Hipertensiunea arteriala endocrina

Sindromul Cushing
Hiperaldosteronismul primar
Feocromocitomul

Corin Badiu, 2015

Blood Pressure Classification (JNC8)

BP Classification

SBP mmHg

DBP mmHg

Normal

<120

and

<80

Prehypertension
HBP Stage1

120139
140159

or
or

8089
9099

HBP Stage 2

160-179

or

100-109

HBP Stage 3

>180

or

>110

James PA et al, 2014 evidence-based guideline for the management of high blood
pressure in adults: report from the panel members appointed to the Eighth Joint
National Committee (JNC 8). JAMA. 2014;311(5):507.

FREQUENCY OF VARIOUS DIAGNOSES IN

HYPERTENSIVE PATIENTS
PRIMARY CARE

REFERRAL

Essential
92-95%
89%
Chronic kidney disease
3-6%
4%
Renovascular disease
0.2-1.0%
4%
Pheochromocytoma
0.1-0.2%
0.2%
Aldosteronism
0.1-0.3%
0.5%
Cushings syndrome
0.1-0.2%
0.2%
Coarctation
0.1-0.2%
1%
Oral contraceptives
0.2-1.0%
1%

HBP in children / adolescents: 50-85% is secondary

Protocol
Confirmarea hipertensiunii
Identifica etiologia
Afectarea periferica
Identifica riscul cardiovascular

Masurare
Metoda

Descriere

In cabinet

Doua determinari, la 5 minute interval, in

sezand. Confirma valorile crescute prin citiri la
bratul contralateral.

Monitorizare
ambulatorie

Indicata pt evaluarea HTA de halat-alb.

Absenta scaderii cu 1020% a TA in somn indica
risc CV crescut.

Auto-determinare

Furnizeaza informatii asupra raspunsului la

terapie. Poate ajuta sa imbunatateasca
complianta la terapie.

Factori de Risc pt Hipertensiune Secundara

Raspuns slab la terapie (HTA rezistenta la > 3 medic din clase )
Pierderea controlului la pacienti stabili pe medicatie anti HTA
Hipertensiune stadiul 3 (SBP>180 sau DBP>110)
Debut inainte de 20 ani sau peste 50 ani
Afectare semnificativa a organelor tinta (cord, ochi, rinichi)
Lipsa istoricului familial de hipertensiune
Elemente de HTA secundara in anamneza, ex clinic sau paraclinic

Hipertensiunea endocrina secundara

suprarenala

Mineralocorticoidexcess
Cushingssyn.

Pheochromocytoma

Suprarenale
Glucocorticoizi (Cortizol)
Cortex Mineralocorticoizi (Aldosteron)
Androgeni Adrenocortical

Medulla

Catecolamine

Histologie
Capsula
Zona glomerulosa
Zona fasciculata
Zona reticularis
Medulosuprarenala

Vena central

Histologie

17HOlaza

CGA

Steroidogeneza specific
Mineralocorticoizi (C21)
Glucocorticoizi (C21)
Androgeni (C19)
Medulosuprarenala

Vena central

Substratul steroidogenezei
22 CH

21 CH 3

20 CH

18

CH 3
12

19
CH 3

HO

A
4

1
2

11

10

8
7

13
14

24 CH

23CH 2

26 CH

25 CH
27 CH 3

17

15

16

Steroidogeneza

Steroidogeneza

Cholesterol
P450CSCC
Pregnenolone

P450C17

3HSD
Progesterone

17-hydroxypregnenolone

P450C17

Dehydroepiandrosterone

(DHEA)

ZR

3HSD
P450C17

17-hydroxyprogesterone

P450C21
Deoxycorticosterone
(DOC)
P450C11B1
Corticosterone
P450C11B2

Aldosterone ZG

P450C21
11-Deoxycortisol

ZG
ZF

P450C11B1

Cortisol

ZF

ZR

Reglarea Axei CSR

CRH / VP
ACTH
Cortisol
Leptina
Citokine
GR, CRHR, V1b, ACTH R,

Ritmul Circadian
600

Stres

Plasma
[ cortisol ]
(nmol/L)

