IPERFUNZIONE SURRENALICAIL PAZIENTE ADULTO

Massimo TerzoloMassimo TerzoloMassimo TerzoloMassimo TerzoloMassimo TerzoloMassimo TerzoloMedicina Interna IMedicina Interna I

AOU S. Luigi AOU S. Luigi -- Orbassano Orbassano

Università di TorinoUniversità di Torino

massimo.terzolo@unito.itmassimo.terzolo@unito.it

Massimo TerzoloMassimo TerzoloMedicina Interna IMedicina Interna I

AOU S. Luigi AOU S. Luigi -- Orbassano Orbassano

Università di TorinoUniversità di Torino

massimo.terzolo@unito.itmassimo.terzolo@unito.it

Fattori determinanti la variabilità fenotipica

della sindrome di Cushing

�Età di presentazione�Presentazione “sindromica”�Patogenesi polimorfa�Durata di malattia (esposizione ai GC)�Patologie concomitati�Patologie concomitati�Livelli circolanti di cortisolo�Cosecrezione di altri steroidi�Ormonogenesi periodica�Legame proteico (livelli di CBG)�Metabolismo pre-recettoriale (attività 11 β-HSD)�Polimorfismo dei recettori

ETIOLOGY OF CUSHING’S SYNDROME ACCORDING TO AGE

3040506070

% 80% 80

0102030

<15 16-25 26-35 36-45 46-55 56-65 >65

Cushing's disease Adrenal adenoma

Adrenal carcinoma Ectopic secretion

years

010

26-35 46-55 56-65 >65

Cushing's disease Adrenal adenoma

Adrenal carcinoma Ectopic secretion

Courtesy of prof. Cavagnini

Cardiac myxoma

Primary pigmented nodular adrenocortical diseasespotty pigmentation

Lacroix et al, 2004

Ectopic ACTH SyndromeEctopic ACTH SyndromeEctopic ACTH SyndromeEctopic ACTH Syndrome

�� A wide spectrum of clinical and biochemical A wide spectrum of clinical and biochemical presentations characterizes the EAS. presentations characterizes the EAS.

�� At one extreme there is the At one extreme there is the “classic”“classic” ectopic ectopic ACTHACTH--producing cancer (SCLC). The syndrome producing cancer (SCLC). The syndrome

�� A wide spectrum of clinical and biochemical A wide spectrum of clinical and biochemical presentations characterizes the EAS. presentations characterizes the EAS.

�� At one extreme there is the At one extreme there is the “classic”“classic” ectopic ectopic ACTHACTH--producing cancer (SCLC). The syndrome producing cancer (SCLC). The syndrome ACTHACTH--producing cancer (SCLC). The syndrome producing cancer (SCLC). The syndrome is rapidly progressive and is characterized by is rapidly progressive and is characterized by severe clinical manifestations and poor prognosis.severe clinical manifestations and poor prognosis.

�� At the other one there is the At the other one there is the “occult”“occult” ACTHACTH--producing tumor (carcinoid). The picture of producing tumor (carcinoid). The picture of Cushing’s syndrome may overlap that seen in Cushing’s syndrome may overlap that seen in patients with pituitary ACTHpatients with pituitary ACTH--dependent disease. dependent disease.

ACTHACTH--producing cancer (SCLC). The syndrome producing cancer (SCLC). The syndrome is rapidly progressive and is characterized by is rapidly progressive and is characterized by severe clinical manifestations and poor prognosis.severe clinical manifestations and poor prognosis.

�� At the other one there is the At the other one there is the “occult”“occult” ACTHACTH--producing tumor (carcinoid). The picture of producing tumor (carcinoid). The picture of Cushing’s syndrome may overlap that seen in Cushing’s syndrome may overlap that seen in patients with pituitary ACTHpatients with pituitary ACTH--dependent disease. dependent disease.

