PROGRAMMA GASTRO-LEARNINGPROGRAMMA GASTRO-LEARNINGBologna, 15 aprile 2013Bologna, 15 aprile 2013EMODINAMICA NEL PAZIENTE C...
NATURAL HISTORY OF CHRONIC LIVER DISEASENATURAL HISTORY OF CHRONIC LIVER DISEASEHBVHCVETOHNASHCHRONICCHRONICHEPATITISHEPAT...
PORTAL HYPERTENSIONPORTAL HYPERTENSIONDEFINITIONDEFINITIONPortal hypertension is a clinical syndromedefined by a portal ve...
PORTAL HYPERTENSIONPORTAL HYPERTENSIONPATHOPHYSIOLOGYPATHOPHYSIOLOGYPP (pressure)(pressure)==QQ (blood flow) x(blood flow)...
PORTAL HYPERTENSIONPORTAL HYPERTENSIONPATHOPHYSIOLOGYPATHOPHYSIOLOGYNagula et al, J Hepatol 2006Sethasine et al, Hepatolog...
PORTAL HYPERTENSIONPORTAL HYPERTENSIONPATHOPHYSIOLOGYPATHOPHYSIOLOGYPP (pressure)(pressure)==QQ (blood flow) x(blood flow)...
PORTAL HYPERTENSIONPORTAL HYPERTENSIONDYNAMIC COMPONENTDYNAMIC COMPONENTAsselah et al, Gut 2009L-arginine L- citrullineNOe...
PORTAL HYPERTENSIONPORTAL HYPERTENSIONDYNAMIC COMPONENTDYNAMIC COMPONENTENDOTHELIAL DYSFUNCTIONENDOTHELIAL DYSFUNCTION↑↑ E...
Garcia-Pagan & Bosch, J Hepatol 2012PORTAL HYPERTENSIONPORTAL HYPERTENSIONNew Tx perspectivesNew Tx perspectivesCOX blocke...
PORTAL HYPERTENSIONPORTAL HYPERTENSIONPATHOPHYSIOLOGYPATHOPHYSIOLOGYDYNAMICDYNAMICCOMPONENTCOMPONENTSTRUCTURALSTRUCTURALCO...
heart ratearterial pressureHYPERDYNAMIC CIRCULATORYHYPERDYNAMIC CIRCULATORYSYNDROMESYNDROMEeffective volemiaeffective vole...
PORTAL HYPERTENTION IN CIRRHOSISPORTAL HYPERTENTION IN CIRRHOSISRETROGRADE AND ANTEROGRADE COMPONENTSRETROGRADE AND ANTERO...
SYSTEMIC HEMODYNAMICS ABNORMALITIESSYSTEMIC HEMODYNAMICS ABNORMALITIESPROGRESSION WITH DISEASE SEVERITYPROGRESSION WITH DI...
HYPERDYNAMIC CIRCULATORYHYPERDYNAMIC CIRCULATORYSYNDROMESYNDROME
• chronic cardiac dysfunctionchronic cardiac dysfunction• absence of known causes of cardiopathyabsence of known causes of...
CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHYPATHOPHYSIOLOGYPATHOPHYSIOLOGYHYPERDYNAMICHYPERDYNAMICCIRCULATIONCIRCULATI...
REDUCED VASCULAR REACTIVITYREDUCED VASCULAR REACTIVITYIN CIRRHOSISIN CIRRHOSISNorepinephrineNorepinephrineAngiotensin IIAn...
THE NITRIC OXIDE PATHWAYTHE NITRIC OXIDE PATHWAYSHEARSHEARSTRESSSTRESSENDOTOXINSENDOTOXINSCYTOKINESCYTOKINESL-ARGININEL-AR...
CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASESHEAR STRESSSHEAR STRESSTazi et al, Gastroenterology 2002eNO...
0204060800 50 100 150 200 250Endotoxin (pg/ml)r = 0,65p < 0,001NO2-/NO3-Guarner et al. Hepatology 1993CAUSES OF NO SYNTHES...
Frances et al, Hepatology 2008CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOKINESENDOTOXIN...
Wiest et al, J Clin Invest 1999CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOKINES / SHEAR...
TNF-TNF-ααEndotheliumEndotheliumLeukocyteLeukocyteactivationactivationLPSLPSBact DNABact DNABacterialBacterialtranslocatio...
Niederberger et al, Gastroenterology 1995NOS INHIBITION IN CIRRHOSISNOS INHIBITION IN CIRRHOSISL-NAME: 0.5 mg/Kg/dayL-NAME...