100
00:00 06:00 12:00
Timp

18:00

00:00

Cortisol
OH

90% - CBG: 3Keto

5% - albumina

OH

HO

5% -liber
T1/2 70-120 min

H
O

cortisol

Sindromul Cushing
Sindrom clinic si biochimic determinat de excesul secretiei autonome
endogene de cortizol mineralocorticoizi si androgeni din CSR
ACTH dependent

82%

ACTH Hipofizar
66%
ACTH Ectopic
12%
ACTH cu sursa necunoscuta

ACTH independent

Adenom adrenal
10%
Carcinom adrenal
7%
Hiperplazie macronodulara
1%

4%

18%

Cushing

Istoric tablou clinic

Crestere ponderala
Tegumentar: piele subtire, acnee, ,
hirsutism, echimoze, vergeturi,
hiperpigmentare (ACTH dependent)
Obezitate centrala, facies in luna plina,
adipozitate interscapulo-vertebral si
mobilizarea tesutului adipos de pe membre
Infectii recurente
Amenoree secundara, infertilitate
Scaderea fortei musculare, urca greu
scarile
Depresie, labilitate psiho-afectiva
HTA, DZ, osteoporoza: secundare

Cushing

Cushing

Screening in Cushing

Teste dinamice in Cushing

Teste screening pentru sindrom Cushing:
Cortizol urinar liber
Overnight (ON) 1-mg dexamethasone suppression test.

Confirmarea dg de sindrom Cushing

Ritm cortizol
DXM 2x2 (0.5mg la 6 ore, 2 zile)
(Normal <50nmol/l dupa 48 h)

Stabilirea formei etiopatogenice

DXM 2x8 (2 mg la 6 ore, 2 zile)

(Normal <50nmol/l dupa 48 h)
Dozare ACTH
Cateterizare de sinus pietros

Teste dinamice in Cushing

Diagnostic in Cushing Syndrome

Diagnostic Diferential
ACTH

- nedetectabil in tumori adrenale

- foarte mare in Cushing paraneoplazic

Hypokaliemie (+alcaloza) posibil ectopic sau KK adrenal

DXM 2x8

75% adenom hipofizar (boala C) cortizolul <50% din baza

10% ectopice prezinta supresie semnificativa

Petrosal sinus sampling (+/- CRH)

Nici un TEST nu este 100% precis!

Inferior Petrosal Sinus Sampling

V. femurala ... IPS

CRH 100 ug i.v.
Control - VCI
IPS: -5, 0, 2, 5, 10 min

Imagistica
CT abdominal
MRI
Scintigrafie cu scintandren

(Colesterol I131)

Boala Cushing

Boala Cushing

Cushing adrenal

Nelson

Anatomie patologica

Anatomie patologica

Tratament

Tratamentul sd Cushing se adreseaza secretiei de cortizol.

Terapia primara pentru tumori adrenale este adrenalectomia.
In ACTH ectopic, controlul hipercortisolismului se obtine prin
medicatie.
In boala Cushing: chirurgia hipofizei, adrenalectomie bilaterala,
radioterapie hipofizara
Sd Cushing iatrogen - scaderea progresiva a dozelor
Cand chirurgia nu se poate efectua, se poate controla
hipercortisolismul cu medicatie

Urmarirea postoperatorie:
Tratament diferit in TSR fata de boala Cushing
TSR: substitutie 3 luni, apoi teste de stimulare
Boala Cushing: reevaluare periodica la 3 - 6 -12 luni

Chimioterapie

Hiperaldosteronism primar

Hipertensiune arteriala
Hipokaliemie
Alcaloza metabolica
Poliurie
Clasificare etiopatogenica:
70%: sindrom Conn (tumora G CSR)
30%: Hiperaldosteronism primar cu
hiperplazie adrenala bilaterala (Liddle)

