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SCLERODERMIA
Prof.Dr.Ruxandra Ionescu
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SCLERODERMIA
Caracteristici:• vasculopatie functionala si structurala• fibroza, lez. degenerative piele, org. interne
Epidemiologie
• Prevalenta- 4 cazuri /1milion(1975) ; 126 cazuri/1miliondupa 1975•
Incidenta18-29 cazuri/1 milion/an• Frecventa >F F/B=3/1
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ETIOLOGIE
• FACTORI TOXICI- uleiuri industriale
hidrocarburi, pulberi siliciu
medicamente
• TERENUL GENETIC HLA DR2, DR3anomalii cromozomiale
gena fibrilina I
•
FACTORI IMUNI AAN, TCD4+, IL2reactie grefa contra gazda
(microchimerism fetal)
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SCLERODERMIA
(SCLEROZA SISTEMICA)
PATOLOGIA
• Vasculopatie functionala si structurala
• Inflamatie perivasculara
• Fibroza si leziuni degenerative piele, organe interne
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PATOGENIA SCLERODERMIEI
Etape :
•
Injuria celulei endoteliale• Activarea imuna
• Selectarea unei populatii de fibroblastiactivi
• Fibroza
-
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CELULA ENDOTELIALA
- implicata in etapele initiale ale bolii-
Injuria celulei endoteliale
- factori neimuni
toxici, stress oxidativ - radicali liberi oxigen
- factori imuni
factor citotoxic limf.T,NK,C5b-C9, ac.antiendoteliali anti colagen IV,
Activarea celulei endoteliale- cresterea expresiei moleculelor de adeziune
- atractia leucocite si infiltrat perivascular
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ROLUL CELULEI ENDOTELIALE
Intervine in:
• Reglarea tonusului vascular
•
Prevenirea trombogenezei• Inflamatie (regleaza traficul leucocite spre
focarul inflam)
•
Raspunsul imun
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REGLAREA TONUSULUI VASCULAR
Factori relaxare Factori constrictori
TONUS VASCULAR
EDRF/NOProstaciclinAdenozina
EndotelinaTxA2
Catecolamine
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INJURIA CELULEI ENDOTELIALE
-modificarea tonusului vascular-vasoconstrictie excesiva
• EXCES ENDOTELINA1 (ET)
- vasoconstrictor puternic-
• SCADEREA NOefect vasodilatatorantitromboticinhiba expresia molec adeziune
Disfunctie endoteliu = sinteza, eliberare scazuta NO
• SCADERE PROSTACICLIN
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CELULA MUSCULARA NETEDA
vasoconstrictie
CELULA ENDOTELIALA
MACROFAGActivare NF-k B
Eliberare citokine
FIBROBLASTProliferare fibroblast
Sinteza colagenInhiba producere MMP
SISTEM NERVOS SIMPATICFunctie baroreceptori
ENDOTELINAInterventia in etapele patogenice ale sclerodermiei
ENDOTELINA1988
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INJURIA CELULEI ENDOTELIALE
• ACTIVARE, AGREGARE TROMBOCITARA
Eliberare de :
• TxA2 , amine vasomotorii – vasoconstrictie, agregare plachetara
• Factori de crestere (TGFb, PDGF)
PDGF - efecte chemotactice, mitogene fibroblast
TGFb - stimuleaza sinteza colagen
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ACTIVAREA CELULEI ENDOTELIALEcresterea expresiei molecule adeziune
E/P-selectina
Activareab2-integrin
INFILTRAT INFLAM.PERIVASCULAR
Endoteliu
van Deventer SJH. Gut. BMJ Publishing Group. 1997; 40: 443-448
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PATOGENIA SCLERODERMIEI
Etape :
•
Injuria celulei endoteliale• Activarea imuna
• Fibroza
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FIBROBLASTUL IN SCLERODERMIEstimulat excesiv
CITOKINEIL-4, IL-6, IL-17,PDGF, TGFb
ENDOTELINA
EXCES COLAGEN, FIBRONECTIN
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FIBROBLASTULCELULA SPECIFICA A TESUTULUI CONJUNCTIV
• IN SCLERODERMIE :EFECTORUL CELULAR AL BOLII
depunere excesiva de colagen, matrice extracelulara in tegument, organe interne
- distrugerea arhitecturii normale- disfunctie tisulara si organica
