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PROGRAMMA GASTRO-LEARNINGPROGRAMMA GASTRO-LEARNINGBologna, 15 aprile 2013Bologna, 15 aprile 2013
EMODINAMICA NEL PAZIENTE CON EMODINAMICA NEL PAZIENTE CON CIRROSI: ASPETTI FISIOPATOLOGICICIRROSI: ASPETTI FISIOPATOLOGICI
Mauro BernardiMauro Bernardi
Semeiotica Medica
Dipartimento di Medicina Clinica
Alma Mater Studiorum - Università di Bologna
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NATURAL HISTORY OF CHRONIC LIVER DISEASENATURAL HISTORY OF CHRONIC LIVER DISEASE
HBV
HCV
ETOH
NASH
CHRONICCHRONICHEPATITISHEPATITIS
…
COMPENSATEDCOMPENSATEDCIRRHOSISCIRRHOSIS
ASYMPTOMATICASYMPTOMATICPHASEPHASE
SYMPTOMATICSYMPTOMATICPHASEPHASE
DECOMPENSATEDDECOMPENSATEDCIRRHOSISCIRRHOSIS
jaundiceascitesg.i. bleedinghepatic encephalopathy
OLT
DEATH
bacterial infections
HCCCARDIOVASCULAR DYSFUNCTIONCARDIOVASCULAR DYSFUNCTIONPORTAL HYPERTENSIONPORTAL HYPERTENSION
HYPERDYNAMIC CIRCULATORY SYNDROMEHYPERDYNAMIC CIRCULATORY SYNDROMECIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHY
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PORTAL HYPERTENSIONPORTAL HYPERTENSIONDEFINITIONDEFINITION
Portal hypertension is a clinical syndrome defined by a portal venous pressure gradient
exceeding 5 mm Hg
HVPG = WHVP - FHVP
First c
ause of d
eath
First c
ause of d
eath
First c
ause of O
LT
First c
ause of O
LT
Courtesy Dr. R. Golfieri
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PORTAL HYPERTENSIONPORTAL HYPERTENSIONPATHOPHYSIOLOGYPATHOPHYSIOLOGY
P P (pressure)(pressure)==
Q Q (blood flow) x (blood flow) x R R (resistance)(resistance)
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PORTAL HYPERTENSIONPORTAL HYPERTENSIONPATHOPHYSIOLOGYPATHOPHYSIOLOGY
Nagula et al, J Hepatol 2006Sethasine et al, Hepatology 2012
INDEPENDENT PREDICTORS OF CSPHINDEPENDENT PREDICTORS OF CSPH
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PORTAL HYPERTENSIONPORTAL HYPERTENSIONPATHOPHYSIOLOGYPATHOPHYSIOLOGY
P P (pressure)(pressure)==
Q Q (blood flow) x (blood flow) x R R (resistance)(resistance)
STRUCTURALSTRUCTURALCOMPONENTCOMPONENT
2/32/3
DYNAMICDYNAMICCOMPONENTCOMPONENT
1/31/3
Ijzer, Vet Sci 2008
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PORTAL HYPERTENSIONPORTAL HYPERTENSIONDYNAMIC COMPONENTDYNAMIC COMPONENT
Asselah et al, Gut 2009 L-arginine L- citrulline
NO
e-NOS
BH4
p-Akt
ENDOTHELIAL DYSFUNCTIONENDOTHELIAL DYSFUNCTIONVascoconstrictor phenotypeVascoconstrictor phenotype
L-arginine L- citrulline
NO
e-NOS
BH4
p-Akt
O2 O2
Caveolin 1
Membrane PL
ARA
PLA2
TXA2PGH2COX-1 TXA2S
CysLT5-LO
Membrane PL
ARA
PLA2
PGH2 COX-1 TXA2S
5-LO
TXA2
CysLT
NorepinephrineNorepinephrineAcetylcholineAcetylcholine……
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PORTAL HYPERTENSIONPORTAL HYPERTENSIONDYNAMIC COMPONENTDYNAMIC COMPONENT
ENDOTHELIAL DYSFUNCTIONENDOTHELIAL DYSFUNCTION