Hipertensiunea mineralocorticoida
Renin - aldosterone system
Low arterial
pressure

Low sodium
intake

Carotid sinus

Low renal
Blood flow

Renin

KIDNEY
Juxtaglomerular
apparatus

Renin substrate

Angiotensin I
(inactive)

Vasoconstriction

Angiotensin II

Thirst

Increased perfusion pressure

Renal sodium &
water retention

Aldosterone

High K+

Dg de forma etiopatogenica
Neoplasm (in cca 60% din cazuri; de obicei adenom,
rar carcinom)
Hiperplazie bilaterala (in 40%)
Sdr. de exces mineralocorticoid includ deficiente
enzimatice
Hiperaldosteronism autosomal dominant corectat de
administrarea de glucocorticoizi

Evaluare paraclinica
Teste de rutin, biochimie i hematologie
Analiza de urin: inclusiv densitatea, albuminurie,
Potasiu seric, calciu, creatinina
Functie tiroidiana,
Colesterol, TG
EKG
radioscopie torace
Catecolamine
Ecocardiografia

Forme etiopatogenice

Adenom CSR cu productie de aldosteron (APA)

Hiperplazie bilateral idiopatic (IHA)

Hiperplazie suprarenala primara (unilateral)

Carcinom adrenocortical cu productie de Aldosteron

Hiperaldosteronism familial

Hiperaldosteronism remediabil cu glucocorticoizi (FH tip I)

Hipertensiune arterial prin deoxicorticosteron

Exces aparent de mineralocorticoizi

Anatomie patologica

Tratament
Adrenalectomie laparoscopica
Terapie medicala daca trat chg este contraindicat
Spironolactona (50-200mg), corecteaza hipertensiunea
R Adv: efecte antiandrogenice care determina TDS si
ginecomastie.

Laparoscopic

Left adrenal mass,

Left laparoscopic
adrenalectomy

Evaluare postoperatorie
Functional: secretie tumorala (aldosteron/ renina,
cortizol), ionograma
Rezerva functionala CSR: test la Synacthen
Morfologic: Imagistica adrenala
Complicatii: Ecografie cord, Oftalmologie

Feocromocitom
0.01-0.1% din populatia HTA
0.5% din cei verificati pt secretie de catecolamine

M=F
Decada de viata 3 -5
Rara, de investigat doar in suspiciune clinica:

Semne sau Simptome

HTA severa, criza HTA
HTA refractara (> 3 clase de medicamente)
HTA la < 20 sau > 50 ani
Leziune adrenala la imagistica SR (ex. incidentalom)

Regula 10

10% extra-adrenal (cca 15%)

10% apar la copii
10% familial (aprox 20%)
10% bilateral sau multiplu (> in F familial)
10% recidiveaza (> cele extra-adrenale)
10% maligne
10% descoperite intamplator

Clinica
Cinci P:

Pressure (HTA) 90%

Pain (Headache) 80%
Perspiration
71%
Palpitation
64%
Pallor
42%
Paroxysms (the sixth P!)

Triada clasica:
Pain (Headache), Perspiration, Palpitations
Lack of all 3 virtually excluded diagnosis of
pheochromocytoma in a series of > 21,0000 patients

Efecte vegetative

Receptori Adrenergici
Alfa-Adrenergici
1: vasoconstrictie, relaxare intestinala, contractie uterina,
dilatare pupilara
2: NE presinaptic (clonidina), agregare plachetara,
vasoconstrictie, secretiei de insulina

Beta-Adrenergici
1: AV / contractilitatii, lipolizei, secretiei de renina
2: vasodilatatie, bronchodilatatie, glicogenoliza
3: lipoliza, termogeneza in tesut adipos brun