EFFECT OF SID IN CIRRHOSISEFFECT OF SID IN CIRRHOSISAORTIC NOS EXPRESSIONAORTIC NOS EXPRESSIONTazi et al, Gastroenterology...
LBPLBPAlbillos et al, Hepatology 2003SVRSVRCAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOK...
CirrhosisControlsSystolic blood pressureSystolic blood pressureBatkai et al, Nature Med 2001SR 141716ASR 141716ACAUSES OF ...
ControlCirrhosis-8 -7 -6 -5 -4Anandamide log [M]%ofrelaxationofprecontractedtone100806040200Domenicali et al, Gut 2005RATS...
Varga, FASEB J 1998-30-20-100102030 60 90 120Min after LPS administration* * * * * ** ***Rimonabant pre-treated ratsContro...
IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSISROLE OF NITRIC OXIDEROLE OF NITRIC OXIDE...
IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSISROLE OF CYTOKINESROLE OF CYTOKINESCardia...
CARDIOVASCULAR DYSFUNCTION IN CIRRHOSISCARDIOVASCULAR DYSFUNCTION IN CIRRHOSISA MULTIFACTORIAL PROCESSCARDIOVASCULAR ABNOR...
ASCITESASCITES&&HEPATORENAL SYNDROMEHEPATORENAL SYNDROME
ASCITESASCITESRenal retentionRenal retentionof Naof Na++/ H/ H22OOPATHOGENESIS OF ASCITESPost-sinusoidalPost-sinusoidalpor...
Bernardi, et al, 1999PROGRESSION OF ASCITESPROGRESSION OF ASCITESPATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUN...
Bernardi et al, 1999030060090012001500Plasma aldosterone (pg/ml)No ascites Ascites HepatorenalsyndromeRecentLong-standingP...
Recentascites ascites020406080100120No ascites Long standing HRS0100200300400500600700RPFGFRml/minml/minPROGRESSIONE OF AS...
RENAL Na+REABSORPTIONRENAL NaRENAL Na++RETENTION IN CIRRHOSISRETENTION IN CIRRHOSISTUBULAR SITES OF NaTUBULAR SITES OF Na+...
010203040RS RFWHVP(mmHg)REFRACTORY ASCITESREFRACTORY ASCITESPATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND5065...
↓ EFFECTIVE VOLEMIAHYPONATREMIA IN CIRRHOSISHYPONATREMIA IN CIRRHOSISPATHOPHYSIOLOGYPATHOPHYSIOLOGYPERIPHERALPERIPHERALVAS...
-20020406080PRA NorE MAP SVR CO HRPERCENTCHANGERuiz del Arbol et al., Hepatology 2005*** *HEPATORENAL SYNDROMEHEPATORENAL ...
CARDIOVASCULAR DYSFUNCTIONCARDIOVASCULAR DYSFUNCTIONPROGRESSION WITH DISEASEPROGRESSION WITH DISEASEPre-ascites AscitesCHA...
ASCITES & HRS: ESSENTIALASCITES & HRS: ESSENTIALPATHOPHYSIOLOGYPATHOPHYSIOLOGYPORTALHYPERTENSIONSYSTEMICHEMODYNAMICCHANGES...
LARGE-VOLUME PARACENTESISLARGE-VOLUME PARACENTESIS
0481216Baseline Post-P 48h Post-P 5 daysPRA(ng/ml/h)PPCD +PPCD - **96%Ginès et al., 1988, 1996No PPCDNo PPCDPPCDPPCDSURVIV...
010203040Baseline Post-P 48h Baseline Post-P 48hPRA(ng/ml/h)050010001500NorE(pg/ml)PRA (ng/ml/h)NorE (pg/ml)**Saló et al.,...
-20-15-10-50510152025PRA MAP SVR HR CIPERCENTCHANGERuiz del Arbol et al., Gastroenterology 1997***POST-PARACENTESIS CIRCUL...
BACTERIAL INFECTIONSBACTERIAL INFECTIONS
TLR4TLR4TLR2TLR2Gram -ve organismLPSNF-NF-κκ-B-BMAP-kMAP-kTNF-TNF-ααIL-1, IL-6IL-1, IL-6Gram +ve organismPGNLPOXIDANTOXIDA...
CARDIOCIRCULATORY DYSFUNCTIONCARDIOCIRCULATORY DYSFUNCTIONIMPACT OF BACTERIAL INFECTIONSIMPACT OF BACTERIAL INFECTIONSARTE...
CentralCentralbaroceptorsbaroceptorsBLOOD VOLUME & EFFECTIVE VOLEMIABLOOD VOLUME & EFFECTIVE VOLEMIAS.N.S. activityS.N.S. ...
