l'emodinamica nel cirrotico: aspetti fisiopatologici - gastrolearning®

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

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

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

PORTAL HYPERTENSIONPORTAL HYPERTENSIONPATHOPHYSIOLOGYPATHOPHYSIOLOGY

P P (pressure)(pressure)==

Q Q (blood flow) x (blood flow) x R R (resistance)(resistance)

PORTAL HYPERTENSIONPORTAL HYPERTENSIONPATHOPHYSIOLOGYPATHOPHYSIOLOGY

Nagula et al, J Hepatol 2006Sethasine et al, Hepatology 2012

INDEPENDENT PREDICTORS OF CSPHINDEPENDENT PREDICTORS OF CSPH

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

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……

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

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

PORTAL HYPERTENSIONPORTAL HYPERTENSIONPATHOPHYSIOLOGYPATHOPHYSIOLOGY

DYNAMICDYNAMICCOMPONENTCOMPONENT

STRUCTURALSTRUCTURALCOMPONENTCOMPONENT

PORTAL HYPERTENSIONPORTAL HYPERTENSION

SPLANCHNIC CIRCULATIONSPLANCHNIC CIRCULATIONSYSTEMIC CIRCULATIONSYSTEMIC CIRCULATION

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

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)

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

**

*

*

*

HYPERDYNAMIC CIRCULATORY HYPERDYNAMIC 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 CARDIOMYOPATHYDEFINITION & FEATURESDEFINITION & FEATURES

CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHYPATHOPHYSIOLOGYPATHOPHYSIOLOGY

HYPERDYNAMICHYPERDYNAMICCIRCULATIONCIRCULATION

ADRENERGICADRENERGICHYPERACTIVITYHYPERACTIVITY

ANGIOTENSIN IIANGIOTENSIN II ALDOSTERONEALDOSTERONE

““CARDIOTOXINS”CARDIOTOXINS”FROM SPLANCHINC AREAFROM SPLANCHINC AREA

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

THE NITRIC OXIDE PATHWAYTHE NITRIC OXIDE PATHWAY

SHEARSHEARSTRESSSTRESS

ENDOTOXINSENDOTOXINSCYTOKINESCYTOKINES

L-ARGININEL-ARGININE L-CITRULLINEL-CITRULLINE

ENDOTHELIUMNO

e-NOSe-NOS i-NOSi-NOS

BH4BH4

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

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

Frances et al, Hepatology 2008

CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES

Wiest et al, J Clin Invest 1999

CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOKINES / SHEAR STRESSENDOTOXIN / CYTOKINES / SHEAR STRESS

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

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

)

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

LBPLBP

Albillos et al, Hepatology 2003

SVRSVR

CAUSES OF NO SYNTHESIS INCREASECAUSES OF NO SYNTHESIS INCREASEENDOTOXIN / CYTOKINESENDOTOXIN / CYTOKINES

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

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

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

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

)

*

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

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

ASCITESASCITES&&

HEPATORENAL SYNDROMEHEPATORENAL SYNDROME

ASCITESASCITES

Renal retentionRenal retentionof Naof Na+ + / H/ H22OO

PATHOGENESIS OF ASCITES

Post-sinusoidalPost-sinusoidalportal hypertension portal hypertension

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

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

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

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

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

EFFECTIVE VOLEMIA

HYPONATREMIA IN CIRRHOSISHYPONATREMIA IN CIRRHOSISPATHOPHYSIOLOGYPATHOPHYSIOLOGY

PERIPHERALPERIPHERALVASODILATIONVASODILATION

ADHADH

DIURETICSDIURETICSImpaireddilution

Na+

-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

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

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

LARGE-VOLUME PARACENTESISLARGE-VOLUME PARACENTESIS

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

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 +

-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

BACTERIAL INFECTIONSBACTERIAL INFECTIONS

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

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

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

EFFECTS OF EFFECTIVE HYPOVOLEMIAEFFECTS OF EFFECTIVE HYPOVOLEMIA

Central baroceptors

S.N.S. activityArginine-vasopressin

Juxtaglomerular apparatus

Renin-angiotensin

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

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%

SMOOTH MUSCLE

cGMP Proteinkinase G

RELAXATION

NO

THE NITRIC OXIDE PATHWAYTHE NITRIC OXIDE PATHWAY

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%

STARLING EQUILIBRIUMSTARLING EQUILIBRIUM

PIF

IF

PC

C

Liver sinusoid

Liver cell

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

-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

** **

**

**

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

** **

**

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

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