Uomo di 52 anniUomo di 52 anni

Hb: 16 g/dl, WBC: 11000/µµµµL, PTLS: 102000/ µµµµL

Glicemia: 360 mg/dl

K: 2.2 mmol/L, Na: 146 mmol/L

EGA: pH: 7.44, HCO3: 27 mmol/L, SBE: 4.6 mmol/L

Creatinina: 0.8 mg/dl, BCC: 83 ml/min

Potassiuria: 41.4 mmol/L, Sodiuria: 58 mmol/L

LDH: 500 U/L

AST, ALT, GGT, Alp, bilirubina, coagulazione, VES, PCR: nella norma

EAS EAS vs. vs. M. di CushingM. di Cushing

EASEAS MdCMdC v.n.v.n.

Cortisolo h.08 (Cortisolo h.08 (µµg/dl)g/dl) 101101 33.133.1 1515--2525

Cortisolo h.24 (Cortisolo h.24 (µµg/dl)g/dl) 100100 17.717.7 00--5.45.4

CLU (CLU (µµg/24h)g/24h) 54905490 250250 3030--150150

ACTH (ng/ml)ACTH (ng/ml) 248248 3030 2020--6060

Cortisone

11β-HSD2

Cortisolo

Cortisone

11β-HSD2

Cortisolo

MR

Cortisolo

MR

Andrews & Walker, 1999

“Occult“ ectopic ACTH syndrome“Occult“ ectopic ACTH syndrome“Occult“ ectopic ACTH syndrome“Occult“ ectopic ACTH syndrome

��ACTHACTH--dependent hypercortisolemia of dependent hypercortisolemia of nonpituitary origin and of more than 6 nonpituitary origin and of more than 6 months’ duration without the emergence of an months’ duration without the emergence of an obvious source.obvious source.

��ACTHACTH--dependent hypercortisolemia of dependent hypercortisolemia of nonpituitary origin and of more than 6 nonpituitary origin and of more than 6 months’ duration without the emergence of an months’ duration without the emergence of an obvious source.obvious source.obvious source.obvious source.

��The bronchial carcinoid is the ectopic ACTHThe bronchial carcinoid is the ectopic ACTH--producing tumor most likely to elude detection producing tumor most likely to elude detection for prolonged periods.for prolonged periods.

��The occult EAS is often clinically and The occult EAS is often clinically and biochemically indistinguishable from pituitarybiochemically indistinguishable from pituitary--dependent Cushing’s disease. dependent Cushing’s disease.

obvious source.obvious source.��The bronchial carcinoid is the ectopic ACTHThe bronchial carcinoid is the ectopic ACTH--

producing tumor most likely to elude detection producing tumor most likely to elude detection for prolonged periods.for prolonged periods.

��The occult EAS is often clinically and The occult EAS is often clinically and biochemically indistinguishable from pituitarybiochemically indistinguishable from pituitary--dependent Cushing’s disease. dependent Cushing’s disease.

Adrenocortical Carcinoma

NON FUNCTIONING

OTHER SECRETIONS

VIRILIZATION

CUSHING and VIRILIZATION

CUSHING

COCHIN SERIES, n=202

36%

5%

4% 11% 24%

20%

SAN LUIGI SERIES, n=187

NON FUNCTIONING

OTHER SECRETIONS

VIRILIZATION

CUSHING and VIRILIZATION

CUSHING

CUSHING and OTHER STEROIDS

48%

16%

24%

7% 5%

Arlt et al. submitted

Cushing ciclico

�� Alternanza di periodi (da pochi giorni a Alternanza di periodi (da pochi giorni a diversi mesi) con elevati livelli plasmatici di diversi mesi) con elevati livelli plasmatici di corticosteroidi a periodi con livelli nella corticosteroidi a periodi con livelli nella norma.norma.norma.norma.

�� Più frequente nel morbo di Cushing, ma Più frequente nel morbo di Cushing, ma anche in EAS, adenoma surrenalico o anche in EAS, adenoma surrenalico o PPNAD.PPNAD.

�� Risposta variabile al desametasone.Risposta variabile al desametasone.

Arnaldi et al. - Cyclical Cushing’s Syndrome in a Bronchial Carcinoid - J Clin Endocrinol Metab 2003

Months

Cyclical Cushing’s syndrome

�� Cyclical Cushing’s syndrome is not a rare variant Cyclical Cushing’s syndrome is not a rare variant or curiosity.or curiosity.

