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PROGRAMMA GASTRO-LEARNINGPROGRAMMA GASTRO-LEARNING
Bologna, 15 aprile 2013Bologna, 15 aprile 2013
EMODINAMICA NEL PAZIENTE CONEMODINAMICA NEL PAZIENTE CON
CIRROSI: ASPETTI FISIOPATOLOGICICIRROSI: ASPETTI FISIOPATOLOGICI
Mauro BernardiMauro Bernardi
Semeiotica Medica
Dipartimento di Medicina Clinica
Alma Mater Studiorum - Università di Bologna
NATURAL HISTORY OF CHRONIC LIVER DISEASENATURAL HISTORY OF CHRONIC LIVER DISEASE
HBV
HCV
ETOH
NASH
CHRONICCHRONIC
HEPATITISHEPATITIS
…
COMPENSATEDCOMPENSATED
CIRRHOSISCIRRHOSIS
ASYMPTOMATICASYMPTOMATIC
PHASEPHASE
SYMPTOMATICSYMPTOMATIC
PHASEPHASE
DECOMPENSATEDDECOMPENSATED
CIRRHOSISCIRRHOSIS
jaundice
ascites
g.i. bleeding
hepatic encephalopathy
OLT
DEATH
bacterial infections
HCCCARDIOVASCULAR DYSFUNCTIONCARDIOVASCULAR DYSFUNCTION
PORTAL HYPERTENSIONPORTAL HYPERTENSION
HYPERDYNAMIC CIRCULATORY SYNDROMEHYPERDYNAMIC CIRCULATORY SYNDROME
CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHY
PORTAL HYPERTENSIONPORTAL HYPERTENSION
DEFINITIONDEFINITION
Portal hypertension is a clinical syndrome
defined by a portal venous pressure gradient
exceeding 5 mm Hg
HVPG = WHVP - FHVP
First cause
of death
First cause
of death
First cause
of OLT
First cause
of OLT
Courtesy Dr. R. Golfieri
PORTAL HYPERTENSIONPORTAL HYPERTENSION
PATHOPHYSIOLOGYPATHOPHYSIOLOGY
PP (pressure)(pressure)
==
QQ (blood flow) x(blood flow) x RR (resistance)(resistance)
PORTAL HYPERTENSIONPORTAL HYPERTENSION
PATHOPHYSIOLOGYPATHOPHYSIOLOGY
Nagula et al, J Hepatol 2006
Sethasine et al, Hepatology 2012
INDEPENDENT PREDICTORS OF CSPHINDEPENDENT PREDICTORS OF CSPH
PORTAL HYPERTENSIONPORTAL HYPERTENSION
PATHOPHYSIOLOGYPATHOPHYSIOLOGY
PP (pressure)(pressure)
==
QQ (blood flow) x(blood flow) x RR (resistance)(resistance)
STRUCTURALSTRUCTURAL
COMPONENTCOMPONENT
2/32/3
DYNAMICDYNAMIC
COMPONENTCOMPONENT
1/31/3
Ijzer, Vet Sci 2008
PORTAL HYPERTENSIONPORTAL HYPERTENSION
DYNAMIC COMPONENTDYNAMIC COMPONENT
Asselah et al, Gut 2009
L-arginine L- citrulline
NO
e-NOS
BH4
p-Akt
ENDOTHELIAL DYSFUNCTIONENDOTHELIAL DYSFUNCTION
Vascoconstrictor phenotypeVascoconstrictor phenotype
L-arginine L- citrulline
NO
↓ e-NOS
BH4
p-Akt
O2
−
O2
−
Caveolin 1
Membrane PL
ARA
PLA2
TXA2PGH2
COX-1 TXA2S
CysLT
5-LO
Membrane PL
ARA
↑ PLA2
PGH2
↑ COX-1 ↑ TXA2S
↑ 5-LO
TXA2
CysLT
NorepinephrineNorepinephrine
AcetylcholineAcetylcholine
……
PORTAL HYPERTENSIONPORTAL HYPERTENSION
DYNAMIC COMPONENTDYNAMIC COMPONENT
ENDOTHELIAL DYSFUNCTIONENDOTHELIAL DYSFUNCTION
↑↑ ET 1ET 1
↑↑ TXA2TXA2
↑↑ CysLTCysLT
↓↓ NONO
↓↓ COCO
Activated
CONTRACTIONCONTRACTION
FIBROGENESISFIBROGENESIS
ANGIOGENESISANGIOGENESIS
SYSTEMICSYSTEMIC VASOCONSTRICTORSVASOCONSTRICTORS
Angiotensin IIAngiotensin II
VasopressinVasopressin
Asselah et al, Gut 2009
Garcia-Pagan & Bosch, J Hepatol 2012
PORTAL HYPERTENSIONPORTAL HYPERTENSION
New Tx perspectivesNew Tx perspectives
COX blockersCOX blockers
COX-1 blockersCOX-1 blockers
TXATXA22 antagonistsantagonists
StatinsStatins
BH4 supplementationBH4 supplementation
SOD supplementationSOD supplementation
Anti-oxydantsAnti-oxydants
PORTAL HYPERTENSIONPORTAL HYPERTENSION
PATHOPHYSIOLOGYPATHOPHYSIOLOGY
DYNAMICDYNAMIC
COMPONENTCOMPONENT
STRUCTURALSTRUCTURAL
COMPONENTCOMPONENT
PORTAL HYPERTENSIONPORTAL HYPERTENSION
SPLANCHNIC CIRCULATIONSPLANCHNIC CIRCULATION
SYSTEMIC CIRCULATIONSYSTEMIC CIRCULATION
heart rate
arterial pressure
HYPERDYNAMIC CIRCULATORYHYPERDYNAMIC CIRCULATORY
SYNDROMESYNDROME
effective volemiaeffective volemia
cardiac output RAA system
SN system
ADH
ARTERIAL VASODILATIONARTERIAL VASODILATION
peripheral vascular resistance
PORTAL HYPERTENTION IN CIRRHOSISPORTAL HYPERTENTION IN CIRRHOSIS
RETROGRADE AND ANTEROGRADE COMPONENTSRETROGRADE AND ANTEROGRADE COMPONENTS
portal
system
systemic
circulation
splanchnic
circulation
PORTALPORTAL
HYPERTENSIONHYPERTENSION
PP (pressure)(pressure)
==
QQ (blood flow) x(blood flow) x RR (resistance)(resistance)
SYSTEMIC HEMODYNAMICS ABNORMALITIESSYSTEMIC HEMODYNAMICS ABNORMALITIES
PROGRESSION WITH DISEASE SEVERITYPROGRESSION WITH DISEASE SEVERITY
50
70
90
110
130
150
170
Child-Pugh A Child-Pugh B Child-Pugh C
SVR (dyn/sec/cm-5]/10) CO ([dl/min] x 3)