EFFECTS OF EFFECTIVE HYPOVOLEMIAEFFECTS OF EFFECTIVE HYPOVOLEMIACentralbaroceptorsS.N.S. activityArginine-vasopressinJuxta...
CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHYCLINICAL RELEVANCECLINICAL RELEVANCECONTRACTILE DYSFUNCTION(s)CONTRACTILE ...
20%57%3,4%VARICES +ASCITES −7%D’Amico et al, J Hepatol 2006Arvaniti et al, Gastroenterology 2010Fede et al, J Hepatol 2012...
SMOOTH MUSCLEcGMP Proteinkinase GRELAXATIONNOTHE NITRIC OXIDE PATHWAYTHE NITRIC OXIDE PATHWAY
Wood et al, J Gastroentrol Hepatol 1987PATHOGENESIS OF ASCITESPATHOGENESIS OF ASCITESDISRUPTION OF STARLING EQUILIBRIUMDIS...
STARLING EQUILIBRIUMSTARLING EQUILIBRIUMPIFΠIFPCΠCLiver sinusoidLiver cell
0500100015002000Plasma norepinephrine (ng/L)No ascites Ascites HepatorenalsyndromeRecentLong-standingPROGRESSION OF ASCITE...
-10-50510152025MAP RAP PRA (/10) CI SVRPercentchangeAlbuminHESALBUMIN vs HES IN PBSALBUMIN vs HES IN PBSHEMODYNAMIC EFFECT...
Fernandez et al., Hepatology 2005ALBUMIN vs HES IN PBSALBUMIN vs HES IN PBSEFFECTS ON ENDOTHELIAL ACTIVATIONEFFECTS ON END...
IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSISEFFECT OF ALBUMIN ADMINISTRATIONEFFECT O...
IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSISEFFECT OF ALBUMIN ADMINISTRATIONEFFECT O...
L'emodinamica nel cirrotico: aspetti fisiopatologici - Gastrolearning®
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L'emodinamica nel cirrotico: aspetti fisiopatologici - Prof. M. Bernardi (Università di Bologna)

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L'emodinamica nel cirrotico: aspetti fisiopatologici - Gastrolearning®

  1. 1. PROGRAMMA GASTRO-LEARNINGPROGRAMMA GASTRO-LEARNINGBologna, 15 aprile 2013Bologna, 15 aprile 2013EMODINAMICA NEL PAZIENTE CONEMODINAMICA NEL PAZIENTE CONCIRROSI: ASPETTI FISIOPATOLOGICICIRROSI: ASPETTI FISIOPATOLOGICIMauro BernardiMauro BernardiSemeiotica MedicaDipartimento di Medicina ClinicaAlma Mater Studiorum - Università di Bologna
  2. 2. NATURAL HISTORY OF CHRONIC LIVER DISEASENATURAL HISTORY OF CHRONIC LIVER DISEASEHBVHCVETOHNASHCHRONICCHRONICHEPATITISHEPATITIS…COMPENSATEDCOMPENSATEDCIRRHOSISCIRRHOSISASYMPTOMATICASYMPTOMATICPHASEPHASESYMPTOMATICSYMPTOMATICPHASEPHASEDECOMPENSATEDDECOMPENSATEDCIRRHOSISCIRRHOSISjaundiceascitesg.i. bleedinghepatic encephalopathyOLTDEATHbacterial infectionsHCCCARDIOVASCULAR DYSFUNCTIONCARDIOVASCULAR DYSFUNCTIONPORTAL HYPERTENSIONPORTAL HYPERTENSIONHYPERDYNAMIC CIRCULATORY SYNDROMEHYPERDYNAMIC CIRCULATORY SYNDROMECIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHY
  3. 3. PORTAL HYPERTENSIONPORTAL HYPERTENSIONDEFINITIONDEFINITIONPortal hypertension is a clinical syndromedefined by a portal venous pressure gradientexceeding 5 mm HgHVPG = WHVP - FHVPFirst causeof deathFirst causeof deathFirst causeof OLTFirst causeof OLTCourtesy Dr. R. Golfieri
  4. 4. PORTAL HYPERTENSIONPORTAL HYPERTENSIONPATHOPHYSIOLOGYPATHOPHYSIOLOGYPP (pressure)(pressure)==QQ (blood flow) x(blood flow) x RR (resistance)(resistance)