�� It should be suspected when the clinical suspicion It should be suspected when the clinical suspicion of the syndrome is high but tests are negative.of the syndrome is high but tests are negative.of the syndrome is high but tests are negative.of the syndrome is high but tests are negative.

�� It can cause problems with differential diagnosis It can cause problems with differential diagnosis and assessment of remission with drugs or and assessment of remission with drugs or surgery.surgery.

�� It can be diagnsoed by careful sequential It can be diagnsoed by careful sequential biochemistry using either urine or salivabiochemistry using either urine or saliva

Atkinson, 2009

Andrews & Walker, 1999

Different polymorphisms of the GR gene have been associated with

variable sensitivity to glucocorticoids

•N363S

•Bcl I

Hypersensitivity to GC

•Bcl I

•ER22/23EK

•Tth III I

Resistance to GC

Polimorfismo Bcl I e BMD

In pazienti con ipercortisolismo, la presenza in omozigosi del polimorfismo G di Bcl I correla con un ridotto Z-score in regione femorale.

Szappanos et al. - Clinical Endocrinology 2009

LA SINDROME DI CUSHING

DEL 21°°°° SECOLO

�� OvertOvert

FullFull--blown phenotypic expressionblown phenotypic expression

�� MildMild

The Spectrum of Endogenous The Spectrum of Endogenous Glucocorticoid ExcessGlucocorticoid Excess

Moderate phenotypic expressionModerate phenotypic expression

�� SubclinicalSubclinical

?Absent? phenotypic expression?Absent? phenotypic expression

�� Pseudo CushingPseudo Cushing

La casistica dell’Ospedale San Luigi(n=117)

80

100Cushing ipofisario, ipertensione 66%Cushing surrenalico, ipertensione 69%Cushing ectopico, ipertensione 75%No correlazione tra PA e livelli di cortisolo

La sindrome di Cushing quale sindrome metabolica secondaria

0

20

40

60

80

IPERTENSIONE IPERGLICEMIA OBESITA'

No correlazione tra PA e livelli di cortisolo

Sindrome di

Cushing

NELLA PRATICA CLINICA…..

Cushing

sospettataSindrome

di Cushing

accertata

Pseudo-Cushing

Cushing ciclico

��AlcoholismAlcoholism

��DepressionDepression

��PCOPCO

PseudoPseudo--Cushing’s SyndromeCushing’s Syndrome

��PCOPCO

��Eating DisordersEating Disorders

��Glucocorticoid resistanceGlucocorticoid resistance

��ObesityObesityMetabolic syndromeMetabolic syndrome

Cushing’s Syndrome Is NOT Rare

�� Catargi et al., JCEM 2003Catargi et al., JCEM 2003�� 2% of patients with NIDDM (HbA1c >8%)2% of patients with NIDDM (HbA1c >8%)

�� Chiodini et al., EJE 2005Chiodini et al., EJE 2005

�� 9.5% of patients with NIDDM9.5% of patients with NIDDM�� 9.5% of patients with NIDDM9.5% of patients with NIDDM

�� Terzolo et al., End Metab Clin N Am 2005Terzolo et al., End Metab Clin N Am 2005

�� 55--20% of patients with adrenal incidentaloma20% of patients with adrenal incidentaloma

�� Reimondo et al., Clin Endo 2007Reimondo et al., Clin Endo 2007

�� 1% of patients with NIDDM 1% of patients with NIDDM

� 294 pazienti con diabete mellito tipo 2 e 189 controlli

� Dex 1 mg overnight, ripetuto se cortisolo >1.8 µµµµg/dL � Non soppressione confermata in 51 casi (17.3%) e 10 controlli (5.3%)controlli (5.3%)

� Diagnosi di S. di Cushing subclinica in 27 pazienti (9.4%) e 4 controlli (2.1%)

�Adenoma surrenalico in 21 casi

�ACTH ipofisario in 4 casi

�ACTH ectopico in 2 casi

�Non definito in 3 casi

520 soggetti (382 uomini e 138 donne, di età compre sa fra 55 e 82 anni) giunti all’osservazione presso il nostro ospe dale nel periodo

