No ACLF - Chirurgie

Ateliers de Printemps de l'ACHBT 2014
MARSEILLE
Vendredi 16 mai 2014
Physiopathologie et histoire
naturelle de la cirrhose
Richard Moreau,1,2,3
1UMR
S_1149, Centre de Recherche sur l’Inflammation (CRI),
Inserm et Université Paris-Diderot, Paris 7,
2DHU UNITY, Service d’Hépatologie, Hôpital Beaujon, APHP, Clichy
3Laboratoire d’Excellence (Labex) INFLAMEX,
PRES Sorbonne Paris Cité, France
[email protected]
Natural History of
Chronic Liver Disease
Development of
cirrhosis
Chronic
liver
disease
Inflammation
Necrosis
Fibrosis
Hepatocellular carcinoma
Compensated
cirrhosis
Median
suvival
9 yr
ACLF
High risk
of death
Decompensated
Cirrhosis
Complications
Ascites
GI bleeding
Median
survival
1.6 yr
No ACLF
No risk
of death
Persistent
insult
ACLF, acute-on-chronic liver failure
Sommaire
• Physiopathologie de la
décompensation
• ACLF :
‒ Définition
‒ Physiopathologie
Augmentation de la résistance vasculaire intrahépatique dans la cirrhose
Circulation
collatérale
portosystémique
Distorsion de
l’angioarchitecture
hépatique
Veine
porte
Diminution de la production
locale de NO
(monoxyde d’azote)
Splénomegalie
AN INCREASE IN PORTAL VENOUS INFLOW SUSTAINS PORTAL HYPERTENSION
Dans la cirrhose, une augmentation du débit
sanguin dans le territoire de la veine porte
maintient l’hypertension portale
Distortion de
l’angioarchitechure
hépatique
Veine
porte
Débit sanguin
augmenté
Vasodilatation
splanchnique
(monoxyde d’azote : NO)
Pateron et al. Gastroenterology 2000;119:196. Tazi et al. Gastroenterology 2002;122:1869.
AN INCREASE IN PORTAL VENOUS INFLOW SUSTAINS PORTAL HYPERTENSION
Dans la cirrhose, la translocation bactérienne
intestinale stimule la production artérielle de NO
Translocation
bactérienne
NO
Tazi et al. Gastroenterology 2005;129:303.
LPS/
cytokines
CIRRHOSIS
Intrahepatic
vascular
resistance
Systemic arteriolar
resistance
(dilation)
Sinusoidal
pressure
Effective
arterial
blood volume
(HVPG≥10-12 mm Hg)
ASCITES
Sodium and
water retention
Activation of
neurohumoral
systems
(sympathetic, RAAS)
HRS Pathophysiology
Splanchnic
/systemic
vasodilation
Decreased effective
arterial blood volume
Decreased cardiac
output
(reduced
venous return)
Increased endogenous
vasoconstrictor systems
Arteriolar vasoconstriction
Nonrenal, nonsplanchnic
territories
Moreau and Lebrec. Hepatology 2006;43:385-94.
Renal
circulation
Decreased
GFR
RCTs of Terlipressin Plus Albumin
in Patients with Type 1 HRS
40
Proportion of patients with HRS reversal
%
P<0.05
20
0
Albumin
153 patients. Sanyal et al. Gastroenterology 2008;134:1360-8.
Martin-Llahi et al. Gastroenterology 2008;134:1352-9.
Terlipressin
+ albumin
Sommaire
• Physiopathologie de la
décompensation
• ACLF :
‒ Définition
‒ Physiopathologie
Patients of the CANONIC Study
• 2149 consecutive patients prospectively
evaluated in 29 European hospitals in 12
countries
• From February to September, 2011
• Inclusion criteria:
‒ Hospitalized patients with cirrhosis and
an acute decompensation of cirrhosis
(ascites, GI hemorrhage, encephalopathy,
bacterial infection).
Moreau et al. Gastroenterology 2013;144:1426-37.
Modified Sequential Organ Failure
Assessment (SOFA) Score For
Patients with Cirrhosis (CLIF-SOFA Score)
Organ/system
0
1
2
3
4
<1.2
≥1.2-<1.9
≥2-< 5.9
≥6-<12
≥12
Kidney: Creatinine, mg/dL <1.2
≥1.2-<1.9
≥2-<3.5
≥3.5-<5
≥5
Liver: Bilirubin, mg/dL
Cerebral (HE grade)
No HE 1
2
3
4
Coagulation: INR
<1.1
1.1-1.25
1.26-1.5
1.51-2.5
>2.5 or platelets
≤20 x 103 /µL
Circulation:
MAP (mm Hg)
≥70
<70
Dopamine
>5-≤15
≤5 or
or E ≤0.1
dobutamine* or NE ≤0.1
or
terlipressin*
Lungs: PaO2/FiO2
or SpO2/FiO2
>400
>512
≤400
≤300
>357-≤512 >214- ≤357
≤200
>89- ≤214
>15
>0.1
>0.1
≤100
≤89
*any dose. E: epinephrine; NE: norepinephrine; doses for catecholamines are µg/kg.min .