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MODIFICARI ANATOMOPATOLOGICE
INJURIA ENDOTELIALAAGREGARE PLACHETARA
1. VASOCONSTRICTIE FUNCTIONALA
EndotelinaCatecolamine
TxA2
Scadere NO, PGI2
2. MODIFICARI STRUCTURALEVASCULARE
infiltrat perivascular,proliferari intimale,
ocluziefibroza intimala
perivascularaDISTRUGERI TISULARE
Endotelina
TGFb
3. FIBROZA DERM, ORG. INTERNE
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TEGUMENT
• LEZIUNI VASCULARE
Sindrom Raynaud
• LEZIUNI INFLAM-EXUDATIVE
• LEZIUNI CRONICE
indurative , atrofie
Acumulare colagen, I,III
Reducere tesut elasticReducere foliculi
pilosebacei
Anomalii pigmentare
Telangiectazii
Calcificari subcutane
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SINDROM RAYNAUD
InitialVasoconstrictia functionala
Ulterior
Leziuni fibrotice obliterative
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ACROOSTEOLIZA
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MANIFESTARI VASCULARE IN SCLERODERMIEULCERATII DIGITALE, TELANGIECTAZII
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MODIFICARI DIGESTIVE
• Subtierea mucoasei
• Atrofia muscularei
•
Acumulare colagen
Scaderea peristalticii
Disfunctie sfincteriana
Diverticuli pulsiune
STRUCTURI AFECTATE
ESOFAGSTOMACINTESTIN SUBTIRE,COLON
FICAT
ULCERATII
AFECTAREA PULMONARA
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AFECTAREA PULMONARA1.HIPERTENSIUNEA ARTERIALA PULMONARA
(HTP)2. FIBROZA INTERSTITIALA DIFUZA
30-50% din pacientidezvolta HTP
HTP
•
izolata(60% pacienti sindrom CREST
In a 2a decada de evolutie a bolii)
• asociata cu FIP SS cu afectare cutanata difuza
dupa 5-10 ani de evolutie a FIP
• Vasoconstrictie reactiva
analoga S.Raynaud
• Vasoconstrictie hipoxica(FIP)
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HIPERTENSIUNE ARTERIALA PULMONARA DINSCLERODERMIE
• Proliferare intimala,ocluzie vasculara
• Fibroza perivasculara
• HTP
( PAP>25mmHg repaus >30mmHg efort)
• Solicitare cord drept
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DIAGNOSTIC HTP
CLINIC• Suspiciune dg
S CRESTAfectare cutanata extinsa
•
Simptome nespecificeDispnee la efortAstenie
• Examen fizicIntarire ZgP2
Jugulare turgescenteSuflu ITEdeme perifericeAscita
PARACLINIC
• TLCO<55%
• Volume pulmonare
(CPT, CV, )
a) normale= HTP izolata b) scazute = HTP sec FID
• Ecocardiografie Doppler(regurgitare tricuspidiana)
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EXPLORARI PARACLINICE
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FIBROZA INTERSTITIALA DIFUZA
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EXPLORARI PARACLINICE
• Cateterism cord drept
(diagnostic standard)
• Lavaj bronhoalveolar
• CT
• CT rezolutie inalta
• Explorari izotopice
(reactii fals pozitive fumatori)
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AFECTAREA RENALACRIZA RENALA SCLERODERMICA
Debut acut
• HTA severa (retinopatie hipertensiva gr III-IV)
•
Insuficienta renala• Anemie hemolitica microangiopatica
• Modificari sediment urinar
(proteinurie usoara, microhematurie, cilindrii granulosi)Modificari histologice
• Artere arcuate si interlobulare
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PATOGENIA CRIZEI RENALE
Injuria celulei endoteliale
Proliferare intimalaOcluzie vasculara
Scadere flux sanguin
Hiperplazie juxtaglomerulara
Cresterea productiei renina
Agregare plachetaraDepozite fibrina
HEMOLIZAMICROANGIOPATICA
Scadere prostaciclin
Crestereangiotensina II
HIPERTENSIUNE
CRIZA RENALA SCLERODERMICA
INHIBITORI ENZIMA CONVERSIE
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FACTORI RISC CRIZA RENALA
• Afectarea cutanata difuza si rapid progresiva
• Sezonul rece(vasospasm, exacerbarea ischemiei, hipersecretie renina)
• Doze mari glucocorticoizi(inhiba productia prostaciclin si cresc activitatea ECA)