Criza

Durata 10-60 min

Frecventa: zilnic ----- la cateva luni
Spontan
Precipitata
Proceduri diagnostice, contrast I.A. (I.V. nu determina criza)
Medicatie (opiode, -blocante fara -bloc. inductia
anesteziei, histamina, ACTH, glucagon, metoclopramida)
Efort fizic, miscari care cresc presiunea intra-abdominala
Mictiune (paragangliom vezical)
Nasterea

Hipotensiune
Hipotensiune (ortostatica/paroxistica)
Mecanisme:
Contractia V LEC
Pierderea reflexelor posturale data de stimulare
adrenergica prelungita
Secretie tumorala de adrenomedulina
(neuropeptid vasodilatator)

Clinica
Dureri abdominale, constipatie severa (megacolon)
Dureri precordiale
Anxietate
Angina/IM cu artere coronare normale:

Catecholamin- indusa: consumul de oxigen miocardic sau

vasospasm coronarian

Insuf cardiaca globala

HTA cardiomiopatie hipertrofica disfunctie diastolica
Cardiomiopatie dilatativa indusa de catecolamine disfunctie
sistolica

Aritmii cardiace & defecte de conducere

Genetica
Sindrom

Anomalie
genetica

Anomalie fenotipica

MEN 2A, 2B

10 q11.2
(RET)

MCT, HPTR, FEO,

neuroame mucoase,
ganglioneurinom

Neuroectodermale
NF-1

17q11 (NF-1)
3p25-26 (VHL)

Neurofibromatoza
Angioame retiniene, KK
renal, Hemang SN

SDH B
SDH C,D

1p36
1q21, 11q23

PGGL, FEO malign

Un sfert din feocromocitoame- determinare genetica

MEN2 screening

S. Radian, C. Badiu et al, Acta Endocrinologica (Buc), vol. III, no. 1, p. 13 - 22, 2007

From genes to clinical picture

F, 50 y, severe HBP, Takotsubo cardiomyopathy
6 mutations (4 SDHC, 2 SDHA)
Preop

Postop

Mariana Dobrescu, Simona Verzea, Corin Badiu Acta Endocrinologica (Buc), vol. V, no. 4, p.543, 2009

Catecolamine
Tyrosine

TH

L-Dopa

Metaboliti
Dopamine

MAO, COMT

DBH

Homovanillic acid
(HVA)

Norepinephrine COMT Normetanephrine

PNMT

Epinephrine

MAO
COMT

Metaneprine
MAO

Vanillymandelic Acid
(VMA)

Catecolamine
Tyrosine

TH

L-Dopa

Metaboliti
Dopamine

MAO, COMT

DBH

Homovanillic acid
(HVA)

COMT
Norepinephrine
Normetanefrine
PNMT

Secretia tumorala:
Feo mare: > metaboliti

Epinephrine COMT

(metabolizare in tumora inainte de secretie)

Feo mic: more catecholamines

Feo Sporadic : NE > E
Feo Familial: E > NE
Paragangliom: NE
Chemodectom, glomus jugular: NE
Ganglioneurom: NE
Feo malign: Dopamina, HVA
Neuroblastom: Dopamina, HVA

MAO

Metanefrine
MAO

Vanilmandelic Acid
(VMA)

HTA paroxistica

Dwight David Eisenhower (1890-1969)

Repetate crize de angor, cu documentarea EKG a 8 episoade de IMA

TSR stg (feocromocitom), 1,5 cm

Messerli et al, Am J Cardiol 2007;99:13251329

Morfologie
Small (mg), circumscribed to large (kg) masses
Small polygonal cells arranged in vascular nests
Electron microscopy - membrane bound granules
(catecholamines)
Malignancy is based on metastasis

Metabolism
Hypercalcaemia
Associated MEN2 HPT
PTHrP secretion by pheochromocytoma

Mild glucose intolerance

Lipolysis
Weight-loss
Ketosis > VLDL synthesis (TG)

