Definition

A constellation of clinical abnormalities due to chronic exposure to excess of cortisol or related corticosteroid

Sindromul Cushing
Exces cronic al hormonilor glucocorticoizi
1. ACTH dependent Adenom hipofizar secretant de ACTH (boala Cushing) Secretie ectopica de ACTH Rar secretie crescuta de CRH 2. ACTH independent Adenom suprarenalian Neoplasm suprarenalian Hiperlazie nodulara (macro/micro) Iatrogen

CAUSES OF ECTOPIC ACTH SECRETION

Carcinoma of the lung Endocrine tumors of foregut origin

Thymic carcinoid Islet cell tumor Medullary carcinoma thyroid Bronchial carcinoid

50% 35%

Pheochromocytoma Ovarian tumors

5% 2%

Fiziopatologie

Boala Cushing

Sindrom Cushing

Secretie ectopica de ACTH

METABOLISMUL GLUCIDIC
- Cresc depozitele hepatice de glicogen prin stimularea glicogen-sintetazei si supresia glicogenfosforilazei. - Stimuleaza gluconeogeneza hepatica prin cresterea activitatii glucozo-6 fosfatazei si PEPCK din AA, lactat si glicerol. - Scad utilizarea periferica a glucozei - Cresc absorbtia intestinala a glucozei. - Stimuleaza secretia pancreatica de insulina,dar cresc rezistenta receptorilor la insulina.

METABOLISMUL LIPIDIC
- Stimuleaza lipoliza atat direct cat si indirect prin actiunea permisiva pentru catecolamine, GH si glucagon. - Excesul cronic de glucocorticoizi determina redistributia tesutului adipos facio-tronculara datorita numarului si sensibilitatii receptorilor insulinici la acest nivel. - Cresc eliberarea de acizi grasi liberitendinta la cetoza.

OSUL SI METABOLISMUL CALCIULUI

- Excesul cronic determina osteopenie si osteoporoza. - Inhiba functia osteoblastelor apoptoza osteoblastelor si scad formarea de os nouscade osteocalcina. - Supreseaza sinteza de IGF1, stimuleaza osteolizacreste hidroxiprolina urinara. - Scade absorbtia intestinala a calciului si reabsorbtia renala a calciului si fosforuluihiperparatiroidism secundar - Creste secretia de PTH prin actiune directa.

INTERACTIUNI CU ALTI HORMONI

- Inhiba secretia de ACTH si CRH; - Inhiba prin feed-back negativ nespecific secretia de GH, TSH, LH, FSH; - Scad eliberarea de ADH; - Cresc eliberarea de insulina; - Stimuleaza sinteza de epinefrina; - Actiune permisiva pentru angiotensina II ; - Creste secretia de PTH; - Creste activitatea renala de 1hidroxilaza.

 Change in weight and body habitus Look at old pictures Not all patients have all signs and symptoms, especially early and periodic patients. Most published data compared severe Cushings with normals. Important to diagnose early before devastating sequelae develop. Initial diagnosis most difficult aspect of Cushings syndrome. Gestalt with as much information as possible Periodic Cushings common, so one positive test may be worth more than 10 negative tests Make the diagnosis before proceeding to the differential diagnosis??

How to Diagnose Cushings Syndrome Careful history and physical

IMPORTANT SYMPTOMS
Wired at night Trouble sleeping-trouble falling asleep or frequent awakenings Severe fatigue-new onset Abrupt weight gain-without other cause such as decreased activity or depression Decreased ability to exercise Menstrual abnormalities Cognitive changes- brain fog Decreased Libido Symptoms of adrenal insufficiency-joint pains, cant get out of bed, nausea and vomiting Depression, anxiety, mood-swings

IMPORTANT SIGNS
Central obesity Muscle atrophy Thin skin Buffalo hump Round, red face Bruising Extra hair growth Acne Loss of hair on head Stretch marks

Signs/Symptoms
Most patients dont have all these signs/symptoms Many doctors may have only seen 1 case of Cushings and textbooks may show only severe cases.

Manifestari clinice in sindromul Cushing

FIGURE . Multiple wide striae on the abdomen of a patient with Cushing's disease.

INVESTIGATII BAZALE
1.CORTIZOLUL PLASMATIC - Valori normale 5-25g/dl dimineata; - 3-10g/dl la ora 16. - Ritmul circadian- 2/3 se secreta dimineata - 1/3 dupa amiaza. - Valori patologice ICSR valori scazute - sdr. adreno-genital-valori scazute sau normale in functie de deficit. - sdr./boala Cushing- valori crescute.