  5. 5. PORTAL HYPERTENSIONPORTAL HYPERTENSIONPATHOPHYSIOLOGYPATHOPHYSIOLOGYNagula et al, J Hepatol 2006Sethasine et al, Hepatology 2012INDEPENDENT PREDICTORS OF CSPHINDEPENDENT PREDICTORS OF CSPH
  6. 6. PORTAL HYPERTENSIONPORTAL HYPERTENSIONPATHOPHYSIOLOGYPATHOPHYSIOLOGYPP (pressure)(pressure)==QQ (blood flow) x(blood flow) x RR (resistance)(resistance)STRUCTURALSTRUCTURALCOMPONENTCOMPONENT2/32/3DYNAMICDYNAMICCOMPONENTCOMPONENT1/31/3Ijzer, Vet Sci 2008
  7. 7. PORTAL HYPERTENSIONPORTAL HYPERTENSIONDYNAMIC COMPONENTDYNAMIC COMPONENTAsselah et al, Gut 2009L-arginine L- citrullineNOe-NOSBH4p-AktENDOTHELIAL DYSFUNCTIONENDOTHELIAL DYSFUNCTIONVascoconstrictor phenotypeVascoconstrictor phenotypeL-arginine L- citrullineNO↓ e-NOSBH4p-AktO2−O2−Caveolin 1Membrane PLARAPLA2TXA2PGH2COX-1 TXA2SCysLT5-LOMembrane PLARA↑ PLA2PGH2↑ COX-1 ↑ TXA2S↑ 5-LOTXA2CysLTNorepinephrineNorepinephrineAcetylcholineAcetylcholine……
  8. 8. PORTAL HYPERTENSIONPORTAL HYPERTENSIONDYNAMIC COMPONENTDYNAMIC COMPONENTENDOTHELIAL DYSFUNCTIONENDOTHELIAL DYSFUNCTION↑↑ ET 1ET 1↑↑ TXA2TXA2↑↑ CysLTCysLT↓↓ NONO↓↓ COCOActivatedCONTRACTIONCONTRACTIONFIBROGENESISFIBROGENESISANGIOGENESISANGIOGENESISSYSTEMICSYSTEMIC VASOCONSTRICTORSVASOCONSTRICTORSAngiotensin IIAngiotensin IIVasopressinVasopressinAsselah et al, Gut 2009
  9. 9. Garcia-Pagan & Bosch, J Hepatol 2012PORTAL HYPERTENSIONPORTAL HYPERTENSIONNew Tx perspectivesNew Tx perspectivesCOX blockersCOX blockersCOX-1 blockersCOX-1 blockersTXATXA22 antagonistsantagonistsStatinsStatinsBH4 supplementationBH4 supplementationSOD supplementationSOD supplementationAnti-oxydantsAnti-oxydants
  10. 10. PORTAL HYPERTENSIONPORTAL HYPERTENSIONPATHOPHYSIOLOGYPATHOPHYSIOLOGYDYNAMICDYNAMICCOMPONENTCOMPONENTSTRUCTURALSTRUCTURALCOMPONENTCOMPONENTPORTAL HYPERTENSIONPORTAL HYPERTENSIONSPLANCHNIC CIRCULATIONSPLANCHNIC CIRCULATIONSYSTEMIC CIRCULATIONSYSTEMIC CIRCULATION
  11. 11. heart ratearterial pressureHYPERDYNAMIC CIRCULATORYHYPERDYNAMIC CIRCULATORYSYNDROMESYNDROMEeffective volemiaeffective volemiacardiac output RAA systemSN systemADHARTERIAL VASODILATIONARTERIAL VASODILATIONperipheral vascular resistance
  12. 12. PORTAL HYPERTENTION IN CIRRHOSISPORTAL HYPERTENTION IN CIRRHOSISRETROGRADE AND ANTEROGRADE COMPONENTSRETROGRADE AND ANTEROGRADE COMPONENTSportalsystemsystemiccirculationsplanchniccirculationPORTALPORTALHYPERTENSIONHYPERTENSIONPP (pressure)(pressure)==QQ (blood flow) x(blood flow) x RR (resistance)(resistance)
  13. 13. SYSTEMIC HEMODYNAMICS ABNORMALITIESSYSTEMIC HEMODYNAMICS ABNORMALITIESPROGRESSION WITH DISEASE SEVERITYPROGRESSION WITH DISEASE SEVERITY507090110130150170Child-Pugh A Child-Pugh B Child-Pugh CSVR (dyn/sec/cm-5]/10) CO ([dl/min] x 3)HR (bpm) MAP (mmHg)Braillon et al., 1986*****
  14. 14. HYPERDYNAMIC CIRCULATORYHYPERDYNAMIC CIRCULATORYSYNDROMESYNDROME