Familial

MEN 2a
50% pheochromocytoma (usually bilateral), MTC, HPT
MEN 2b
50% pheochromocytoma (usually bilateral), MTC, mucosal
neuroma, marfanoid habitus
Von Hippel-Landau
50% pheochromocytoma (usually bilateral), retinoblastoma,
cerebellar haemangioma, nephroma, renal/pancreas cysts
NF1 (Von Recklinghausen's)
2% pheochromocytoma (50% if NF-1 and HTN)
Caf-au-lait spots, neurofibroma, optic glioma
Familial paraganglioma
Familial pheochromocytoma & islet cell tumor
Other: Tuberous sclerosis, Sturge-Weber, ataxia-telangectgasia,
Carneys Triad (Pheochromocytoma, Gastric Leiomyoma, Pulmonary
chondroma)

Metanefrine plasmatice
Nu sunt dependente postural: pot fi recoltate normal

Secretate continuu de feocromocitom

Sensibilitate 99%, specificitate 89%
Fals pozitiv: acetaminophen

Interferente de dozare
Medicatie care creste fals pozitiv nivelul metanefrinelor
urinare:

Tricyclic antidepressants
Levodopa
Labetalol
Ethanol
Sotalol
Amphetamines
Buspirone
Benzodiazepines
Methyldopa
Chlorpromazine

Medicatie care scade nivelul metanefrinelor urinare :

Methyltyrosine, which inhibits tyrosine hydroxylase, the ratelimiting enzyme in catecholamine synthesis
Methylglucamine, which is present in radiocontrast media
Reserpine

Teste in urina
24h: Creatinina, catecolamine, metanefrine, normetanefrine
Rezultate Pozitive (> 2-3 ori):
24h Ucatechols > 2 ori
24h Utotal metanephrines > 1.2 ug/d (6.5 umol/d)

Teste salivare

A. M. Stefanescu et al, Acta Endocrinologica (Buc), vol. VII, no. 4, p. 431-442, 2011

Localizare imagistica
Ultrasonografia
CT abdomen
Feocromocitom adrenal - sensibilitate 93-100%
Feocromocitom extra-adrenal - sensibilitate 90%

MRI
> sensibilitate CT pt feocromocitom extra-adrenal

MIBG Scan
sensibilitate 77-90%, specificitate 95-100%

Ecografia

A fost inlocuita de CT si MRI; este limitata de

pregatirea tractului digestiv

Valoare limitata in diferentierea leziunilor chistice de

cele solide in adrenala

MRI este preferata ca modalitate de investigare.

Ecografia in Feocromocitom

CT in Feo

Leziuni adrenale >1 cm, extra-adrenale >2 cm, sensibilitate 95%, specificitate 70%

Cavografie / CT in Feo

NMN=1608/1304 pg/mL, MN=23/17 pg/mL, NMN/24 ore=2898 mcg, MN/24 ore=59 mcg
Cromogranina A=638 ng/mL

IRM in feocromocitom

T1 weighted

T2 weighted

Localizare imagistica nucleara

MIBG

Indium-pentreotide

111

Some pheochromocytomas have somatostatin

receptors

PET
18F-fluorodeoxyglucose (FDG)
6-[18F]-fluorodopamine

Imagistica nucleara
I-MIBG si 123I-MIBG sunt concentrate in sistemul simpatomedular si pastrate in granule de neurosecretie

131

Aproximativ 30% din patienti, au un uptake mai mic decat cel

hepatic.

In feocromocitom, 131I-MIBG evidentiaza tumora ca o arie in

glanda suprarenala cu captare crescuta.

123

I-MIBG permite o calitate mai buna a imaginii, poate fi

evaluat prin single photon emission computed tomography
(SPECT), are expunere mai mica la radiatii si rezultate in timp
mai scurt.

MIBG

In feocromocitom, 131I-MIBG evidentiaza tumora ca o

arie in glanda suprarenala cu captare crescuta.