INVESTIGATII BAZALE
2. CORTIZOLUL SALIVAR - Este util in evaluarea secretiei de cortizol la pacientii ambulatori. 3. CORTIZOLUL LIBER URINAR - Reprezinta 1% din secretia zilnica de cortizol. - Este un index util in apreciarea secretiei/24 ore. - Este indicator sensibil al hipercortizolismului endogen, creste dupa depasirea capacitatii de legare a CBG( >25g/dl).

INVESTIGATII BAZALE
4. 17HIDROXICORTICOSTEROIZII(17OHCS) = produsii de metabolism urinari ai glucocorticoizilor. - Valori normale: 3,5-5,5mg/24ore- la femeie; 5,5-7 mg/24ore- la barbat. - se exprima pe gram de creatinina urinara.

INVESTIGATII BAZALE
5. PRECURSORII CORTIZOLULUI - 11-DEOXICORTIZOL valori<1g/dl la ora 8. - 17OH-PROGESTERON util in diagnosticul deficitului de 21-hidroxilaza,inainte si dupa ACTH. - valori normale: -barbati:60-300ng/dl; -femeie:20-100ng/dl faza foliculara 50-350ng/dl faza luteala >600ng/dl la sfarsitul sarcinii.

INVESTIGATII BAZALE
5. DEHIDROEPIANDROSTERON (DHEAS) - Este principalul androgen CSR. - Valori normale DHEA:2-9g/dl; - DHEAS:0,75-3,7g/dl la barbat 1,1-4,7g/dl la femeie - Valori crescute - boala/sdr.Cushing , carcinom adrenal, sdr. adreno-genital congenital. - Valori scazute insuficienta CSR, deficit de 17hidroxilaza.

TESTE DINAMICE
7. TESTUL DE SUPRESIE CU DEXAMETAZONA # DXM over-night - 1mg la ora 23-24. -raspuns normal-cortizol<5g/dl,ACTH<10pg/ml . # DXM 2mg2 zile -raspuns normal reducerea cortizolului,17OHCS, 17CS cu 50% fata de valoarea bazala. -raspuns pozitiv : hipercorticismul reactiv. # DXM 8mg2 zile -raspuns pozitiv : boala Cushing. -raspuns negativ : sdr. Cushing, ACTH ectopic.

Investigatii diagnostice
2. Precizarea cauzei Dozarea ACTH Teste de supresie la DXM 8mgx2 Testul la CRH Investigatii imagistice pentru vizualizarea SR (TC, RMN, Scintigrama cu I-colesterol), hipofizei (b.Cushing), plamanilor (secretie ectopica) Cateterizarea bilaterala a sinusului pietros cu dozarea ACTH

A Carcinom suprarenalian cu metastaze hepatice (B)

Scintigrama cu Iod-colesterol

A Microadenom si B macroadenom hipofizar

A. Hiperplazie SR bilaterala la unpacient cu B.Cushing B. Adenom SR C. Hiperplazie adrenala macronodulara D. Hiperplazie nodulara

Differential diagnosis
Simple obesity
General obesity, long history, over nourished Narrow and short striae Urinary free cortisol can be suppressed by screening ( overnight ) test and/or lowdose DX suppression test Normal diurnal rhythm, almost normal plasma cortisol

Type 2 DM
Normal plasma cortisol and rhythm Once blood glucose controlled, urinary free cortisol turns to normal

Alcoholic Cushingnoid Syndrome

No drinking for one week, plasma cortisol and urinary free cortisol become normal

Depression
Lack of clinical manifestation of Cushings Syndrome

Tratamentul sindromului Cushing

Chirurgical - Boala Cushing adenomectomie hipofizara transsfenoidala (de electie) sau suprarenalectomie bilaterala - Sindrom Cushing extirparea tumorii suprarenaliene - Cushing paraneoplazic extirparea tumorii

Tratamentul sindromului Cushing

Radioterapie hipofizara pentru prevenirea sd. Nelson dupa suprarenalectomia bilaterala in boala Cushing Tratament medicamentos: - Inhibitori ai sintezei de steroizi: ketoconazol, metyrapon, aminoglutetimid - Mitotan: inhibitor enzimatic, adrenolitic, citostatic (carcinomul suprarenalian)

Sdr. Nelson

2006-RMN adenom hipofizar cu

dimensiunile maxime de 25/16mm

2007 : cortizol seric= 1,56mg/dl ACTH>1250 pg/ml

Sdr. Nelson
Diagnostic
1.

Insuficienta corticosuprarenala primara iatrogena (postsuprarenalectomie bilaterala pentru boala Cushing) Sdr Nelson

2.

Prognosis
Benign adrenal adenoma- 95% 5 year survival, 90% 10 year Cushings disease (pituitary adenoma) same survival, but 10-20% transphenoidal resection failure rate over 10 years. Ectopic ACTH survival depends on malignancy Unknown cause of elevated ACTH- 65% 5 year survival, 55% 10 year survival Adrenal carcinoma- median survival 7 months