ET 1 ET 1 TXA2TXA2 CysLTCysLT
NONO COCO
Activated
CONTRACTIONCONTRACTIONFIBROGENESISFIBROGENESISANGIOGENESISANGIOGENESIS
SYSTEMICSYSTEMIC VASOCONSTRICTORSVASOCONSTRICTORSAngiotensin IIAngiotensin IIVasopressinVasopressin
Asselah et al, Gut 2009
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Garcia-Pagan & Bosch, J Hepatol 2012
PORTAL HYPERTENSIONPORTAL HYPERTENSION New Tx perspectivesNew Tx perspectives
COX blockersCOX blockersCOX-1 blockersCOX-1 blockersTXATXA22 antagonists antagonists
StatinsStatinsBH4 supplementationBH4 supplementationSOD supplementationSOD supplementationAnti-oxydantsAnti-oxydants
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PORTAL HYPERTENSIONPORTAL HYPERTENSIONPATHOPHYSIOLOGYPATHOPHYSIOLOGY
DYNAMICDYNAMICCOMPONENTCOMPONENT
STRUCTURALSTRUCTURALCOMPONENTCOMPONENT
PORTAL HYPERTENSIONPORTAL HYPERTENSION
SPLANCHNIC CIRCULATIONSPLANCHNIC CIRCULATIONSYSTEMIC CIRCULATIONSYSTEMIC CIRCULATION
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heart rate arterial pressure
HYPERDYNAMIC CIRCULATORY HYPERDYNAMIC CIRCULATORY SYNDROMESYNDROME
effective volemiaeffective volemia
cardiac output RAA system SN system ADH
ARTERIAL VASODILATIONARTERIAL VASODILATION
peripheral vascular resistance
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PORTAL HYPERTENTION IN CIRRHOSISPORTAL HYPERTENTION IN CIRRHOSISRETROGRADE AND ANTEROGRADE COMPONENTSRETROGRADE AND ANTEROGRADE COMPONENTS
portal system
systemic circulation
splanchniccirculation
PORTAL PORTAL HYPERTENSIONHYPERTENSION
P P (pressure)(pressure)==
Q Q (blood flow) x (blood flow) x R R (resistance)(resistance)
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SYSTEMIC HEMODYNAMICS ABNORMALITIESSYSTEMIC HEMODYNAMICS ABNORMALITIESPROGRESSION 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
**
*
*
*
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HYPERDYNAMIC CIRCULATORY HYPERDYNAMIC CIRCULATORY SYNDROMESYNDROME
Page 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 CARDIOMYOPATHYDEFINITION & FEATURESDEFINITION & FEATURES
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CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHYPATHOPHYSIOLOGYPATHOPHYSIOLOGY
HYPERDYNAMICHYPERDYNAMICCIRCULATIONCIRCULATION
ADRENERGICADRENERGICHYPERACTIVITYHYPERACTIVITY
ANGIOTENSIN IIANGIOTENSIN II ALDOSTERONEALDOSTERONE
““CARDIOTOXINS”CARDIOTOXINS”FROM SPLANCHINC AREAFROM SPLANCHINC AREA
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REDUCED VASCULAR REACTIVITYREDUCED VASCULAR REACTIVITYIN CIRRHOSISIN CIRRHOSIS
NorepinephrineNorepinephrine
Angiotensin IIAngiotensin II
VasopressinVasopressin
EndothelinEndothelin -1 -1
++ANP ANP GlucagonGlucagonVIPVIPCGrPCGrP
-
Circulating Circulating vasodilatorsvasodilators
-
ET-derivedET-derivedvasodilatorsvasodilators
NO NO COCOProstacyclinProstacyclineCBseCBs
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THE NITRIC OXIDE PATHWAYTHE NITRIC OXIDE PATHWAY
