologist to confirm or exclude thediagnosis (1| ).

3.7. In other individuals with normal test results (in whomCushing’s syndrome is very unlikely), we suggest reevaluationin 6 months if signs or symptoms progress (2| ).

3.8. In individuals with at least one abnormal test result (forwhom the results could be falsely positive or indicateCushing’s syndrome), we recommend further evaluation by anendocrinologist to confirm or exclude the diagnosis(1| ).

Subsequent evaluation3.9. For the subsequent evaluation of abnormal initial testresults, we recommend performing another recommended test(Fig. 1, 1| ).

3.9.1. We suggest the additional use of the dexamethasone-CRH test or the midnight serum cortisol test in specificsituations (Fig. 1, 1| ).

3.9.2. We suggest against the use of the desmopressintest, except in research studies, until additional data validateits utility (2| ).

3.9.3. We recommend against any further testing forCushing’s syndrome in individuals with concordantly negativeresults on two different tests (except in patients suspected ofhaving the very rare case of cyclical disease) (1| ).

3.9.4. We recommend tests to establish the cause ofCushing’s syndrome in patients with concordantly positiveresults from two different tests, provided there is no concernregarding possible non-Cushing’s hypercortisolism (Table 2)(1| ).

3.9.5. We suggest further evaluation and follow-up forthe few patients with concordantly negative results who aresuspected of having cyclical disease and also for patients withdiscordant results, especially if the pretest probability ofCushing’s syndrome is high (2| ).

4.0. SPECIAL POPULATIONS/CONSIDERATIONS

4.1. Pregnancy: We recommend the use of UFC and againstthe use of dexamethasone testing in the initial evaluation ofpregnant women (1| ).

4.2. Epilepsy: We recommend against the use ofdexamethasone testing in patients receiving antiepilepticdrugs known to enhance dexamethasone clearance andrecommend instead measurements of nonsuppressed cortisolin blood, saliva, or urine (1| ).

4.3. Renal failure: We suggest using the 1-mg overnight DSTrather than UFC for initial testing for Cushing’s syndrome inpatients with severe renal failure (2| ).

4.4. Cyclic Cushing’s syndrome: We suggest use of UFC ormidnight salivary cortisol tests rather than DSTs in patientssuspected of having cyclic Cushing’s syndrome (2| ).

4.5. Adrenal incidentaloma: We suggest use of the 1-mg DSTor late-night cortisol test, rather than UFC, in patientssuspected of having mild Cushing’s syndrome (2| ).

- cortisolo libero urinario ( x 2 volte; escludere interferenze)

- cortisolo salivare/sierico alle h 23-h24

- DST 1 mg / 2 mg (cut – off variabile)

- test al CRH / CRH-DST / CRH-Desmopressina

DIAGNOSI di SINDROME di CUSHING

- DST 8 mg

- cortisolo salivare/sierico (< 2 mcg/dl) alle h8 - Test ACTH

NEL POSTINTERVENTO

DURANTE TERAPIA FARMACOLOGICA

- cortisolo libero urinario

remissione

recidiva

- cortisolo libero urinario - cortisolo salivare/sierico alle h 23-h24 - cortisolo sierico dopo DST

- cortisolo salivare/sierico alle h24 - cortisolo sierico dopo DST

- cortisolo libero urinario

Scegliere il test più ada`o alla situazione

clinica in esame, eventualmente

ripetendolo, secondo le disponibilità locali




















MMTD07

particularly in patients with very mild disease in whomthe benefits of intervention are unproven. Conversely,once the clinical scenario suggests a high pretestprobability of the disorder, sensitivity needs to be highso that cases are not missed. This approach also seeksto use more convenient and less expensive tests.

Initial testing3.4. For the initial testing for Cushing’s syndrome, werecommend one of the following tests based on itssuitability for a given patient (Fig. 1) (1| ):

3.4.1. UFC (at least two measurements)3.4.2. Late-night salivary cortisol (two measurements)3.4.3. 1-mg overnight DST3.4.4. Longer low-dose DST (2 mg/d for 48 h)

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3.5. We recommend against the use of the followingto test for Cushing’s syndrome (1| ):• Random serum cortisol or plasma ACTH levels• Urinary 17-ketosteroids• Insulin tolerance test• Loperamide test• Tests designed to determine the cause of Cushing’s


3.6. In individuals with normal test results in whomthe pretest probability is high (patients with clinicalfeatures suggestive of Cushing’s syndrome and adrenal incidentaloma or suspected cyclic hyper-cortisolism), we recommend further evaluation by anendocrinologist to confirm or exclude the diagnosis(1| ).

Cushing’s syndrome suspected(consider endocrinological consultation)

Exclude exogenous glucocorticoid exposure

Perform one of the following tests

ANY ABNORMAL RESULT Normal (CS unlikely)

Consult endocrinologist

Perform 1 or 2 other studies shown above

Suggest consider repeating the abnormal studySuggest Dex-CRH or midnight serum cortisol in certain populations (see text)

Discrepant ABNORMAL Normal (CS unlikely)(Suggest additional evaluation)


Exclude physiologic causes of hypercortisolism (Table 2)

24-h UFC (≥2 tests) Overnight Late-night salivary1-mg DST cortisol (≥2 tests)

Consider caveats for each test (see text)Use 48-h, 2-mg DST in certain populations (see text)

Figure 1. Algorithm for testing patients suspected of having Cushing’s syndrome (CS). All statements are recommendations except forthose prefaced by suggest. Diagnostic criteria that suggest Cushing’s syndrome are UFC greater than the normal range for the assay,serum cortisol greater than 1.8 µg/dl (50 nmol/liter) after 1 mg dexamethasone (1-mg DST), and late-night salivary cortisol greater than145 ng/dl (4 nmol/liter).

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