HR (bpm) MAP (mmHg)
Braillon et al., 1986
*
*
*
*
*
HYPERDYNAMIC CIRCULATORYHYPERDYNAMIC CIRCULATORY
SYNDROMESYNDROME
• 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 abnormalities
Montreal workshop, 2005
CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHY
DEFINITION & FEATURESDEFINITION & FEATURES
CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHY
PATHOPHYSIOLOGYPATHOPHYSIOLOGY
HYPERDYNAMICHYPERDYNAMIC
CIRCULATIONCIRCULATION
ADRENERGICADRENERGIC
HYPERACTIVITYHYPERACTIVITY
↑ANGIOTENSIN IIANGIOTENSIN II
↑ ALDOSTERONEALDOSTERONE
““CARDIOTOXINS”CARDIOTOXINS”
FROM SPLANCHINC AREAFROM SPLANCHINC AREA
REDUCED VASCULAR REACTIVITYREDUCED VASCULAR REACTIVITY
IN CIRRHOSISIN CIRRHOSIS
NorepinephrineNorepinephrine
Angiotensin IIAngiotensin II
VasopressinVasopressin
EndothelinEndothelin -1-1
++ANPANP
GlucagonGlucagon
VIPVIP
CGrPCGrP
-
CirculatingCirculating
vasodilatorsvasodilators
-
ET-derivedET-derived
vasodilatorsvasodilators
NONO
COCO
ProstacyclinProstacyclin
eCBseCBs
THE NITRIC OXIDE PATHWAYTHE NITRIC OXIDE PATHWAY
SHEARSHEAR
STRESSSTRESS
ENDOTOXINSENDOTOXINS
CYTOKINESCYTOKINES
L-ARGININEL-ARGININE L-CITRULLINEL-CITRULLINE
ENDOTHELIUMNO
e-NOSe-NOS i-NOSi-NOS
BH4BH4
CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASE
SHEAR STRESSSHEAR STRESS
Tazi et al, Gastroenterology 2002
eNOS expressioneNOS expression
eNOS expressioneNOS expression
Effect ofEffect of β-blokadeβ-blokade
0
20
40
60
80
0 50 100 150 200 250
Endotoxin (pg/ml)
r = 0,65
p < 0,001
NO2
-
/NO3
-
Guarner et al. Hepatology 1993
CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASE
ENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
Frances et al, Hepatology 2008
CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASE
ENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
Wiest et al, J Clin Invest 1999
CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASE
ENDOTOXIN / CYTOKINES / SHEAR STRESSENDOTOXIN / CYTOKINES / SHEAR STRESS
TNF-TNF-αα
EndotheliumEndothelium
LeukocyteLeukocyte
activationactivation
LPSLPS
Bact DNABact DNA
BacterialBacterial
translocationtranslocation
Wiest et al, J Clin Invest 1999
TNF-TNF-αα
Nucleus+
eNOS
NO
+ BH4
CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASE
ENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
Niederberger et al, Gastroenterology 1995
NOS INHIBITION IN CIRRHOSISNOS INHIBITION IN CIRRHOSIS
L-NAME: 0.5 mg/Kg/dayL-NAME: 0.5 mg/Kg/day
L-NAME: 3 mg/Kg/dayL-NAME: 3 mg/Kg/day
2
3
4
5
6
Controls Untreated L-NAME L-NAME
SYSTEMICVASCULARRESISTANCE
(mmg.min.ml-1.100g-1)
100
120
140
160
Controls Untreated L-NAME L-NAME
MEANARTERIALPRESSURE
(mmHg)
20
30
40
50
60
Controls Untreated L-NAME L-NAME
CARDIACINDEX
(ml.min-1.100g-1)
EFFECT OF SID IN CIRRHOSISEFFECT OF SID IN CIRRHOSIS
AORTIC NOS EXPRESSIONAORTIC NOS EXPRESSION
Tazi et al, Gastroenterology 2005
eNOS iNOS
• Rats with bile duct ligation
• Norfloxacin 10 mg/Kg for 5 days
• Colistin 15 mg/Kg for 5 days
LBPLBP
Albillos et al, Hepatology 2003
SVRSVR
CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASE
ENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
Cirrhosis
Controls
Systolic blood pressureSystolic blood pressure
Batkai et al, Nature Med 2001
SR 141716ASR 141716A
CAUSES OF VASODILATIONCAUSES OF VASODILATION
ROLE OF eCBsROLE OF eCBs
RATS WITH DECOMPENSATED CClRATS WITH DECOMPENSATED CCl44 – INDUCED CIRRHOSIS– INDUCED CIRRHOSIS
Control
Cirrhosis
-8 -7 -6 -5 -4
Anandamide log [M]
%ofrelaxationofprecontractedtone
100
80
60
40
20
0
Domenicali et al, Gut 2005
RATS WITH DECOMPENSATED CClRATS WITH DECOMPENSATED CCl44 – INDUCED CIRRHOSIS– INDUCED CIRRHOSIS
Mesenteric arteryMesenteric artery
CAUSES OF VASODILATIONCAUSES OF VASODILATION
ROLE OF eCBsROLE OF eCBs
Varga, FASEB J 1998
-30
-20
-10
0
10
20
30 60 90 120
Min after LPS administration
* * * * * *
* *
*
*
Rimonabant pre-treated rats
Controls rats
DMAP(mmHg)
* P < 0.05
LPS-INDUCED HEMODYNAMIC CHANGESLPS-INDUCED HEMODYNAMIC CHANGES
EFFECT OF ENDOGENOUS CANNABINOID INHIBITON
0
20
40
60
80
100
H after LPS administration
6 12 18 240
PERCENT
LPS + Rim
LPS
SURVIVALSURVIVAL
P < 0.05
Domenicali et al, Monotematica AISF 2012
IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSIS
ROLE OF NITRIC OXIDEROLE OF NITRIC OXIDE
Bortoluzzi et al, Hepatology 2012
Cardiac tissue iNOS
0
0,5
1
1,5
2
2,5
Control rats Cirrhotic ratsPROTEINEXPRESSION(foldincrease)
*
IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSIS
ROLE OF CYTOKINESROLE OF CYTOKINES
Cardiac tissue TNF-a
0
0,5
1
1,5
2
2,5
Control rats Cirrhotic rats
PROTEINEXPRESSION(foldincrease)
*
Cardiac tissue NFkB
0
0,5
1
1,5
2
2,5
Control rats Cirrhotic ratsPROTEINEXPRESSION(foldincrease)
*
Bortoluzzi et al, Hepatology 2012
CARDIOVASCULAR DYSFUNCTION IN CIRRHOSISCARDIOVASCULAR DYSFUNCTION IN CIRRHOSIS
A MULTIFACTORIAL PROCESS
CARDIOVASCULAR ABNORMALITIES
NITRIC OXIDENITRIC OXIDE
PROSTAGLANDINSPROSTAGLANDINS
CARBON MONOXYDECARBON MONOXYDE
ENDOGENOUS CANNABINOIDSENDOGENOUS CANNABINOIDS
UROTENSINUROTENSIN
APELINAPELIN
BACTERIAL TRANSLOCATIONBACTERIAL TRANSLOCATION
CYTOKINE RELEASECYTOKINE RELEASE
SPECIFICSPECIFIC
INHIBITIONINHIBITION
SIDSID
OTHERSOTHERS
DIRECTDIRECT
ACTING TxACTING Tx
ASCITESASCITES
&&
HEPATORENAL SYNDROMEHEPATORENAL SYNDROME
ASCITESASCITES
Renal retentionRenal retention
of Naof Na++
/ H/ H22OO
PATHOGENESIS OF ASCITES
Post-sinusoidalPost-sinusoidal
portal hypertensionportal hypertension
Bernardi, et al, 1999
PROGRESSION OF ASCITESPROGRESSION OF ASCITES
PATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND
Bernardi et al, 1999
0
30
60
90
120
No ascites Ascites Hepatorenal
syndrome
Renal sodium excretion (mmol/24 h)
Recent
Long-standing
Bernardi et al, 1999
0
300
600
900
1200
1500
Plasma aldosterone (pg/ml)
No ascites Ascites Hepatorenal
syndrome
Recent
Long-standing
PROGRESSION OF ASCITESPROGRESSION OF ASCITES
PATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND
Recent
ascites ascites
0
20
40
60
80
100
120
No ascites Long standing HRS
0
100
200
300
400
500
600
700
RPF
GFR
ml/min
ml/min
PROGRESSIONE OF ASCITESPROGRESSIONE OF ASCITES
PATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND
Bernardi et al, 1999
RENAL Na+
REABSORPTION
RENAL NaRENAL Na++
RETENTION IN CIRRHOSISRETENTION IN CIRRHOSIS
TUBULAR SITES OF NaTUBULAR SITES OF Na++
RETENTIONRETENTION
PRESERVED GFRPRESERVED GFR
(~(~ ≥≥ 60 ml/min)60 ml/min)
DISTALDISTAL
PROXIMALPROXIMAL
REDUCED GFRREDUCED GFR
(~ < 60 ml/min)(~ < 60 ml/min)
DISTALDISTAL
PROXIMALPROXIMAL
0
10
20
30
40
RS RF
WHVP(mmHg)
REFRACTORY ASCITESREFRACTORY ASCITES
PATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND
50
65
80
95
110
RS RF
*
MAP(mmHg)
0
30
60
90
120
150
RS RF
*
GFR(ml/min)
RS = responsive ascites – RF = refractory ascitesRS = responsive ascites – RF = refractory ascites
↓ EFFECTIVE VOLEMIA
HYPONATREMIA IN CIRRHOSISHYPONATREMIA IN CIRRHOSIS
PATHOPHYSIOLOGYPATHOPHYSIOLOGY
PERIPHERALPERIPHERAL
VASODILATIONVASODILATION
ADHADH
DIURETICSDIURETICS
Impaired
dilution
Na+
-20
0
20
40
60
80
PRA NorE MAP SVR CO HR
PERCENTCHANGE
Ruiz del Arbol et al., Hepatology 2005
*
*
* *
HEPATORENAL SYNDROMEHEPATORENAL SYNDROME
CARDIOVASCULAR CHANGESCARDIOVASCULAR CHANGES
CARDIOVASCULAR DYSFUNCTIONCARDIOVASCULAR DYSFUNCTION
PROGRESSION WITH DISEASEPROGRESSION WITH DISEASE
Pre-ascites Ascites
CHANGES
↓ Effective
blood volume
Normal
effective
blood
volume
Splanchnic arterialSplanchnic arterial
vasodilationvasodilation
RAAS, SNS, AVPRAAS, SNS, AVP
ExtrasplanchnicExtrasplanchnic
vasoconstrictionvasoconstriction
↓ Renal perfusion / hyponatremia
HRS type 1
Arroyo et al,J Hepatol 2007
Systemic vascularSystemic vascular
resistanceresistance
Cardiac outputCardiac output
ASCITES & HRS: ESSENTIALASCITES & HRS: ESSENTIAL
PATHOPHYSIOLOGYPATHOPHYSIOLOGY
PORTAL
HYPERTENSION
SYSTEMIC
HEMODYNAMIC
CHANGES
↓ EFFECTIVE
VOLEMIA
RENAL RETENTION
OF Na+
& WATER
ASCITES
PORTAL
HYPERTENSION
CARDIOVASCULAR
DYSFUNCTION
REFRACTORYREFRACTORY
ASCITESASCITES
RENAL FAILURERENAL FAILURE
(HRS)(HRS)TIPS
TIPS
↑ RAA
↑ SNS
↑ ADH
↓ Renal perfusion
VO
LUM
E
VO
LUM
E
EXPANSIO
N
EXPANSIO
N
VASO
-
VASO
-
CO
NSTRICTO
RS
CO
NSTRICTO
RS
LARGE-VOLUME PARACENTESISLARGE-VOLUME PARACENTESIS
0
4
8
12
16
Baseline Post-P 48h Post-P 5 days
PRA(ng/ml/h)
PPCD +
PPCD - *
*96%
Ginès et al., 1988, 1996
No PPCDNo PPCD
PPCDPPCD
SURVIVALSURVIVAL