  15. 15. • chronic cardiac dysfunctionchronic cardiac dysfunction• absence of known causes of cardiopathyabsence of known causes of cardiopathy• usually subclinicalusually subclinical• ↓↓ contractile response to stress and/orcontractile response to stress and/or• ↓↓ diastolic relaxationdiastolic relaxation• frequent electrophysiological abnormalitiesfrequent electrophysiological abnormalitiesMontreal workshop, 2005CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHYDEFINITION & FEATURESDEFINITION & FEATURES
  16. 16. CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHYPATHOPHYSIOLOGYPATHOPHYSIOLOGYHYPERDYNAMICHYPERDYNAMICCIRCULATIONCIRCULATIONADRENERGICADRENERGICHYPERACTIVITYHYPERACTIVITY↑ANGIOTENSIN IIANGIOTENSIN II↑ ALDOSTERONEALDOSTERONE““CARDIOTOXINS”CARDIOTOXINS”FROM SPLANCHINC AREAFROM SPLANCHINC AREA
  17. 17. REDUCED VASCULAR REACTIVITYREDUCED VASCULAR REACTIVITYIN CIRRHOSISIN CIRRHOSISNorepinephrineNorepinephrineAngiotensin IIAngiotensin IIVasopressinVasopressinEndothelinEndothelin -1-1++ANPANPGlucagonGlucagonVIPVIPCGrPCGrP-CirculatingCirculatingvasodilatorsvasodilators-ET-derivedET-derivedvasodilatorsvasodilatorsNONOCOCOProstacyclinProstacyclineCBseCBs
  18. 18. THE NITRIC OXIDE PATHWAYTHE NITRIC OXIDE PATHWAYSHEARSHEARSTRESSSTRESSENDOTOXINSENDOTOXINSCYTOKINESCYTOKINESL-ARGININEL-ARGININE L-CITRULLINEL-CITRULLINEENDOTHELIUMNOe-NOSe-NOS i-NOSi-NOSBH4BH4
  19. 19. CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASESHEAR STRESSSHEAR STRESSTazi et al, Gastroenterology 2002eNOS expressioneNOS expressioneNOS expressioneNOS expressionEffect ofEffect of β-blokadeβ-blokade
  20. 20. 0204060800 50 100 150 200 250Endotoxin (pg/ml)r = 0,65p < 0,001NO2-/NO3-Guarner et al. Hepatology 1993CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
  21. 21. Frances et al, Hepatology 2008CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
  22. 22. Wiest et al, J Clin Invest 1999CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOKINES / SHEAR STRESSENDOTOXIN / CYTOKINES / SHEAR STRESS
  23. 23. TNF-TNF-ααEndotheliumEndotheliumLeukocyteLeukocyteactivationactivationLPSLPSBact DNABact DNABacterialBacterialtranslocationtranslocationWiest et al, J Clin Invest 1999TNF-TNF-ααNucleus+eNOSNO+ BH4CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
  24. 24. Niederberger et al, Gastroenterology 1995NOS INHIBITION IN CIRRHOSISNOS INHIBITION IN CIRRHOSISL-NAME: 0.5 mg/Kg/dayL-NAME: 0.5 mg/Kg/dayL-NAME: 3 mg/Kg/dayL-NAME: 3 mg/Kg/day23456Controls Untreated L-NAME L-NAMESYSTEMICVASCULARRESISTANCE(mmg.min.ml-1.100g-1)100120140160Controls Untreated L-NAME L-NAMEMEANARTERIALPRESSURE(mmHg)2030405060Controls Untreated L-NAME L-NAMECARDIACINDEX(ml.min-1.100g-1)
  25. 25. EFFECT OF SID IN CIRRHOSISEFFECT OF SID IN CIRRHOSISAORTIC NOS EXPRESSIONAORTIC NOS EXPRESSIONTazi et al, Gastroenterology 2005eNOS iNOS• Rats with bile duct ligation• Norfloxacin 10 mg/Kg for 5 days• Colistin 15 mg/Kg for 5 days
  26. 26. LBPLBPAlbillos et al, Hepatology 2003SVRSVRCAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
  27. 27. CirrhosisControlsSystolic blood pressureSystolic blood pressureBatkai et al, Nature Med 2001SR 141716ASR 141716ACAUSES OF VASODILATIONCAUSES OF VASODILATIONROLE OF eCBsROLE OF eCBsRATS WITH DECOMPENSATED CClRATS WITH DECOMPENSATED CCl44 – INDUCED CIRRHOSIS– INDUCED CIRRHOSIS