Aprile – Dicembre 2001

Esecuzione di TC torace e addome superiore nell’ambito di un

programma di screening per il carcinoma del polmone

23 masse surrenaliche23 masse surrenaliche(4.4%)(4.4%)

1 mielolipoma1 mielolipoma1 mielolipoma1 mielolipoma21 adenomi21 adenomi21 adenomi21 adenomi1 metastasi1 metastasi1 metastasi1 metastasi

Bovio S et al. Bovio S et al. 200620064.2%4.2%

Il termine “sindrome di Cushing subclinica”, o“ipercortisolismo subclinico”, definisce una diagnosibiochimica di ipercortisolismo in assenza di evidentistigmate cliniche Cushinghiane.La SCS è stata inizialmente proposta per definirealcuni pazienti con incidentaloma surrenalico.alcuni pazienti con incidentaloma surrenalico.Recentemente, la SCS è stata individuata in alcunipazienti con sindrome metabolica o osteoporosi neiquali viene dimostrato un ipercortisolismo occulto.La SCS può anche essere dimostrata in pazienti coniposurrenalismo primario o secondario in terapiasostitutiva.

Proactive Proactive Proactive Proactive

screening in the screening in the screening in the screening in the

“general” “general” “general” “general”

population or population or population or population or population or population or population or population or

not?not?not?not?

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21%21%

22%22%

SIGN/SYMPTOM in 210 SIGN/SYMPTOM in 210 adrenal incidentalomasadrenal incidentalomas

SIGN/SYMPTOM in 302 SIGN/SYMPTOM in 302 patients with Cushing’s’ patients with Cushing’s’

syndromesyndrome

Boscaro M, Lancet 2000Boscaro M, Lancet 2000

54%54%

25%25%

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O E' utile diagnosticare E' utile diagnosticare l'ipercortisolismo subclinico?l'ipercortisolismo subclinico?

Terzolo et al.

Adrenal Incidentaloma: A New Cause of the

Metabolic Syndrome?JCEM 2002

Terzolo et al.

Adrenal Incidentaloma: A New Cause of the

Metabolic Syndrome?JCEM 2002

Tauchmanovà et al.

Patients with subclinical Cushing's syndrome due to adrenal adenoma

have increased cradiovascular risk

Tauchmanovà et al.

Patients with subclinical Cushing's syndrome due to adrenal adenoma

have increased cradiovascular risk

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Chiodini et al.

Eugonadal male patients with adrenal incidentalomas and subclinical

hypercortisolism have increased rate of vertebral fractures. Clin Endocrinol (Oxf). 2008

Chiodini et al.

Eugonadal male patients with adrenal incidentalomas and subclinical

hypercortisolism have increased rate of vertebral fractures. Clin Endocrinol (Oxf). 2008

have increased cradiovascular riskJCEM 2002

have increased cradiovascular riskJCEM 2002

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� Impatto della diagnosi sulla mortalità

� Dati incerti sull'effetto della terapia

chirurgica su morbidità e mortalità

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Subclinical Cushing’s SyndromeSubclinical Cushing’s Syndrome

Cortisol secretion varies according to a spectrum of intensity from non-functioning adenomas to adenomas

associated with subclinical Cushing’s syndrome

1-mg DST>1.8 µµµµg/dL

1-mg DST>5 µµµµg/dL

55%

4%

87 patients, unpublished data

MSC > 3 µµµµg/L 8.8%

100

ACTH<10 pg/mL

UFC>150 µµµµg/24h

>5 µµµµg/dL

27%

4.6%

0 10 20 30 40 50

Causes of Cushing’s syndrome (data based on 423 patients)

Boscaro & Arnaldi, JCEM 2009

THE CUSHING SYNDROME: QUEST FOR THE HOLY GRAIL

THE CUSHING SYNDROME: QUEST FOR THE HOLY GRAIL

D.N. ORTHAnnals of Internal Medicine 1994; 121: 377-8

G. ReimondoS. BovioA. PiaB. AllasinoA. Termine

Grazie per l’attenzione