SHEARSHEARSTRESSSTRESS
ENDOTOXINSENDOTOXINSCYTOKINESCYTOKINES
L-ARGININEL-ARGININE L-CITRULLINEL-CITRULLINE
ENDOTHELIUMNO
e-NOSe-NOS i-NOSi-NOS
BH4BH4
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CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASESHEAR STRESSSHEAR STRESS
Tazi et al, Gastroenterology 2002
eNOS expressioneNOS expression
eNOS expressioneNOS expressionEffect of Effect of β-blokadeβ-blokade
Page 20
0
20
40
60
80
0 50 100 150 200 250
Endotoxin (pg/ml)
r = 0,65p < 0,001
NO
2- /NO
3-
Guarner et al. Hepatology 1993
CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
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Frances et al, Hepatology 2008
CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
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Wiest et al, J Clin Invest 1999
CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOKINES / SHEAR STRESSENDOTOXIN / CYTOKINES / SHEAR STRESS
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TNF-TNF-
Endothelium Endothelium
Leukocyte Leukocyte activationactivation
LPSLPSBact DNABact DNA
Bacterial Bacterial translocationtranslocation
Wiest et al, J Clin Invest 1999
TNF-TNF-
Nucleus+
eNOS
NO
+ BH4
CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
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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
SY
ST
EM
IC V
AS
CU
LA
R R
ES
IST
AN
CE
(m
mg
.min
.ml-
1.10
0 g
-1)
100
120
140
160
Controls Untreated L-NAME L-NAME
ME
AN
AR
TE
RIA
L P
RE
SS
UR
E
(mm
Hg
)
20
30
40
50
60
Controls Untreated L-NAME L-NAME
CA
RD
IAC
IND
EX
(m
l.min
-1.1
00
g-1
)
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EFFECT OF SID IN CIRRHOSISEFFECT OF SID IN CIRRHOSISAORTIC 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
Page 26
LBPLBP
Albillos et al, Hepatology 2003
SVRSVR
CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES
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Cirrhosis
Controls
Systolic blood pressureSystolic blood pressure
Batkai et al, Nature Med 2001
SR 141716ASR 141716A
CAUSES OF VASODILATIONCAUSES OF VASODILATIONROLE OF eCBsROLE OF eCBs
RATS WITH DECOMPENSATED CClRATS WITH DECOMPENSATED CCl44 – INDUCED CIRRHOSIS – INDUCED CIRRHOSIS
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Control
Cirrhosis
-8 -7 -6 -5 -4
Anandamide log [M]
% o
f re
laxa
tio
n o
f p
reco
ntr
acte
d t
on
e
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 VASODILATIONROLE OF eCBsROLE OF eCBs
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Varga, FASEB J 1998
-30
-20
-10
0
10
20
30 60 90 120
Min after LPS administration
* * * * * *
* *
*
*
Rimonabant pre-treated ratsControls rats
D M
AP
(m
mH
g)
* P < 0.05
LPS-INDUCED HEMODYNAMIC CHANGES LPS-INDUCED HEMODYNAMIC CHANGES EFFECT OF ENDOGENOUS CANNABINOID INHIBITON
0
20
40
60
80
100