POST-PARACENTESIS CIRCULATORYPOST-PARACENTESIS CIRCULATORY
DYSFUNCTIONDYSFUNCTION
0
10
20
30
40
Baseline Post-P 48h Baseline Post-P 48h
PRA(ng/ml/h)
0
500
1000
1500
NorE(pg/ml)
PRA (ng/ml/h)
NorE (pg/ml)
*
*
Saló et al., 1997
POST-PARACENTESIS CIRCULATORYPOST-PARACENTESIS CIRCULATORY
DYSFUNCTIONDYSFUNCTION
PPCD – PPCD +
0
1
2
3
4
5
Baseline Post-P 48h Baseline Post-P 48h
Plasmavolume(L)
0
5
10
15
20
TERa(%)
Plasma volume (L)
TERa (%)
PPCD – PPCD +
-20
-15
-10
-5
0
5
10
15
20
25
PRA MAP SVR HR CI
PERCENTCHANGE
Ruiz del Arbol et al., Gastroenterology 1997
*
*
*
POST-PARACENTESIS CIRCULATORYPOST-PARACENTESIS CIRCULATORY
DYSFUNCTIONDYSFUNCTION
BACTERIAL INFECTIONSBACTERIAL INFECTIONS
TLR4TLR4
TLR2TLR2
Gram -ve organism
LPS
NF-NF-κκ-B-B
MAP-kMAP-k
TNF-TNF-αα
IL-1, IL-6IL-1, IL-6
Gram +ve organism
PGN
LP
OXIDANTOXIDANT
STRESSSTRESS
COAGULATIONCOAGULATION
CASCADECASCADE
MICROVASCULARMICROVASCULAR
DAMAGEDAMAGE
ARTERIALARTERIAL
VASODILATIONVASODILATION
CARDIOCIRCULATORY DYSFUNCTIONCARDIOCIRCULATORY DYSFUNCTION
IMPACT OF BACTERIAL INFECTIONSIMPACT OF BACTERIAL INFECTIONS
ARTERIAL
VASODILATION
CARDIAC
DYSFUNCTION
REDUCED
EFFECTIVE VOLEMIA
REDUCED RENAL PERFUSIONREDUCED RENAL PERFUSIONRENAL FAILURE / MOFRENAL FAILURE / MOF
SEVERELY REDUCED
EFFECTIVE VOLEMIA
L'emodinamica nel cirrotico: aspetti fisiopatologici - Gastrolearning®
CentralCentral
baroceptorsbaroceptors
BLOOD VOLUME & EFFECTIVE VOLEMIABLOOD VOLUME & EFFECTIVE VOLEMIA
S.N.S. activityS.N.S. activity
Arginine-vasopressinArginine-vasopressin
Renin-angiotensinRenin-angiotensin
Juxtaglomerular apparatusJuxtaglomerular apparatus
EFFECTS OF EFFECTIVE HYPOVOLEMIAEFFECTS OF EFFECTIVE HYPOVOLEMIA
Central
baroceptors
S.N.S. activity
Arginine-vasopressin
Juxtaglomerular apparatus
Renin-angiotensin
CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHY
CLINICAL RELEVANCECLINICAL RELEVANCE
CONTRACTILE DYSFUNCTION(s)CONTRACTILE DYSFUNCTION(s)
• Prognostic meaningPrognostic meaning
• G.I. bleedingG.I. bleeding
QTQT INTERVALINTERVAL PROLONGATIONPROLONGATION
• PBS-induced renal failure / HRSPBS-induced renal failure / HRS
• TIPSTIPS
• OLTOLT
20%
57%
3,4%VARICES +
ASCITES −
7%
D’Amico et al, J Hepatol 2006
Arvaniti et al, Gastroenterology 2010
Fede et al, J Hepatol 2012
NATURAL HISTORY OF CHRONIC LIVER DISEASENATURAL HISTORY OF CHRONIC LIVER DISEASE
67%
4,4%
VARICES ±
ASCITES +
6.6%
1%
DEATH
VARICES −
ASCITES −
decompensated
Stage 3
Stage 4
compensated
Stage 1
Stage 2
Stage 5
INFECTIONS
RENAL FAILURE
4%
BLEEDING ±
ASCITES +
7.6%
SMOOTH MUSCLE
cGMP Protein
kinase G
RELAXATION
NO
THE NITRIC OXIDE PATHWAYTHE NITRIC OXIDE PATHWAY
Wood et al, J Gastroentrol Hepatol 1987
PATHOGENESIS OF ASCITESPATHOGENESIS OF ASCITES
DISRUPTION OF STARLING EQUILIBRIUMDISRUPTION OF STARLING EQUILIBRIUM
0
5
10
15
20
25
30
ABSENT I II III
ASCITES
cWHVP(mmHg)
20
25
30
35
40
45
50
ABSENT I II III
ASCITES
PLASMAALBUMIN(g/L)
94%94%
82%82%
STARLING EQUILIBRIUMSTARLING EQUILIBRIUM
PIF
ΠIF
PC
ΠC
Liver sinusoid
Liver cell
0
500
1000
1500
2000
Plasma norepinephrine (ng/L)
No ascites Ascites Hepatorenal
syndrome
Recent
Long-standing
PROGRESSION OF ASCITESPROGRESSION OF ASCITES
PATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND
Bernardi et al, 1999
-10
-5
0
5
10
15
20
25
MAP RAP PRA (/10) CI SVR
Percentchange
Albumin
HES
ALBUMIN vs HES IN PBSALBUMIN vs HES IN PBS
HEMODYNAMIC EFFECTSHEMODYNAMIC EFFECTS
Fernandez et al, Hepatology 2005
** **
**
**
Fernandez et al., Hepatology 2005
ALBUMIN vs HES IN PBSALBUMIN vs HES IN PBS
EFFECTS ON ENDOTHELIAL ACTIVATIONEFFECTS ON ENDOTHELIAL ACTIVATION
-40
-20
0
20
40
60
80
vWF:Ag Factor VIII Nox
Percentchange
Albumin
HES
** **
**
IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSIS
EFFECT OF ALBUMIN ADMINISTRATIONEFFECT OF ALBUMIN ADMINISTRATION
Bortoluzzi et al, Hepatology 2012
Cardiac tissue iNOS
0
0,5
1
1,5
2
2,5
Control rats Cirrhotic ratsPROTEINEXPRESSION(foldincrease)
ALBUMIN
IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSIS
EFFECT OF ALBUMIN ADMINISTRATIONEFFECT OF ALBUMIN ADMINISTRATION
Cardiac tissue TNF-a
0
0,5
1
1,5
2
2,5
Control rats Cirrhotic rats
PROTEINEXPRESSION(foldincrease)
Cardiac tissue NFkB
0
0,5
1
1,5
2
2,5