Metastatic Pheo
12.2012: I131- MIBG scan: tracer pathological uptake
on both lungs, without abdominal or cervical uptake

17.01.2013: I131- MIBG therapy 150 m Ci

07.2012- present: asymptomatic, normotensive
patient

MEN2 screening

S. Radian, C. Badiu et al, Acta Endocrinologica (Buc), vol. III, no. 1, p. 13 - 22, 2007

Macroscopic view of a malignant pheochromocytoma,

demonstrating capsular invasion, hemorrhage, necrosis,
and multinodularity

The characteristic small nests pattern was seen in all

pheochromocytomas, whether benign or malignant. A
granular, basophilic cytoplasm was usually
identified surrounding slightly irregular nuclei (right)

The characteristic chromogranin (left) immunoreactivity

in the pheochromocytes is contrasted to the S-100
protein immunoreactivity of the supporting sustentacular
supporting cells (right) in this benign pheochromocytoma

Management: medical si anestezic

Antagonisti Alfa fenoxibenzamina* +/- metirosina*

Incepe cu 10mg /zi cu crestere progresiva sub control HTA

Corecteaza depletia volumica

Beta blocada doar dupa alfa blocada completa, cu propranolol, atenolol,
labetalol
Evita eliberarea de histamina
Monitorizare invaziva arteriala IOp
Anestezie si sedare pre-op. Se evita halotanul (poate precipita aritmii)
Control volum intravascular si TA
Nitroprusiat Na i.v in perfuzie lenta, sub monitorizarea invaziva a TA
Norartrinal i.v in perfuzie lenta, sub monitorizarea invaziva a TA
*Nota: tipic, sunt necesare 10-14 zile de tratament pre-op

Clase de Terapie
Vasodilatatoare

Nitroprusiat, Nitroglicerina

Beta-blocante eg. Labetalol

Alfa-blocante eg. Fentolamina
Blocante de Ca eg. Nicardipine

Regim de pregatire preoperatorie

+ blocada combinata
Fenoxibenzamina
Selective 1-blocker (ex. Prazosin)
Propranolol

Metirozina
Blocante de Calciu (CCB)
Nicardipina

Preop: + blockade
Start at least 10-14d preop
Allow sufficient time for ECFv re-expansion

Phenoxybenzamine

Special pharmacy access only (no DIN)

Drug of choice
Covalently binds -receptors (1 > 2)
Start 10 mg po bid increase q2d by 10-20 mg/d
Increase until BP cntrl and no more paroxysms
Maintenance 40-80 mg/d (some need > 200 mg/d)
Salt load: NaCl 600 mg od-tid as tolerated

Preop: + blockade
-blockade
Used to control reflex tachycardia and prophylaxis
against arrhythmia during surgery
Start only after effective -blockade (may ppt
HTN)
If suspect CHF/dilated CMY start low dose
Propanolol most studied in pheo prep
Start 10 mg po bid increase to cntrl HR

Management: rezectie chirurgicala

Midline or transverse abdominal incision
Bilateral adrenal exploration along with exploration
of para-aortic and paracaval retroperitoneum
(diaphragm to pelvis)
Laparoscopic approach acceptable via a flank,
retroperitoneal, or transabdominal approach

Shorter hospital LOS

Lower morbidity rate
Higher incidence of missed paragangliomas/multiple
tumors
Robotic surgery

Feocromocitom malign

Recidivele apar in 5 -10 ani dupa rezectia leziunii primare

Pot fi detectate 20 ani mai tarziu.
Supravietuirea la cinci ani: 36 - 60%.
Tratament

Resectia metastazelor
Controlul TA
Radioterapia (paliativ) pentru metastaze osoase.
Terapie ablativa cu I-MIBG - raspuns partial
Chemoterapie combinata (ciclofosfamida, vincristina si
dacarbazina) poate fi eficace.

Concluzii

HTA endocrina HTA secundara

CSR / MSR
Teste diagnostice functionale in dinamica
Tratament chirurgical