  28. 28. ControlCirrhosis-8 -7 -6 -5 -4Anandamide log [M]%ofrelaxationofprecontractedtone100806040200Domenicali et al, Gut 2005RATS WITH DECOMPENSATED CClRATS WITH DECOMPENSATED CCl44 – INDUCED CIRRHOSIS– INDUCED CIRRHOSISMesenteric arteryMesenteric arteryCAUSES OF VASODILATIONCAUSES OF VASODILATIONROLE OF eCBsROLE OF eCBs
  29. 29. Varga, FASEB J 1998-30-20-100102030 60 90 120Min after LPS administration* * * * * ** ***Rimonabant pre-treated ratsControls ratsDMAP(mmHg)* P < 0.05LPS-INDUCED HEMODYNAMIC CHANGESLPS-INDUCED HEMODYNAMIC CHANGESEFFECT OF ENDOGENOUS CANNABINOID INHIBITON020406080100H after LPS administration6 12 18 240PERCENTLPS + RimLPSSURVIVALSURVIVALP < 0.05Domenicali et al, Monotematica AISF 2012
  30. 30. IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSISROLE OF NITRIC OXIDEROLE OF NITRIC OXIDEBortoluzzi et al, Hepatology 2012Cardiac tissue iNOS00,511,522,5Control rats Cirrhotic ratsPROTEINEXPRESSION(foldincrease)*
  31. 31. IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSISROLE OF CYTOKINESROLE OF CYTOKINESCardiac tissue TNF-a00,511,522,5Control rats Cirrhotic ratsPROTEINEXPRESSION(foldincrease)*Cardiac tissue NFkB00,511,522,5Control rats Cirrhotic ratsPROTEINEXPRESSION(foldincrease)*Bortoluzzi et al, Hepatology 2012
  32. 32. CARDIOVASCULAR DYSFUNCTION IN CIRRHOSISCARDIOVASCULAR DYSFUNCTION IN CIRRHOSISA MULTIFACTORIAL PROCESSCARDIOVASCULAR ABNORMALITIESNITRIC OXIDENITRIC OXIDEPROSTAGLANDINSPROSTAGLANDINSCARBON MONOXYDECARBON MONOXYDEENDOGENOUS CANNABINOIDSENDOGENOUS CANNABINOIDSUROTENSINUROTENSINAPELINAPELINBACTERIAL TRANSLOCATIONBACTERIAL TRANSLOCATIONCYTOKINE RELEASECYTOKINE RELEASESPECIFICSPECIFICINHIBITIONINHIBITIONSIDSIDOTHERSOTHERSDIRECTDIRECTACTING TxACTING Tx
  33. 33. ASCITESASCITES&&HEPATORENAL SYNDROMEHEPATORENAL SYNDROME
  34. 34. ASCITESASCITESRenal retentionRenal retentionof Naof Na++/ H/ H22OOPATHOGENESIS OF ASCITESPost-sinusoidalPost-sinusoidalportal hypertensionportal hypertension
  35. 35. Bernardi, et al, 1999PROGRESSION OF ASCITESPROGRESSION OF ASCITESPATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUNDBernardi et al, 19990306090120No ascites Ascites HepatorenalsyndromeRenal sodium excretion (mmol/24 h)RecentLong-standing
  36. 36. Bernardi et al, 1999030060090012001500Plasma aldosterone (pg/ml)No ascites Ascites HepatorenalsyndromeRecentLong-standingPROGRESSION OF ASCITESPROGRESSION OF ASCITESPATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND
  37. 37. Recentascites ascites020406080100120No ascites Long standing HRS0100200300400500600700RPFGFRml/minml/minPROGRESSIONE OF ASCITESPROGRESSIONE OF ASCITESPATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUNDBernardi et al, 1999
  38. 38. RENAL Na+REABSORPTIONRENAL NaRENAL Na++RETENTION IN CIRRHOSISRETENTION IN CIRRHOSISTUBULAR SITES OF NaTUBULAR SITES OF Na++RETENTIONRETENTIONPRESERVED GFRPRESERVED GFR(~(~ ≥≥ 60 ml/min)60 ml/min)DISTALDISTALPROXIMALPROXIMALREDUCED GFRREDUCED GFR(~ < 60 ml/min)(~ < 60 ml/min)DISTALDISTALPROXIMALPROXIMAL
