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Giorgio ArnaldiClinica di Endocrinologia e Malattie del Metabolismo
Ospedali Riuniti di AnconaAncona [email protected]
Cushing e diabete
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December 29, 1910
Minnie G23 year old woman
obesityhirsutismhypertensionamenorrhea
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• Cushing’s syndrome is a disorder of chronic hypercortisolism
• Cushing’s Syndrome was described by Harvey Cushing in 1932 as the ‘killing disease’
• Cushing’s disease is the most frequent form of endogenous hypercortisolism
Cushing’s disease
Cushing’s disease is a form of Cushing’s syndrome
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......la sindrome di Cushing iatrogena è comune:
•1% della popolazione usa glucocorticoidi per via orale (3% neipazienti >70 anni)
• diffuso e cronico uso di glucocorticoidi per via parenterale, topica e per inalazione
La sindrome di Cushing endogena è rara ma……
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Definizione
Sindrome di CushingCondizione clinica dovuta ad eccesso inappropriato e prolungato di glucocorticoidi
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Aldosterone
Cortisolo
Ormoni sessuali
Catecolamine
Struttura, ormoni e funzioni del surrene
GLUCOcorticoidi
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7
Hypercortisolism stimulates gluconeogenesisand inhibits insulin sensitivity
● Glucocorticoid excess contributes to the development of insulin resistance and can impair insulin secretion
● These mechanisms are related to the development of diabetes mellitus
Pivonello R et al. Neuroendocrinology 2010;92(Suppl 1):77–81
Glucose production (EGP)
Gluconeogenesis Insulin sensitivity
Directly Indirectly
Glucose uptake (IMGU) Glycogen synthesis (IMGS)
Insulin sensitivity
Inhibition of insulin receptor signaling
Change in lipid and protein metabolism
Directly Indirectly
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Agenda
• Forma esogena vs endogena• Prevalenza del diabete nel Cushing• Prevalenza del Cushing nel diabete ?• Quali conseguenze ?• Quale terapia ipoglicemizzante ?
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Diabete nel Cushing esogeno
• Complicanza comune• Difficile stimare il rischio di sviluppare il diabete
in corso di trattamento steroideo– popolazioni con diversa suscettibilità legata alla
malattia di base ed alle caratteristiche individuali del paziente (età, comorbidità, fattori genetici)
• Il rischio di iniziare un trattamento ipoglicemizzante aumenta con l’aumentare della dose di steroide (Gruwitz et al. Arch Int Med 1994)
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GLUCOCORTICOID RECEPTOR GENE
LOCUS 5q31
GR GENE POLYMORPHISMS(A3669G)
Crucial role for the variable response to glucocorticoids ?
dbSNP list
• 500 SNPs in 2008• 3016 SNPs now
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Trapianto renale127 PAZIENTI(2004-2014)
4 DM PRIMA TRAPIANTO
2 NUMEROSI EPISODI RIGETTO 1 TRAPIANTO COMBINATO
Basale(n120)
Mese-3(n120)
Mese-6(n116)
Mese-12(n112)
LFU(n110)
5,38 ± 2,58 anni
14,92 ± 3,94 mg/die
6,34 ± 3,12 mg/die
5,34 ± 1,68 mg/die
5 mg/die
Prednisone
77,5%
19,2%
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0
5
10
15
20
25
30
35
40
45
50
BASALE 3 MESI 6 MESI 12 MESI LFU
DM
IFG e/o IGT
87,5%
4
4,5
5
5,5
6
6,5
7
70
80
90
100
110
120
130
140
basale Mese-3 Mese-6 Mese-12 LFU
Glicemia
HbA1c
57% 60% 72%
17,5% 20%16,9%14,6%
Diabete Mellito post trapianto di rene: prevalenza
Andamento di glicemia ed emoglobina glicata nei pazienti chesviluppano alterazioni del metabolismo glucidico. Lepercentuali in basso al grafico si riferiscono ai pazienti interapia ipoglicemizzante.
Prevalenza della alterazioni del metabolismoglucidico a 3-6-12 Mesi e al LFU dopotrapianto di rene
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VARIABILI Odds ratio (95% CI) p
Età al trapianto, (anni) 1,60 (1.26–1.91) 0.002
BMI, (Kg/m2) 1,17 (1.03–3.31) 0.004Polimorfismo BclI
Recettore dei Glucocorticoidi 3,40 (1.90-5.45) 0.032
A HuGE Review and Meta-Analyses of Genetic Associations in New Onset Diabetes after Kidney Transplantation, 2016
Variabili cliniche indipendenti per lo sviluppo di NODAT
Analisi Multivariata dei fattori di rischio indipendenti per NODAT
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Agenda
• Forma esogena vs endogena• Prevalenza del diabete nel Cushing• Prevalenza del Cushing nel diabete ?• Quali conseguenze ?• Quale terapia ipoglicemizzante ?