Moreau et al. Gastroenterology 2013;144:1426-37.
Acute Organ Failures at Admission of
Patients with Cirrhosis and Acute Decompensation
Patients
(N=1,343)
901
Prevalence
(%)
67.1
Liver
442
207
32.9
15.4
Kidney (Screat ≥2 mg/dL)
169
12.6
Coagulation
105
7.8
Cerebral
99
7.4
Cardiovascular
64
4.8
Lungs
32
2.4
No organ failure
1 organ failure or more*
*Modified SOFA score. Moreau et al. Gastroenterology 2013;144:1426-37.
Definition of ACLF and Grades
ACLF Grade
Definition
28-day
Mortality (%)
No ACLF
• No organ failure (OF)
• Single OF (liver, coagulation,
circulation, lungs) + Screat <1.5 mg/dL
+ no HE
• Single cerebral failure + Screat <1.5
4.7
• Single kidney failure
• Single OF (liver, coagulation,
circulation, lungs) + Screat 1.5‒≤1.9
mg/dL and/or grade 1-2 HE
• Single cerebral failure
+ Screat 1.5‒≤1.9 mg/dL
22.1
ACLF-1
ACLF-2
2 OF
32.0
ACLF-3
≥ 3 OF
78.6
Moreau et al. Gastroenterology 2013;144:1426-37.
Moreau et al. Gastroenterology 2013;144:1426-37.
Potential Precipitating Events of ACLF
at Enrollment in the CANONIC Study
No ACLF
(N=1040)
226 (21.8)
ACLF
(N=303)
98 (32.6)
P value
Active alcoholism
within the past 3
months
Gastrointestinal
hemorrhage
147 (14.9)
69 (24.5)
<0.001
180 (17.3)
40 (13.2)
0.09
Other precipitating
event
34 (3.5)
25 (8.6)
<0.001
584 (58.9)
126 (43.6)
<0.001
Bacterial infection
No precipitating event
Values are n (%). Moreau et al. Gastroenterology 2013;144:1426-37.
<0.001
Sommaire
• Physiopathologie de la
décompensation
• ACLF :
‒ Définition
‒ Physiopathologie
ACLF is Associated with Systemic Inflammation
Leukocyte count*
14
C-reactive Protein*
70
**
12
**
60
**
50
10
8
mg/L
x10^9 cells
**
*
6
30
4
20
2
10
0
0
NO ACLF
ACLF-1
ACLF-2
ACLF-3
**
40
NO ACLF
* p<0.05 with respect to No ACLF
** p<0.001 with respect to No ACLF
Moreau et al. Gastroenterology 2013;144:1426-37.
ACLF-1
ACLF-2
ACLF-3
Conclusions
• La physiopathologie de la décompensation de la
cirrhose implique l’hypertension portale et la
vasodilatation splanchnique.
• L’ACLF est un syndrome distinct de la
décompensation.
• L’ACLF se développe dans un contexte
d’inflammation systémique. Celle-ci peut être en
relation avec une infection bactérienne ou la prise
d’alcool. Cependant, dans 50 % des cas la cause
de l’inflammation reste inexpliquée.
AN INCREASE IN PORTAL VENOUS INFLOW SUSTAINS PORTAL HYPERTENSION
Une augmentation du débit sanguin dans le
territoire de la veine porte maintient
l’hypertension portale
Distortion de
l’angioarchitechure
hépatique
Veine
porte
Débit sanguin
augmenté
Veines
mésenteriques
Vasodilatation
splanchnique
T
r
T
Tension = Pressure x radius
(Laplace law)
r
AN INCREASE IN PORTAL VENOUS INFLOW SUSTAINS PORTAL HYPERTENSION
La vasodilatation splanchnique est impliquée dans
le mécanisme des complications de la cirrhose
Hémorragies
Ascite
SHR*
*SHR : syndrome hépato-rénal.
Vasodilatation
splanchnique
(NO)
AN INCREASE IN PORTAL VENOUS INFLOW SUSTAINS PORTAL HYPERTENSION
Dans la cirrhose, la translocation bactérienne
intestinale stimule la production artérielle de NO
Translocation
bactérienne
NO
Tazi et al. Gastroenterology 2005;129:303.
LPS/
cytokines
Strategy Used in the CANONIC Study
Prespecified criteria for the diagnosis
of ACLF:
• Acute decompensation
• Organ failure(s)
• High in-hospital mortality (>15%)
A RCT of Terlipressin for Type 1 HRS
Sanyal et al. Gastroenterology 2008;134:1360-8.
Patients Characteristics at Enrollment
Age (year)
No ACLF
(N=1040)
58±12
ACLF
(N=303)
56±11
P
value
.02
Male sex
655 (63.0) 195 (64.4)
.66
Alcohol
483 (49.2) 170 (60.3)
<.01
HCV
Alcohol + HCV
210 (21.4) 38 (13.0)
95 (9.7)
27 (9.3)
<.01
.83
Cause of cirrhosis
mean±SD or n (%). Moreau et al. Gastroenterology 2013;144:1426-37.