H after LPS administration
6 12 18 240
PE
RC
EN
T
LPS + Rim
LPS
SURVIVALSURVIVAL
P < 0.05
Domenicali et al, Monotematica AISF 2012
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IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSISROLE 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 ratsP
RO
TE
IN E
XP
RE
SS
ION
(fo
ld i
ncr
ease
)
*
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IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSISROLE OF CYTOKINESROLE OF CYTOKINES
Cardiac tissue TNF-a
0
0,5
1
1,5
2
2,5
Control rats Cirrhotic rats
PR
OT
EIN
EX
PR
ES
SIO
N (
fold
in
crea
se)
*
Cardiac tissue NFkB
0
0,5
1
1,5
2
2,5
Control rats Cirrhotic ratsP
RO
TE
IN E
XP
RE
SS
ION
(fo
ld i
ncr
ease
)
*
Bortoluzzi et al, Hepatology 2012
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CARDIOVASCULAR DYSFUNCTION IN CIRRHOSISCARDIOVASCULAR DYSFUNCTION IN CIRRHOSIS
A MULTIFACTORIAL PROCESS
CARDIOVASCULAR ABNORMALITIES
NITRIC OXIDENITRIC OXIDEPROSTAGLANDINSPROSTAGLANDINS
CARBON MONOXYDECARBON MONOXYDEENDOGENOUS CANNABINOIDSENDOGENOUS CANNABINOIDS
UROTENSINUROTENSINAPELINAPELIN
BACTERIAL TRANSLOCATIONBACTERIAL TRANSLOCATION
CYTOKINE RELEASECYTOKINE RELEASESPECIFICSPECIFIC
INHIBITIONINHIBITION
SIDSIDOTHERSOTHERS
DIRECTDIRECTACTING TxACTING Tx
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ASCITESASCITES&&
HEPATORENAL SYNDROMEHEPATORENAL SYNDROME
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ASCITESASCITES
Renal retentionRenal retentionof Naof Na+ + / H/ H22OO
PATHOGENESIS OF ASCITES
Post-sinusoidalPost-sinusoidalportal hypertension portal hypertension
Page 35
Bernardi, et al, 1999
PROGRESSION OF ASCITESPROGRESSION OF ASCITESPATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND
Bernardi et al, 1999
0
30
60
90
120
No ascites Ascites Hepatorenalsyndrome
Renal sodium excretion (mmol/24 h)
Recent
Long-standing
Page 36
Bernardi et al, 1999
0
300
600
900
1200
1500Plasma aldosterone (pg/ml)
No ascites Ascites Hepatorenalsyndrome
Recent
Long-standing
PROGRESSION OF ASCITESPROGRESSION OF ASCITESPATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND
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Recentascites 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/m
in
PROGRESSIONE OF ASCITESPROGRESSIONE OF ASCITESPATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND
Bernardi et al, 1999
Page 38
RENAL Na+ REABSORPTION
RENAL NaRENAL Na++ RETENTION IN CIRRHOSIS RETENTION IN CIRRHOSISTUBULAR SITES OF NaTUBULAR SITES OF Na++ RETENTION RETENTION
PRESERVED GFRPRESERVED GFR(~ (~ 60 ml/min) 60 ml/min)
DISTALDISTAL
PROXIMALPROXIMAL
REDUCED GFRREDUCED GFR(~ < 60 ml/min)(~ < 60 ml/min)
DISTALDISTAL
PROXIMALPROXIMAL
Page 39
0
10
20
30
40
RS RF
WH
VP
(m
mH
g)
REFRACTORY ASCITESREFRACTORY ASCITESPATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND
50
65
80
95
110
RS RF
*M
AP
(m
mH
g)
0
30
60
90
120
150
