CLINICAL TYPES OF
HEPATORENAL SYNDROME (HRS)
Type-2 HRS
6
Creatinine (mg/dL)
5
Type-1 HRS
Cefotaxime
4
Therapeutic
paracentesis
3
Encephalopathy
Jaundice
2
1
0
-6
-4
-2
Months
0
1
2
Weeks
3
DIFFERENCES BETWEEN TYPE-1 AND TYPE-2 HRS
Type-2
Type-1
Moderate and steady
Severe and progressive
Setting
Non-azotemic cirrhosis
Type-2 HRS
Onset
Spontaneous
Precipitated
Refractory ascites
Terminal hepatorenal failure
Months
Days
Renal failure
Consequence
Survival
HRS. SURVIVAL
1.0
Median survival
Type-1
Type-2
Probability
0.8
15 days
150 days
0.6
Type-2
0.4
p<0.0001
0.2
Type-1
0.0
0
100
200
300
400
500
600
Days
TIME-COURSE OF THE CIRCULATORY, NEUROHORMONAL
AND RENAL FUNCTION ABNORMALITIES IN CIRRHOSIS
No Ascites
Ascites
Time
Hyperdinamic circulation
 RAAS, SNS and sodium retention
 ADH and hyponatremia
HRS
CARDIOVASCULAR HEMODYNAMICS IN 8 PATIENTS
DEVELOPING TYPE-1 HRS AFTER SBP
At SBP diagnosis
SBP-HRS
MAP (mmHg)
83±7
73±8*
PRA (ng/mL.h)
18±11
28±12*
1137±220
1268±320
5.7±0.9
4.6±0.7*
SVR (dyn.s/cm-5)
CO (L/min)
* p<0.02
Ruiz del Arbol et al., Hepatology 2002
CARDIOVASCULAR HEMODYNAMICS
IN 12 PATIENTS DEVELOPING TYPE-1 HRS*
Baseline
Type-1 HRS
p
MAP (mmHg)
84±2.6
70±2.3
<0.001
PRA (ng/mL.h)
12.9±2.6
25.8±3.4
<0.01
NE (pg/mL)
735±69
1385±99
<0.001
SVR (dyn.s/cm-5)
1099±81
1211±97
NS
CO (L/min)
5.8±0.2
4.6±0.3
<0.01
RAP (mmHg)
7±0.8
5±0.5
<0.01
PCP (mmHg)
8.7±1
6.5±1
<0.01
HR (bpm)
86±5
84±4
NS
* baseline measurements: 9±1 months prior HRS
Ruiz del Arbol et al., Hepatology 2005
80
0.9
* p<0.05
60
40
*
*
20
Resistive index middle
cerebral artery
Brachial blood flow (mL/min)
REGIONAL CIRCULATORY CHANGES IN CIRRHOSIS
p<0.001
0.8
0.7
0.6
0.5
0.4
0
H
NA
A
HRS
Maroto et al., Hepatology 1993
H
NA
A
Guevara et al., Hepatology 1998
Healthy subjects (H), cirrhotic patients without ascites (NA),
with ascites (A) and with hepatorenal syndrome (HRS)
CHANGES IN HEPATIC HEMODYNAMICS
ASSOCIATED WITH TYPE-1 HRS
30
HVPG (mmHg)
p<0.05
25
20
15
At SBP
diagnosis
After SBP
resolution
HBF IN PATIENTS DEVELOPING
TYPE-1 HRS
Hepatic blood flow (mL/min)
HVPG IN PATIENTS DEVELOPING
TYPE-1 HRS AFTER SBP
1000
800
600
400
Baseline
Type-1
HRS
Baseline measurements:
9±1 months prior HRS
Ruiz del Arbol et al., Hepatology 2002
Ruiz del Arbol et al., Hepatology 2005
INCIDENCE OF RELATIVE ADRENAL INSUFFICIENCY*
IN CIRRHOTIC PATIENTS (n=20) WITH SEPTIC SHOCK
Non-cirrhotic patients
10-40%
Cirrhotics Child B
25%
Cirrhotics Child C
75%
* Diagnostic criteria:
- baseline cortisol <9 mg/dL
- increase in cortisol after ACTH <9 mg/dL
- peak cortisol <20 mg/dL
Fernández et al. (unpublished)
TYPE-I HRS AS A PART OF A MULTIORGAN FAILURE
Spontaneous bacterial peritonitis
or other precipitating event
Adrenal
dysfunction
Increase in arterial vasodilation
Decrease in cardiac output
A-II, NE, ADH
resistance to
portal venous flow
Aggravation of
portal hypertension
Regional arterial
vasoconstriction
Kidneys