Control rats Cirrhotic ratsPROTEINEXPRESSION(foldincrease)
Bortoluzzi et al, Hepatology 2012
ALBUMINALBUMIN

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L'emodinamica nel cirrotico: aspetti fisiopatologici - Gastrolearning®

  • 1. PROGRAMMA GASTRO-LEARNINGPROGRAMMA GASTRO-LEARNING Bologna, 15 aprile 2013Bologna, 15 aprile 2013 EMODINAMICA NEL PAZIENTE CONEMODINAMICA NEL PAZIENTE CON CIRROSI: ASPETTI FISIOPATOLOGICICIRROSI: ASPETTI FISIOPATOLOGICI Mauro BernardiMauro Bernardi Semeiotica Medica Dipartimento di Medicina Clinica Alma Mater Studiorum - Università di Bologna
  • 2. NATURAL HISTORY OF CHRONIC LIVER DISEASENATURAL HISTORY OF CHRONIC LIVER DISEASE HBV HCV ETOH NASH CHRONICCHRONIC HEPATITISHEPATITIS … COMPENSATEDCOMPENSATED CIRRHOSISCIRRHOSIS ASYMPTOMATICASYMPTOMATIC PHASEPHASE SYMPTOMATICSYMPTOMATIC PHASEPHASE DECOMPENSATEDDECOMPENSATED CIRRHOSISCIRRHOSIS jaundice ascites g.i. bleeding hepatic encephalopathy OLT DEATH bacterial infections HCCCARDIOVASCULAR DYSFUNCTIONCARDIOVASCULAR DYSFUNCTION PORTAL HYPERTENSIONPORTAL HYPERTENSION HYPERDYNAMIC CIRCULATORY SYNDROMEHYPERDYNAMIC CIRCULATORY SYNDROME CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHY
  • 3. PORTAL HYPERTENSIONPORTAL HYPERTENSION DEFINITIONDEFINITION Portal hypertension is a clinical syndrome defined by a portal venous pressure gradient exceeding 5 mm Hg HVPG = WHVP - FHVP First cause of death First cause of death First cause of OLT First cause of OLT Courtesy Dr. R. Golfieri
  • 4. PORTAL HYPERTENSIONPORTAL HYPERTENSION PATHOPHYSIOLOGYPATHOPHYSIOLOGY PP (pressure)(pressure) == QQ (blood flow) x(blood flow) x RR (resistance)(resistance)
  • 5. PORTAL HYPERTENSIONPORTAL HYPERTENSION PATHOPHYSIOLOGYPATHOPHYSIOLOGY Nagula et al, J Hepatol 2006 Sethasine et al, Hepatology 2012 INDEPENDENT PREDICTORS OF CSPHINDEPENDENT PREDICTORS OF CSPH
  • 6. PORTAL HYPERTENSIONPORTAL HYPERTENSION PATHOPHYSIOLOGYPATHOPHYSIOLOGY PP (pressure)(pressure) == QQ (blood flow) x(blood flow) x RR (resistance)(resistance) STRUCTURALSTRUCTURAL COMPONENTCOMPONENT 2/32/3 DYNAMICDYNAMIC COMPONENTCOMPONENT 1/31/3 Ijzer, Vet Sci 2008
  • 7. PORTAL HYPERTENSIONPORTAL HYPERTENSION DYNAMIC COMPONENTDYNAMIC COMPONENT Asselah et al, Gut 2009 L-arginine L- citrulline NO e-NOS BH4 p-Akt ENDOTHELIAL DYSFUNCTIONENDOTHELIAL DYSFUNCTION Vascoconstrictor phenotypeVascoconstrictor phenotype L-arginine L- citrulline NO ↓ e-NOS BH4 p-Akt O2 − O2 − Caveolin 1 Membrane PL ARA PLA2 TXA2PGH2 COX-1 TXA2S CysLT 5-LO Membrane PL ARA ↑ PLA2 PGH2 ↑ COX-1 ↑ TXA2S ↑ 5-LO TXA2 CysLT NorepinephrineNorepinephrine AcetylcholineAcetylcholine ……
  • 8. PORTAL HYPERTENSIONPORTAL HYPERTENSION DYNAMIC COMPONENTDYNAMIC COMPONENT ENDOTHELIAL DYSFUNCTIONENDOTHELIAL DYSFUNCTION ↑↑ ET 1ET 1 ↑↑ TXA2TXA2 ↑↑ CysLTCysLT ↓↓ NONO ↓↓ COCO Activated CONTRACTIONCONTRACTION FIBROGENESISFIBROGENESIS ANGIOGENESISANGIOGENESIS SYSTEMICSYSTEMIC VASOCONSTRICTORSVASOCONSTRICTORS Angiotensin IIAngiotensin II VasopressinVasopressin Asselah et al, Gut 2009
  • 9. Garcia-Pagan & Bosch, J Hepatol 2012 PORTAL HYPERTENSIONPORTAL HYPERTENSION New Tx perspectivesNew Tx perspectives COX blockersCOX blockers COX-1 blockersCOX-1 blockers TXATXA22 antagonistsantagonists StatinsStatins BH4 supplementationBH4 supplementation SOD supplementationSOD supplementation Anti-oxydantsAnti-oxydants
  • 10. PORTAL HYPERTENSIONPORTAL HYPERTENSION PATHOPHYSIOLOGYPATHOPHYSIOLOGY DYNAMICDYNAMIC COMPONENTCOMPONENT STRUCTURALSTRUCTURAL COMPONENTCOMPONENT PORTAL HYPERTENSIONPORTAL HYPERTENSION SPLANCHNIC CIRCULATIONSPLANCHNIC CIRCULATION SYSTEMIC CIRCULATIONSYSTEMIC CIRCULATION
  • 11. heart rate arterial pressure HYPERDYNAMIC CIRCULATORYHYPERDYNAMIC CIRCULATORY SYNDROMESYNDROME effective volemiaeffective volemia cardiac output RAA system SN system ADH ARTERIAL VASODILATIONARTERIAL VASODILATION peripheral vascular resistance
  • 12. PORTAL HYPERTENTION IN CIRRHOSISPORTAL HYPERTENTION IN CIRRHOSIS RETROGRADE AND ANTEROGRADE COMPONENTSRETROGRADE AND ANTEROGRADE COMPONENTS portal system systemic circulation splanchnic circulation PORTALPORTAL HYPERTENSIONHYPERTENSION PP (pressure)(pressure) == QQ (blood flow) x(blood flow) x RR (resistance)(resistance)