RS RF
*
GF
R (
ml/m
in)
RS = responsive ascites – RF = refractory ascitesRS = responsive ascites – RF = refractory ascites
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EFFECTIVE VOLEMIA
HYPONATREMIA IN CIRRHOSISHYPONATREMIA IN CIRRHOSISPATHOPHYSIOLOGYPATHOPHYSIOLOGY
PERIPHERALPERIPHERALVASODILATIONVASODILATION
ADHADH
DIURETICSDIURETICSImpaireddilution
Na+
Page 41
-20
0
20
40
60
80
PRA NorE MAP SVR CO HR
PE
RC
EN
T C
HA
NG
E
Ruiz del Arbol et al., Hepatology 2005
**
* *
HEPATORENAL SYNDROMEHEPATORENAL SYNDROMECARDIOVASCULAR CHANGESCARDIOVASCULAR CHANGES
Page 42
CARDIOVASCULAR DYSFUNCTIONCARDIOVASCULAR DYSFUNCTIONPROGRESSION WITH DISEASEPROGRESSION WITH DISEASE
Pre-ascites Ascites
CH
AN
GE
S
↓ Effectiveblood volume
Normaleffective
bloodvolume
Splanchnic arterialSplanchnic arterialvasodilationvasodilation
RAAS, SNS, AVPRAAS, SNS, AVP
ExtrasplanchnicExtrasplanchnicvasoconstrictionvasoconstriction
Renal perfusion / hyponatremia
HRS type 1Arroyo et al,J Hepatol 2007
Systemic vascularSystemic vascularresistanceresistance
Cardiac outputCardiac output
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ASCITES & HRS: ESSENTIAL ASCITES & HRS: ESSENTIAL PATHOPHYSIOLOGYPATHOPHYSIOLOGY
PORTALHYPERTENSION
SYSTEMIC HEMODYNAMIC
CHANGES
EFFECTIVE VOLEMIA
RENAL RETENTIONOF Na+ & WATER
ASCITES
PORTALHYPERTENSION
CARDIOVASCULAR DYSFUNCTION
REFRACTORYREFRACTORYASCITESASCITES
RENAL FAILURERENAL FAILURE(HRS)(HRS)TIP
STIP
S
RAA SNS ADH Renal perfusion
VOLUME
VOLUME
EXPANSION
EXPANSION
VASO-
VASO-
CONSTRICTORS
CONSTRICTORS
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LARGE-VOLUME PARACENTESISLARGE-VOLUME PARACENTESIS
Page 45
0
4
8
12
16
Baseline Post-P 48h Post-P 5 days
PR
A (
ng
/ml/h
)
PPCD +
PPCD - **96%
Ginès et al., 1988, 1996
No PPCDNo PPCD
PPCDPPCD
SURVIVALSURVIVAL
POST-PARACENTESIS CIRCULATORY POST-PARACENTESIS CIRCULATORY DYSFUNCTIONDYSFUNCTION
Page 46
0
10
20
30
40
Baseline Post-P 48h Baseline Post-P 48h
PR
A (
ng
/ml/
h)
0
500
1000
1500
No
rE (
pg
/ml)
PRA (ng/ml/h)
NorE (pg/ml)*
*
Saló et al., 1997
POST-PARACENTESIS CIRCULATORY POST-PARACENTESIS CIRCULATORY DYSFUNCTIONDYSFUNCTION
PPCD – PPCD +0
1
2
3
4
5
Baseline Post-P 48h Baseline Post-P 48h
Pla
sma
volu
me
(L)
0
5
10
15
20
TE
Ra
(%)
Plasma volume (L)
TERa (%)
PPCD – PPCD +
Page 47
-20
-15
-10
-5
0
5
10
15
20
25
PRA MAP SVR HR CI
PE
RC
EN
T C
HA
NG
E
Ruiz del Arbol et al., Gastroenterology 1997
**
*
POST-PARACENTESIS CIRCULATORY POST-PARACENTESIS CIRCULATORY DYSFUNCTIONDYSFUNCTION
Page 48
BACTERIAL INFECTIONSBACTERIAL INFECTIONS
Page 49
TLR4TLR4
TLR2TLR2
Gram -ve organism
LPS
NF-NF--B-B
MAP-kMAP-k
TNF-TNF-IL-1, IL-6IL-1, IL-6
Gram +ve organism
PGN
LP
OXIDANTOXIDANTSTRESSSTRESS
COAGULATIONCOAGULATIONCASCADECASCADE
MICROVASCULARMICROVASCULARDAMAGEDAMAGE
ARTERIALARTERIALVASODILATIONVASODILATION
Page 50
CARDIOCIRCULATORY DYSFUNCTION CARDIOCIRCULATORY DYSFUNCTION IMPACT OF BACTERIAL INFECTIONSIMPACT OF BACTERIAL INFECTIONS
