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
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
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
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
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