  • 13. SYSTEMIC HEMODYNAMICS ABNORMALITIESSYSTEMIC HEMODYNAMICS ABNORMALITIES PROGRESSION WITH DISEASE SEVERITYPROGRESSION WITH DISEASE SEVERITY 50 70 90 110 130 150 170 Child-Pugh A Child-Pugh B Child-Pugh C SVR (dyn/sec/cm-5]/10) CO ([dl/min] x 3) HR (bpm) MAP (mmHg) Braillon et al., 1986 * * * * *
  • 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 abnormalities Montreal workshop, 2005 CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHY DEFINITION & FEATURESDEFINITION & FEATURES
  • 17. REDUCED VASCULAR REACTIVITYREDUCED VASCULAR REACTIVITY IN CIRRHOSISIN CIRRHOSIS NorepinephrineNorepinephrine Angiotensin IIAngiotensin II VasopressinVasopressin EndothelinEndothelin -1-1 ++ANPANP GlucagonGlucagon VIPVIP CGrPCGrP - CirculatingCirculating vasodilatorsvasodilators - ET-derivedET-derived vasodilatorsvasodilators NONO COCO ProstacyclinProstacyclin eCBseCBs
  • 18. THE NITRIC OXIDE PATHWAYTHE NITRIC OXIDE PATHWAY SHEARSHEAR STRESSSTRESS ENDOTOXINSENDOTOXINS CYTOKINESCYTOKINES L-ARGININEL-ARGININE L-CITRULLINEL-CITRULLINE ENDOTHELIUMNO e-NOSe-NOS i-NOSi-NOS BH4BH4
  • 19. CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASE SHEAR STRESSSHEAR STRESS Tazi et al, Gastroenterology 2002 eNOS expressioneNOS expression eNOS expressioneNOS expression Effect ofEffect of β-blokadeβ-blokade
  • 20. 0 20 40 60 80 0 50 100 150 200 250 Endotoxin (pg/ml) r = 0,65 p < 0,001 NO2 - /NO3 - Guarner et al. Hepatology 1993 CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASE ENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
  • 21. Frances et al, Hepatology 2008 CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASE ENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
  • 22. Wiest et al, J Clin Invest 1999 CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASE ENDOTOXIN / CYTOKINES / SHEAR STRESSENDOTOXIN / CYTOKINES / SHEAR STRESS
  • 23. TNF-TNF-αα EndotheliumEndothelium LeukocyteLeukocyte activationactivation LPSLPS Bact DNABact DNA BacterialBacterial translocationtranslocation Wiest et al, J Clin Invest 1999 TNF-TNF-αα Nucleus+ eNOS NO + BH4 CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASE ENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
  • 24. Niederberger et al, Gastroenterology 1995 NOS INHIBITION IN CIRRHOSISNOS INHIBITION IN CIRRHOSIS L-NAME: 0.5 mg/Kg/dayL-NAME: 0.5 mg/Kg/day L-NAME: 3 mg/Kg/dayL-NAME: 3 mg/Kg/day 2 3 4 5 6 Controls Untreated L-NAME L-NAME SYSTEMICVASCULARRESISTANCE (mmg.min.ml-1.100g-1) 100 120 140 160 Controls Untreated L-NAME L-NAME MEANARTERIALPRESSURE (mmHg) 20 30 40 50 60 Controls Untreated L-NAME L-NAME CARDIACINDEX (ml.min-1.100g-1)
  • 25. EFFECT OF SID IN CIRRHOSISEFFECT OF SID IN CIRRHOSIS AORTIC NOS EXPRESSIONAORTIC NOS EXPRESSION Tazi et al, Gastroenterology 2005 eNOS iNOS • Rats with bile duct ligation • Norfloxacin 10 mg/Kg for 5 days • Colistin 15 mg/Kg for 5 days
  • 26. LBPLBP Albillos et al, Hepatology 2003 SVRSVR CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASE ENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
  • 27. Cirrhosis Controls Systolic blood pressureSystolic blood pressure Batkai et al, Nature Med 2001 SR 141716ASR 141716A CAUSES OF VASODILATIONCAUSES OF VASODILATION ROLE OF eCBsROLE OF eCBs RATS WITH DECOMPENSATED CClRATS WITH DECOMPENSATED CCl44 – INDUCED CIRRHOSIS– INDUCED CIRRHOSIS
  • 28. Control Cirrhosis -8 -7 -6 -5 -4 Anandamide log [M] %ofrelaxationofprecontractedtone 100 80 60 40 20 0 Domenicali et al, Gut 2005 RATS WITH DECOMPENSATED CClRATS WITH DECOMPENSATED CCl44 – INDUCED CIRRHOSIS– INDUCED CIRRHOSIS Mesenteric arteryMesenteric artery CAUSES OF VASODILATIONCAUSES OF VASODILATION ROLE OF eCBsROLE OF eCBs
  • 29. Varga, FASEB J 1998 -30 -20 -10 0 10 20 30 60 90 120 Min after LPS administration * * * * * * * * * * Rimonabant pre-treated rats Controls rats DMAP(mmHg) * P < 0.05 LPS-INDUCED HEMODYNAMIC CHANGESLPS-INDUCED HEMODYNAMIC CHANGES EFFECT OF ENDOGENOUS CANNABINOID INHIBITON 0 20 40 60 80 100 H after LPS administration 6 12 18 240 PERCENT LPS + Rim LPS SURVIVALSURVIVAL P < 0.05 Domenicali et al, Monotematica AISF 2012