• Folosirea ciclosporinei(vasoconstrictor renal)
• Ac anti ARN polimeraza III
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AFECTAREA CARDIACA
• Fibroza miocardica –tulb ritm, conducere
• Leziuni coronare
•
Pericardita
•SECUNDARA
–afectarii renale
–HTA
- afectarii pulmonare HTP
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ALTE AFECTARI
• ARTICULARE
• MUSCULARE
• NERVOASE
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EXPLORARI PARACLINICE
• Afectarea vasculara
-lezarea cel endoteliale
val crescute f.VIII, endotelina
- agregare trombocitara
- Anomalii vascularecapilaroscopie, arteriografie
• Anomalii imune
Hipergamaglobulinemie
CrioglobulinemieAc antinucleari
anticentromer
anti SCL70
anti ARN polimeraza III
anti U3 RNP (fibrilarina)
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ALTE ANOMALII PARACLINICE
• Anemie
•
Sindrom inflamator• Exporari specifice diverselor afectari
viscerale
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DIAGNOSTIC POZITIV
• Criteriu major
Scleredem proximal de MCF sau MTF
•
Criteriu minorSclerodactilie
Cicatrici stelate pulpa degete
Fibroza pulmonara bibazala Diagnostic= criteriu major + 2 criterii minore
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FORME CLINICE
• Scleroza sistemica cu:
afectare cutanata difuza
afectare cutanata limitata =sindrom CREST• Sclerodermia localizata
liniara
morfeaScleroza sine scleroderma
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Diagnostic diferential
• Sindrom Raynaud
• Fasciita cu eozinofile
• Scleredemul Buschke
• Boala mixta tesut conjunctiv
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TRATAMENTUL SCLERODERMEI
Corectarea:
• Anomaliilor vasculare Terapie vasodilat.
•Perturbarilor imune Imunosupresoare
• Fibrozei excesive Terapie antifibrotica
colchicina, D penicilamina,
interferon, inhibitori TGF beta
piascledine, p aminobenzoic
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EDRF/NOProstaciclinAdenozina
Endotelina
Factori constrictoriderivati endoteli
OBIECTIVELE TERAPIEI VASCULAREVASODILATATOARE:
•BLOCANTE CANAL CALCIU•PROSTACICLIN EXOGEN
•INHIBITORIRECEPTORI ENDOTELINA
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TRATAMENTTerapie vasodilatatoare Blocante canal calciu (nifedipina)
Unguente nitroglicerina
Pentoxifilin
Prostaciclin1. Epoprostenol/prostaciclin
Administrarea perfuzie continua, risc infectii/tromboza2. Iloprost inhalator
3. Treprostinil sc
Inhibitori selectivi 5 fosfodiesteraza
Sildenafil (Viagra)
Inhibitori receptori endotelinaBosentan (Tracleer)
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TRATAMENTULSINDROM RAYNAUD
Evitare frig, traumatisme
Vasodilatatoare
• Blocante canal calciu
• Nitroglicerina unguent
• Inhibitori a adrenergici
Pentoxifilin
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TRATAMENTUL ULCERATIILOR DIGITALE
PROSTACICLINE
BOSENTANSILDENAFIL
SIMPATECTOMIE
VASODILATATOARE INTRAARTERIAL
ANTIBIOTICE
TRATAMENTUL AFECTARII
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TRATAMENTUL AFECTARII
DIGESTIVE
• Prochinetice
• IPP
•
Antibiotice
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TRATAMENTULHIPERTENSIUNII ARTERIALE PULMONARE
INITIAL
Blocante canal calciu
AnticoagulanteClasa funct WHO III/IV
Bosentan oral
ProstaciclinaTRANSPLANT CORD-PULMON
TRATAMENTUL FIBROZEI
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TRATAMENTUL FIBROZEI
PULMONARE
• Imunosupresoare- imuran , ciclofosfamida
•
Cortizonice• Antagonisti receptori endotelina
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Tratamentul sclerodermiei
• CRIZA RENALASCLERODERMICA
• Inhibitori enzimaconversie
• Dializa
• AFECTAREA CARDIACA
• Trat tulb ritm, conducere
• Trat. Insuficienteicoronariene
• Trat. Insuficientei cardiace
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