  39. 39. 010203040RS RFWHVP(mmHg)REFRACTORY ASCITESREFRACTORY ASCITESPATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND50658095110RS RF*MAP(mmHg)0306090120150RS RF*GFR(ml/min)RS = responsive ascites – RF = refractory ascitesRS = responsive ascites – RF = refractory ascites
  40. 40. ↓ EFFECTIVE VOLEMIAHYPONATREMIA IN CIRRHOSISHYPONATREMIA IN CIRRHOSISPATHOPHYSIOLOGYPATHOPHYSIOLOGYPERIPHERALPERIPHERALVASODILATIONVASODILATIONADHADHDIURETICSDIURETICSImpaireddilutionNa+
  41. 41. -20020406080PRA NorE MAP SVR CO HRPERCENTCHANGERuiz del Arbol et al., Hepatology 2005*** *HEPATORENAL SYNDROMEHEPATORENAL SYNDROMECARDIOVASCULAR CHANGESCARDIOVASCULAR CHANGES
  42. 42. CARDIOVASCULAR DYSFUNCTIONCARDIOVASCULAR DYSFUNCTIONPROGRESSION WITH DISEASEPROGRESSION WITH DISEASEPre-ascites AscitesCHANGES↓ Effectiveblood volumeNormaleffectivebloodvolumeSplanchnic arterialSplanchnic arterialvasodilationvasodilationRAAS, SNS, AVPRAAS, SNS, AVPExtrasplanchnicExtrasplanchnicvasoconstrictionvasoconstriction↓ Renal perfusion / hyponatremiaHRS type 1Arroyo et al,J Hepatol 2007Systemic vascularSystemic vascularresistanceresistanceCardiac outputCardiac output
  43. 43. ASCITES & HRS: ESSENTIALASCITES & HRS: ESSENTIALPATHOPHYSIOLOGYPATHOPHYSIOLOGYPORTALHYPERTENSIONSYSTEMICHEMODYNAMICCHANGES↓ EFFECTIVEVOLEMIARENAL RETENTIONOF Na+& WATERASCITESPORTALHYPERTENSIONCARDIOVASCULARDYSFUNCTIONREFRACTORYREFRACTORYASCITESASCITESRENAL FAILURERENAL FAILURE(HRS)(HRS)TIPSTIPS↑ RAA↑ SNS↑ ADH↓ Renal perfusionVOLUMEVOLUMEEXPANSIONEXPANSIONVASO-VASO-CONSTRICTORSCONSTRICTORS
  44. 44. LARGE-VOLUME PARACENTESISLARGE-VOLUME PARACENTESIS
  45. 45. 0481216Baseline Post-P 48h Post-P 5 daysPRA(ng/ml/h)PPCD +PPCD - **96%Ginès et al., 1988, 1996No PPCDNo PPCDPPCDPPCDSURVIVALSURVIVALPOST-PARACENTESIS CIRCULATORYPOST-PARACENTESIS CIRCULATORYDYSFUNCTIONDYSFUNCTION
  46. 46. 010203040Baseline Post-P 48h Baseline Post-P 48hPRA(ng/ml/h)050010001500NorE(pg/ml)PRA (ng/ml/h)NorE (pg/ml)**Saló et al., 1997POST-PARACENTESIS CIRCULATORYPOST-PARACENTESIS CIRCULATORYDYSFUNCTIONDYSFUNCTIONPPCD – PPCD +012345Baseline Post-P 48h Baseline Post-P 48hPlasmavolume(L)05101520TERa(%)Plasma volume (L)TERa (%)PPCD – PPCD +
  47. 47. -20-15-10-50510152025PRA MAP SVR HR CIPERCENTCHANGERuiz del Arbol et al., Gastroenterology 1997***POST-PARACENTESIS CIRCULATORYPOST-PARACENTESIS CIRCULATORYDYSFUNCTIONDYSFUNCTION
  48. 48. BACTERIAL INFECTIONSBACTERIAL INFECTIONS
  49. 49. TLR4TLR4TLR2TLR2Gram -ve organismLPSNF-NF-κκ-B-BMAP-kMAP-kTNF-TNF-ααIL-1, IL-6IL-1, IL-6Gram +ve organismPGNLPOXIDANTOXIDANTSTRESSSTRESSCOAGULATIONCOAGULATIONCASCADECASCADEMICROVASCULARMICROVASCULARDAMAGEDAMAGEARTERIALARTERIALVASODILATIONVASODILATION
  50. 50. CARDIOCIRCULATORY DYSFUNCTIONCARDIOCIRCULATORY DYSFUNCTIONIMPACT OF BACTERIAL INFECTIONSIMPACT OF BACTERIAL INFECTIONSARTERIALVASODILATIONCARDIACDYSFUNCTIONREDUCEDEFFECTIVE VOLEMIAREDUCED RENAL PERFUSIONREDUCED RENAL PERFUSIONRENAL FAILURE / MOFRENAL FAILURE / MOFSEVERELY REDUCEDEFFECTIVE VOLEMIA