ARTERIALVASODILATION
CARDIACDYSFUNCTION
REDUCEDEFFECTIVE VOLEMIA
REDUCED RENAL PERFUSIONREDUCED RENAL PERFUSIONRENAL FAILURE / MOFRENAL FAILURE / MOF
SEVERELY REDUCEDEFFECTIVE VOLEMIA
Page 52
Central Central baroceptorsbaroceptors
BLOOD VOLUME & EFFECTIVE VOLEMIABLOOD VOLUME & EFFECTIVE VOLEMIA
S.N.S. activityS.N.S. activity
Arginine-vasopressinArginine-vasopressin
Renin-angiotensinRenin-angiotensin
Juxtaglomerular apparatusJuxtaglomerular apparatus
Page 53
EFFECTS OF EFFECTIVE HYPOVOLEMIAEFFECTS OF EFFECTIVE HYPOVOLEMIA
Central baroceptors
S.N.S. activityArginine-vasopressin
Juxtaglomerular apparatus
Renin-angiotensin
Page 54
CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHYCLINICAL 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
Page 55
20%
57%
3,4%VARICES ASCITES
7%
D’Amico et al, J Hepatol 2006Arvaniti 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
dec
om
pe
nsa
ted
Stage 3
Stage 4
com
pen
sate
d Stage 1
Stage 2
Stage 5INFECTIONS
RENAL FAILURE
4%
BLEEDING ASCITES
7.6%
Page 56
SMOOTH MUSCLE
cGMP Proteinkinase G
RELAXATION
NO
THE NITRIC OXIDE PATHWAYTHE NITRIC OXIDE PATHWAY
Page 57
Wood et al, J Gastroentrol Hepatol 1987
PATHOGENESIS OF ASCITESPATHOGENESIS OF ASCITESDISRUPTION OF STARLING EQUILIBRIUMDISRUPTION OF STARLING EQUILIBRIUM
0
5
10
15
20
25
30
ABSENT I II III
ASCITES
cWH
VP
(m
mH
g)
20
25
30
35
40
45
50
ABSENT I II III
ASCITES
PL
AS
MA
AL
BU
MIN
(g
/L)
94%94%
82%82%
Page 58
STARLING EQUILIBRIUMSTARLING EQUILIBRIUM
PIF
IF
PC
C
Liver sinusoid
Liver cell
Page 59
0
500
1000
1500
2000Plasma norepinephrine (ng/L)
No ascites Ascites Hepatorenalsyndrome
Recent
Long-standing
PROGRESSION OF ASCITESPROGRESSION OF ASCITESPATHOPHYSIOLOGICAL BACKGROUNDPATHOPHYSIOLOGICAL BACKGROUND
Bernardi et al, 1999
Page 60
-10
-5
0
5
10
15
20
25
MAP RAP PRA (/10) CI SVR
Pe
rce
nt
ch
an
ge
Albumin
HES
ALBUMIN vs HES IN PBSALBUMIN vs HES IN PBSHEMODYNAMIC EFFECTSHEMODYNAMIC EFFECTS
Fernandez et al, Hepatology 2005
** **
**
**
Page 61
Fernandez et al., Hepatology 2005
ALBUMIN vs HES IN PBSALBUMIN vs HES IN PBSEFFECTS ON ENDOTHELIAL ACTIVATIONEFFECTS ON ENDOTHELIAL ACTIVATION
-40
-20
0
20
40
60
80
vWF:Ag Factor VIII Nox
Pe
rce
nt
ch
an
ge
Albumin
HES
** **
**
Page 62
IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSISEFFECT 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 ratsP
RO
TE
IN E
XP
RE
SS
ION
(fo
ld i
ncr
ease
)
ALBUMIN
Page 63
IMPAIRED HEART CONTRACTILITY IN CIRRHOSISIMPAIRED HEART CONTRACTILITY IN CIRRHOSISEFFECT OF ALBUMIN ADMINISTRATIONEFFECT OF ALBUMIN ADMINISTRATION
Cardiac tissue TNF-a
0
0,5
1
1,5
2
2,5
Control rats Cirrhotic rats
PR
OT
EIN
EX
PR
ES
SIO
N (
fold
in
crea
se)
Cardiac tissue NFkB
0
0,5
1
1,5
2
2,5
Control rats Cirrhotic ratsP
RO
TE
IN E
XP
RE
SS
ION
(fo
ld i
ncr
ease
)
Bortoluzzi et al, Hepatology 2012
ALBUMINALBUMIN