  • 30. IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSIS ROLE OF NITRIC OXIDEROLE OF NITRIC OXIDE Bortoluzzi et al, Hepatology 2012 Cardiac tissue iNOS 0 0,5 1 1,5 2 2,5 Control rats Cirrhotic ratsPROTEINEXPRESSION(foldincrease) *
  • 31. IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSIS ROLE OF CYTOKINESROLE OF CYTOKINES Cardiac tissue TNF-a 0 0,5 1 1,5 2 2,5 Control rats Cirrhotic rats PROTEINEXPRESSION(foldincrease) * Cardiac tissue NFkB 0 0,5 1 1,5 2 2,5 Control rats Cirrhotic ratsPROTEINEXPRESSION(foldincrease) * Bortoluzzi et al, Hepatology 2012
  • 32. CARDIOVASCULAR DYSFUNCTION IN CIRRHOSISCARDIOVASCULAR DYSFUNCTION IN CIRRHOSIS A MULTIFACTORIAL PROCESS CARDIOVASCULAR ABNORMALITIES NITRIC OXIDENITRIC OXIDE PROSTAGLANDINSPROSTAGLANDINS CARBON MONOXYDECARBON MONOXYDE ENDOGENOUS CANNABINOIDSENDOGENOUS CANNABINOIDS UROTENSINUROTENSIN APELINAPELIN BACTERIAL TRANSLOCATIONBACTERIAL TRANSLOCATION CYTOKINE RELEASECYTOKINE RELEASE SPECIFICSPECIFIC INHIBITIONINHIBITION SIDSID OTHERSOTHERS DIRECTDIRECT ACTING TxACTING Tx
  • 34. ASCITESASCITES Renal retentionRenal retention of Naof Na++ / H/ H22OO PATHOGENESIS OF ASCITES Post-sinusoidalPost-sinusoidal portal hypertensionportal hypertension
  • 35. Bernardi, et al, 1999 PROGRESSION OF ASCITESPROGRESSION OF ASCITES PATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND Bernardi et al, 1999 0 30 60 90 120 No ascites Ascites Hepatorenal syndrome Renal sodium excretion (mmol/24 h) Recent Long-standing
  • 36. Bernardi et al, 1999 0 300 600 900 1200 1500 Plasma aldosterone (pg/ml) No ascites Ascites Hepatorenal syndrome Recent Long-standing PROGRESSION OF ASCITESPROGRESSION OF ASCITES PATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND
  • 37. Recent ascites ascites 0 20 40 60 80 100 120 No ascites Long standing HRS 0 100 200 300 400 500 600 700 RPF GFR ml/min ml/min PROGRESSIONE OF ASCITESPROGRESSIONE OF ASCITES PATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND Bernardi et al, 1999
  • 38. RENAL Na+ REABSORPTION RENAL NaRENAL Na++ RETENTION IN CIRRHOSISRETENTION IN CIRRHOSIS TUBULAR SITES OF NaTUBULAR SITES OF Na++ RETENTIONRETENTION PRESERVED GFRPRESERVED GFR (~(~ ≥≥ 60 ml/min)60 ml/min) DISTALDISTAL PROXIMALPROXIMAL REDUCED GFRREDUCED GFR (~ < 60 ml/min)(~ < 60 ml/min) DISTALDISTAL PROXIMALPROXIMAL
  • 39. 0 10 20 30 40 RS RF WHVP(mmHg) REFRACTORY ASCITESREFRACTORY ASCITES PATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND 50 65 80 95 110 RS RF * MAP(mmHg) 0 30 60 90 120 150 RS RF * GFR(ml/min) RS = responsive ascites – RF = refractory ascitesRS = responsive ascites – RF = refractory ascites
  • 40. ↓ EFFECTIVE VOLEMIA HYPONATREMIA IN CIRRHOSISHYPONATREMIA IN CIRRHOSIS PATHOPHYSIOLOGYPATHOPHYSIOLOGY PERIPHERALPERIPHERAL VASODILATIONVASODILATION ADHADH DIURETICSDIURETICS Impaired dilution Na+
  • 41. -20 0 20 40 60 80 PRA NorE MAP SVR CO HR PERCENTCHANGE Ruiz del Arbol et al., Hepatology 2005 * * * * HEPATORENAL SYNDROMEHEPATORENAL SYNDROME CARDIOVASCULAR CHANGESCARDIOVASCULAR CHANGES
  • 42. CARDIOVASCULAR DYSFUNCTIONCARDIOVASCULAR DYSFUNCTION PROGRESSION WITH DISEASEPROGRESSION WITH DISEASE Pre-ascites Ascites CHANGES ↓ Effective blood volume Normal effective blood volume Splanchnic arterialSplanchnic arterial vasodilationvasodilation RAAS, SNS, AVPRAAS, SNS, AVP ExtrasplanchnicExtrasplanchnic vasoconstrictionvasoconstriction ↓ Renal perfusion / hyponatremia HRS type 1 Arroyo et al,J Hepatol 2007 Systemic vascularSystemic vascular resistanceresistance Cardiac outputCardiac output
  • 43. ASCITES & HRS: ESSENTIALASCITES & HRS: ESSENTIAL PATHOPHYSIOLOGYPATHOPHYSIOLOGY PORTAL HYPERTENSION SYSTEMIC HEMODYNAMIC CHANGES ↓ EFFECTIVE VOLEMIA RENAL RETENTION OF Na+ & WATER ASCITES PORTAL HYPERTENSION CARDIOVASCULAR DYSFUNCTION REFRACTORYREFRACTORY ASCITESASCITES RENAL FAILURERENAL FAILURE (HRS)(HRS)TIPS TIPS ↑ RAA ↑ SNS ↑ ADH ↓ Renal perfusion VO LUM E VO LUM E EXPANSIO N EXPANSIO N VASO - VASO - CO NSTRICTO RS CO NSTRICTO RS
  • 45. 0 4 8 12 16 Baseline Post-P 48h Post-P 5 days PRA(ng/ml/h) PPCD + PPCD - * *96% Ginès et al., 1988, 1996 No PPCDNo PPCD PPCDPPCD SURVIVALSURVIVAL POST-PARACENTESIS CIRCULATORYPOST-PARACENTESIS CIRCULATORY DYSFUNCTIONDYSFUNCTION