HRS
Brain
Encephalopathy
Liver
Liver failure
EFFECT OF VASOCONSTRICTORS
(Ornipressin and Terlipressin)
PLUS I.V. ALBUMIN IN TYPE-1 HRS
Baseline
(n=15)
Day 7
(n=9)
Day 14
(n=7)
MAP (mmHg)
70±8
77±9
79±12
PRA (ng/mL.h)
15±15
2±3
1±1
1257±938
550±410
316±161
Creatinine (mg/dL)
3±1
2±1
1±1
GFR (mL/min)
9±1
25±2.5
41±1.5
NE (pg/mL)
Guevara et al., Hepatology 1998; Uriz et al., J Hepatol 2000
SERUM CREATININE BEFORE AND AFTER
TREATMENT OF TYPE-1 HRS (11 cases)
WITH TERLIPRESSIN PLUS ALBUMIN
Serum creatinine (mg/dL)
5
4
3
2
1
0
Baseline
1 day
1 month
After treatment
Ortega et al., Hepatology 2002
TREATMENT OF HRS WITH VASOCONSTRICTORS
AND ALBUMIN (Group 1) AND STANDARD MEDICAL
THERAPY (Group 2). REVIEW OF 18 STUDIES
Group 1
(n=154)
Group 2
(n=137)
MCFS*
(n=99)
Reversal of HRS
61.7%
2.9%
58%
HRS recurrence
20%
-
-
Survival 1 month
41.6%
3%
40%
Survival 3 months
30%
0%
22%
12.3%
-
13%
Liver transplantation
* Multicenter French Study
TREATMENT OF TYPE-1 HRS
WITH TERLIPRESSIN PLUS
I.V. ALBUMIN vs TERLIPRESSIN
Terlipressin + Terlipressin
albumin (n=13)
(n=8)
Complete response
10
2
Survival >1 month
12
2
OLT
5
0
Ortega et al., Hepatology 2002
TIPS IMPROVES CIRCULATORY AND RENAL
FUNCTION IN TYPE-1 HRS (7 patients)
After treatment
Baseline
Renin (ng/mL/h)
NE (pg/mL)
Creatinine (mg/dL)
GFR (mL/min)
Day 7
Day 30
18±5
6±2
3±1
1257±187
853±102
612±197
5.0±0.8
3.7±1.0
1.8±0.4
9±4
11±5
27±7
Guevara et al., Hepatology 1998
PRA (ng/mL.h)
CIRCULATORY SUPPORT WITH I.V. ALBUMIN IN PATIENTS
WITH SBP. EFFECT ON ARTERIAL BLOOD VOLUME
9
8
7
6
5
4
3
2
1
0
*
*
*
* p<0.05
1
3
Cefotaxime + albumin
6
9
Days
Cefotaxime
Sort et al., N Engl J Med 1999
CIRCULATORY SUPPORT WITH I.V. ALBUMIN
IN PATIENTS WITH SBP. EFFECT ON HRS
DEVELOPMENT AND HOSPITAL MORTALITY
Cefotaxime
(n=63)
Cefotaxime +
albumin (n=63)
Resolution of infection
57 (93%)
59 (98%)
HRS
20 (32%)
6 (10%)*
Hospital mortality
17 (27%)
6 (10%)*
* p<0.001
Sort et al., N Engl J Med 1999
EFFECTS OF HYDROXYETHYL STARCH (HES) AND
ALBUMIN (ALB) ON EFFECTIVE BLOOD VOLUME IN SBP
MAP (mmHg)
PRA (ng.mL/h)
Baseline
At resolution
p
HES
80±15
81±8
NS
ALB
76±9
85±13
0.01
HES
8.5±7.3
16.8±24.6
NS
ALB
5.7±4.7
3.1±3.4
0.04
Fernandez et al., Hepatology 2005
EFFECTS OF HYDROXYETHYL STARCH (HES)
AND ALBUMIN (ALB) ON PERIPHERAL ARTERIAL
CIRCULATION IN SBP
SVR
(dyn/cm5)
NO (nmol/mL)
vWF:Ag (U/dL)*
Baseline
At resolution
p
HES
777±239
778±290
NS
ALB
668±134
803±197
0.03
HES
39±13
63±32
0.03
ALB
61±30
78±55
NS
HES
ALB
297±44
331±35
278±47
257±65
NS
0.01
* vWF:Ag Von Willebrand-related antigen factor
Fernandez et al., Hepatology 2005
EFFECT OF I.V. ALBUMIN ON
SYSTEMIC HEMODYNAMICS IN CIRRHOSIS
Albumin infusion
Intravascular
volume expansion
Inhibition of
endothelial activation
Increased
cardiac preload
Decreased
NO synthesis
Improvement in left
ventricular function
Increased systemic
vascular resistance
IMPROVEMENT
OF CIRCULATORY
DYSFUNCTION