  51. 51. CentralCentralbaroceptorsbaroceptorsBLOOD VOLUME & EFFECTIVE VOLEMIABLOOD VOLUME & EFFECTIVE VOLEMIAS.N.S. activityS.N.S. activityArginine-vasopressinArginine-vasopressinRenin-angiotensinRenin-angiotensinJuxtaglomerular apparatusJuxtaglomerular apparatus
  52. 52. EFFECTS OF EFFECTIVE HYPOVOLEMIAEFFECTS OF EFFECTIVE HYPOVOLEMIACentralbaroceptorsS.N.S. activityArginine-vasopressinJuxtaglomerular apparatusRenin-angiotensin
  53. 53. CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHYCLINICAL RELEVANCECLINICAL RELEVANCECONTRACTILE DYSFUNCTION(s)CONTRACTILE DYSFUNCTION(s)• Prognostic meaningPrognostic meaning• G.I. bleedingG.I. bleedingQTQT INTERVALINTERVAL PROLONGATIONPROLONGATION• PBS-induced renal failure / HRSPBS-induced renal failure / HRS• TIPSTIPS• OLTOLT
  54. 54. 20%57%3,4%VARICES +ASCITES −7%D’Amico et al, J Hepatol 2006Arvaniti et al, Gastroenterology 2010Fede et al, J Hepatol 2012NATURAL HISTORY OF CHRONIC LIVER DISEASENATURAL HISTORY OF CHRONIC LIVER DISEASE67%4,4%VARICES ±ASCITES +6.6%1%DEATHVARICES −ASCITES −decompensatedStage 3Stage 4compensatedStage 1Stage 2Stage 5INFECTIONSRENAL FAILURE4%BLEEDING ±ASCITES +7.6%
  55. 55. SMOOTH MUSCLEcGMP Proteinkinase GRELAXATIONNOTHE NITRIC OXIDE PATHWAYTHE NITRIC OXIDE PATHWAY
  56. 56. Wood et al, J Gastroentrol Hepatol 1987PATHOGENESIS OF ASCITESPATHOGENESIS OF ASCITESDISRUPTION OF STARLING EQUILIBRIUMDISRUPTION OF STARLING EQUILIBRIUM051015202530ABSENT I II IIIASCITEScWHVP(mmHg)20253035404550ABSENT I II IIIASCITESPLASMAALBUMIN(g/L)94%94%82%82%
  57. 57. STARLING EQUILIBRIUMSTARLING EQUILIBRIUMPIFΠIFPCΠCLiver sinusoidLiver cell
  58. 58. 0500100015002000Plasma norepinephrine (ng/L)No ascites Ascites HepatorenalsyndromeRecentLong-standingPROGRESSION OF ASCITESPROGRESSION OF ASCITESPATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUNDBernardi et al, 1999
  59. 59. -10-50510152025MAP RAP PRA (/10) CI SVRPercentchangeAlbuminHESALBUMIN vs HES IN PBSALBUMIN vs HES IN PBSHEMODYNAMIC EFFECTSHEMODYNAMIC EFFECTSFernandez et al, Hepatology 2005** ******
  60. 60. Fernandez et al., Hepatology 2005ALBUMIN vs HES IN PBSALBUMIN vs HES IN PBSEFFECTS ON ENDOTHELIAL ACTIVATIONEFFECTS ON ENDOTHELIAL ACTIVATION-40-20020406080vWF:Ag Factor VIII NoxPercentchangeAlbuminHES** ****
  61. 61. IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSISEFFECT OF ALBUMIN ADMINISTRATIONEFFECT OF ALBUMIN ADMINISTRATIONBortoluzzi et al, Hepatology 2012Cardiac tissue iNOS00,511,522,5Control rats Cirrhotic ratsPROTEINEXPRESSION(foldincrease)ALBUMIN
  62. 62. IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSISEFFECT OF ALBUMIN ADMINISTRATIONEFFECT OF ALBUMIN ADMINISTRATIONCardiac tissue TNF-a00,511,522,5Control rats Cirrhotic ratsPROTEINEXPRESSION(foldincrease)Cardiac tissue NFkB00,511,522,5Control rats Cirrhotic ratsPROTEINEXPRESSION(foldincrease)Bortoluzzi et al, Hepatology 2012ALBUMINALBUMIN

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