  • 46. 0 10 20 30 40 Baseline Post-P 48h Baseline Post-P 48h PRA(ng/ml/h) 0 500 1000 1500 NorE(pg/ml) PRA (ng/ml/h) NorE (pg/ml) * * Saló et al., 1997 POST-PARACENTESIS CIRCULATORYPOST-PARACENTESIS CIRCULATORY DYSFUNCTIONDYSFUNCTION PPCD – PPCD + 0 1 2 3 4 5 Baseline Post-P 48h Baseline Post-P 48h Plasmavolume(L) 0 5 10 15 20 TERa(%) Plasma volume (L) TERa (%) PPCD – PPCD +
  • 47. -20 -15 -10 -5 0 5 10 15 20 25 PRA MAP SVR HR CI PERCENTCHANGE Ruiz del Arbol et al., Gastroenterology 1997 * * * POST-PARACENTESIS CIRCULATORYPOST-PARACENTESIS CIRCULATORY DYSFUNCTIONDYSFUNCTION
  • 49. TLR4TLR4 TLR2TLR2 Gram -ve organism LPS NF-NF-κκ-B-B MAP-kMAP-k TNF-TNF-αα IL-1, IL-6IL-1, IL-6 Gram +ve organism PGN LP OXIDANTOXIDANT STRESSSTRESS COAGULATIONCOAGULATION CASCADECASCADE MICROVASCULARMICROVASCULAR DAMAGEDAMAGE ARTERIALARTERIAL VASODILATIONVASODILATION
  • 50. CARDIOCIRCULATORY DYSFUNCTIONCARDIOCIRCULATORY DYSFUNCTION IMPACT OF BACTERIAL INFECTIONSIMPACT OF BACTERIAL INFECTIONS ARTERIAL VASODILATION CARDIAC DYSFUNCTION REDUCED EFFECTIVE VOLEMIA REDUCED RENAL PERFUSIONREDUCED RENAL PERFUSIONRENAL FAILURE / MOFRENAL FAILURE / MOF SEVERELY REDUCED EFFECTIVE VOLEMIA
  • 52. CentralCentral baroceptorsbaroceptors BLOOD VOLUME & EFFECTIVE VOLEMIABLOOD VOLUME & EFFECTIVE VOLEMIA S.N.S. activityS.N.S. activity Arginine-vasopressinArginine-vasopressin Renin-angiotensinRenin-angiotensin Juxtaglomerular apparatusJuxtaglomerular apparatus
  • 53. EFFECTS OF EFFECTIVE HYPOVOLEMIAEFFECTS OF EFFECTIVE HYPOVOLEMIA Central baroceptors S.N.S. activity Arginine-vasopressin Juxtaglomerular apparatus Renin-angiotensin
  • 54. CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHY CLINICAL RELEVANCECLINICAL RELEVANCE CONTRACTILE DYSFUNCTION(s)CONTRACTILE DYSFUNCTION(s) • Prognostic meaningPrognostic meaning • G.I. bleedingG.I. bleeding QTQT INTERVALINTERVAL PROLONGATIONPROLONGATION • PBS-induced renal failure / HRSPBS-induced renal failure / HRS • TIPSTIPS • OLTOLT
  • 55. 20% 57% 3,4%VARICES + ASCITES − 7% D’Amico et al, J Hepatol 2006 Arvaniti et al, Gastroenterology 2010 Fede et al, J Hepatol 2012 NATURAL HISTORY OF CHRONIC LIVER DISEASENATURAL HISTORY OF CHRONIC LIVER DISEASE 67% 4,4% VARICES ± ASCITES + 6.6% 1% DEATH VARICES − ASCITES − decompensated Stage 3 Stage 4 compensated Stage 1 Stage 2 Stage 5 INFECTIONS RENAL FAILURE 4% BLEEDING ± ASCITES + 7.6%
  • 56. SMOOTH MUSCLE cGMP Protein kinase G RELAXATION NO THE NITRIC OXIDE PATHWAYTHE NITRIC OXIDE PATHWAY
  • 57. Wood et al, J Gastroentrol Hepatol 1987 PATHOGENESIS OF ASCITESPATHOGENESIS OF ASCITES DISRUPTION OF STARLING EQUILIBRIUMDISRUPTION OF STARLING EQUILIBRIUM 0 5 10 15 20 25 30 ABSENT I II III ASCITES cWHVP(mmHg) 20 25 30 35 40 45 50 ABSENT I II III ASCITES PLASMAALBUMIN(g/L) 94%94% 82%82%
  • 59. 0 500 1000 1500 2000 Plasma norepinephrine (ng/L) No ascites Ascites Hepatorenal syndrome Recent Long-standing PROGRESSION OF ASCITESPROGRESSION OF ASCITES PATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND Bernardi et al, 1999
  • 60. -10 -5 0 5 10 15 20 25 MAP RAP PRA (/10) CI SVR Percentchange Albumin HES ALBUMIN vs HES IN PBSALBUMIN vs HES IN PBS HEMODYNAMIC EFFECTSHEMODYNAMIC EFFECTS Fernandez et al, Hepatology 2005 ** ** ** **
  • 61. Fernandez et al., Hepatology 2005 ALBUMIN vs HES IN PBSALBUMIN vs HES IN PBS EFFECTS ON ENDOTHELIAL ACTIVATIONEFFECTS ON ENDOTHELIAL ACTIVATION -40 -20 0 20 40 60 80 vWF:Ag Factor VIII Nox Percentchange Albumin HES ** ** **
  • 62. IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSIS EFFECT OF ALBUMIN ADMINISTRATIONEFFECT OF ALBUMIN ADMINISTRATION Bortoluzzi et al, Hepatology 2012 Cardiac tissue iNOS 0 0,5 1 1,5 2 2,5 Control rats Cirrhotic ratsPROTEINEXPRESSION(foldincrease) ALBUMIN
  • 63. IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSIS EFFECT OF ALBUMIN ADMINISTRATIONEFFECT OF ALBUMIN ADMINISTRATION Cardiac tissue TNF-a 0 0,5 1 1,5 2 2,5 Control rats Cirrhotic rats PROTEINEXPRESSION(foldincrease) Cardiac tissue NFkB 0 0,5 1 1,5 2 2,5 Control rats Cirrhotic ratsPROTEINEXPRESSION(foldincrease) Bortoluzzi et al, Hepatology 2012 ALBUMINALBUMIN