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Metabolismo glucidico nella Sindrome di Cushing
% dei pazienti
Patients with Cushing‘s Syndrome often have insulin resistance and beta-cell dysfunction
Mancini et al., Clinical Endocrinology ,2004
• Indipendente dalla eziologia del Cushing
• Correla con la severità dell’ipercortisolismo
• Non correla con la sua durata
• FGP spesso normale
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Eur J Endocrinol 166: 35-42, 2012
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CUSHING’S SYNDROME
INCREASED CARDIOVASCULAR RISK
(4-times HIGHER MORTALITY RATE compared with
general population) due to:
- Hypertension
- Impaired glucose tolerance or diabetes
- Insulin resistance
- Central obesity
- Dyslipidemia
Metabolic Syndrome
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Cardiovascular Comorbidities in patients with Cushing’s syndrome
0
5
10
15
20
25
30
35
40Pa
tient
s %
1 2 3 40Number of comorbity in the same patient
Arnaldi et al, Pituitary 2004
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Pazienti con diabete mellitopossono nascondere unaSindrome di Cushing?
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Agenda
• Forma esogena vs endogena• Prevalenza del diabete nel Cushing• Prevalenza del Cushing nel diabete ?
– Necessità di diagnosi precoce
• Quali conseguenze ?• Quale terapia ipoglicemizzante ?
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Quadro clinico• Manifestazioni cliniche variabili
– Grado e durata dell’ipercortisolismo– Sensibilità individuale
• Nella forma tipica il quadro clinico è chiaro ma……..
• In molti casi, il fenotipo è meno chiaro e può ingannare
• Alcuni pazienti hanno solo segni e sintomi isolati
• Presentazioni atipiche – Ipercortisolismo lieve (mild)– Ipercortisolismo intermittente e ciclico
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J Clin Endocrinol Metab 94: 3121–3131, 2009
Sign/symptom Frequency %
Truncal obesity 97Moon face 89Hypertension 76Skin atrophy and bruising 75Diabetes or glucose intolerance 70Gonadal dysfunction 69Muscle weakness 68Hirsutism, acne 56Mood disorders 55Osteoporosis 40Oedema 15Polydipsia/polyuria 10Fungal infection 8
Tromboembolism
Recurrent infections
Difficult wounds
Hypokalemia
Nephrolitiasis
Fractures
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E’ necessario essere un endocrinologo per fare diagnosi di sindrome di Cushing ?
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• Obesità addominale Ipertensione Diabete/Intolleranza Dislipidemia Stato Protrombotico PCOS/iperandrog. Acne Oligo-amenorrea Osteoporosi Fratture Miopatia /fragilità cute Depressione/labilità
emotiva Nefrolitiasi Deficit erettile/calo libido
E’ necessario essere un endocrinologo per fare diagnosi di sindrome di Cushing ?
Medico di base
Ginecologo
Diabetologo
Internista
Ortopedico
Urologo
Cardiologo
Neurologo
Dermatologo
Reumatologo
Psichiatra
Andrologo
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Clinical Case - 52 year old woman • Worsening of diabetes mellitus
– Fasting glycemia 180 mg/dl– HbA1c 10,5%
• Diabetes mellitus (for 1 year) in therapy with metformin• Hypertension (for 10 years) in medical treatment• BMI 33 Kg/m2
Past history
Cholecystectomy (1985)Hysterectomy for uterine fibromas (1996)Kidney lithiasis (2000)Thyroidectomy for toxic multinodular goiter (2006)•Thyroid papillary carcinoma (2 mm diameter)
Family historyNo known specific disease
Cushing?
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Screening di pazienti conDiabete Mellito
Come e con quali costi economici ed organizzativi?
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HbA1c ScreeningTest
True Positive False positive(cut-off used)
Leibovitz et al., 1996(n=90)
>9% oDST 3% 1% (140 nmol/L)
Catargi et al. , 2003(n=200)
>7% oDST 2% 15% (60 nmol/L)
Chiodini et al., 2005(n=294)
9.6±2.4% oDST 9.4% 7% (50 nmol/l)
Reimondo et al., 2007 (n=100)
12% (inpatient)
9.6% (outpatient)
oDST 1% 32% (50 nmol/l)5% (110 nmol/l)
Mullan et al., 2010(n=201)
>7% MSC 0% 23% (10 nmol/l)
Terzolo et al., 2012 (n=813)
8.4±1.9% oDST 0.7% 22% (50 nmol/l)4% (138 nmol/l)
Summary of screening studies in diabetic populations
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Terzolo et al.J Clin Endocrinol Metab, October 2012, 97(10):0000–0000
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None was found to have Cushing
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Effetti dell’ invecchiamento sull’asse HPA• Aumento del cortisolo plasmatico (totale e libero)• Aumento del cortisolo salivare• Anticipo del picco della cortisolemia del mattino• Ritmo del cortisolo tendenzialmente appiattito• Ridotta ampiezza della secrezione del cortisolo nelle 24 ore• Aumento della frammentazione della secrezione del cortisolo• Invariato il cortisolo urinario 24 ore• Invariata la CBG• Aumento della produzione giornaliera del cortisolo• Lieve decremento della clearance plasmatica del cortisolo• Minore soppressione della cortisolemia dopo test con desametazone• Non differenza nella risposta dell’ACTH dopo CRH ma ridotta capacità• del desametazone ad inibirne lo stimolo• Ridotta risposta del cortisolo dopo ACTH• Ridotta risposta dell’ACTH e del cortisolo allo stress nei più anziani
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o Poorly controlled diabetes mellitus and chronic complications of diabetes mellitusmay result in HPA axis activation
o This drawback may cause numerousfalse-positive results when the screening strategy was applied toindividuals with diabetes mellitus
Underlying diseases influence the diagnostic performance of testing
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L’asse ipotalamo-ipofisi-surrene puòessere influenzato dalla presenzadel diabete mellito :
1.falsi positivi diagnostici ?
2.correlazioni cliniche ?
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2013
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L’ asse ipotalamo-ipofisi-surrene può essere influenzatodalla presenza di diabete mellito :
1. falsi positivi diagnostici?
2. correlazioni cliniche ?
L’ asse ipotalamo-ipofisi-surrene è attivato in corso didiabete mellito specialmente se scompensato.
1. Attenzione ai falsi positivi durante screeningdiagnostico per l’ipercortisolismo
2. I livelli di cortisolo anche entro range di normalitàcorrelano con le complicanze
Diabete mellito ed ipercortisolismo
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Overt Cushing’s syndrome1-3/milion/year
Pseudo-CushingObesity
HypertensionDepression
DiabetesOsteoporosis
Possible, probableand confirmed Cushing’s syndrome
Mild / subclinicalCushing’s syndrome ???
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Sindrome di Cushing e Diabete Mellito
Quale test usare per lo screening?Conoscenza
Sospetto diagnosticoGiudizio clinico
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Agenda
• Forma esogena vs endogena• Prevalenza del diabete nel Cushing• Prevalenza del Cushing nel diabete ?• Quali conseguenze ?• Quale terapia ipoglicemizzante ?
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Cushing’s Disease: Which drug ?
Approved in patients with endogenous Cushing’s syndrome who have type 2 diabetes or glucose intolerance and are not candidates for surgery or who have not responded to prior surgery
Law 648/96
Pasireotide Approved SSN
Approved SSN
Approved SSN
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Trementino at al., Pituitary 2014
Control of disease may outweigh any negative effects on glucose
metabolism
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Liver AMPK Adipose AMPK
Glucocorticoids
Hypothalamic AMPK
Increased food intake
Fatty liverlipolysis
=Flux of free fatty acids
lipogenesis
Insulin Resistance
Christ-Crain & Kola et al.
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Double-blind, placebo-controlledtrial, patients startingglucocorticoid treatment for fourweeks were randomised to concomitantly receive metformin(850 mg once daily for one week followed by 850 mg twice daily for three weeks) or placebo.
29 patients who did not havediabetes mellitus
All patients underwent astandardised oral glucosetolerance test at baseline and after four weeks.
The primary endpoint was changein the 2-h area under the curve (AUC) of glucose during the oralglucose tolerance test betweenbaseline and four weeks.
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La Sindrome di Cushing: percorsi per il paziente
Ancona 28 Ottobre 2017
Hotel Ego
…..a tutti voi per l’attenzione !!!