treatment of portal hypertension and variceal bleeding · prevent portal hypertension and variceal...
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Treatment of portal hypertension and variceal bleeding
Falk Symposium 157Freiburg Oktober 10, 2006
Portal hypertension
Hepatic venous pressuregradient > 5 mm Hg (HVPG)
Pathogenesis of variceal bleeding
Escorsell and Bosch, Kluwer 2004
Prevalence of varices in patients with liver cirrhosis without prior bleeding
18 % 58 % 24 %(n = 548)
Lay et al., Hepatology 1997; 25: 1346
The chain of treatment
?
Non-selective ß-blocker for primary prophylaxis in patients with large varices
• Placebo : bleeding rate 35 %• Propranolol : bleeding rate 22 %
Poynard et al, N Engl J Med 1991; 324:1532
N = 589, mean follow-up 2 years
The chain of treatment
?
ß-blockers : Preprimary prevention of complications
Timolol,n=108
Placebo,n=105
Varices 39 39Variceal bl. 3 3Ascites/Enc. 32 24Adverse ev. 20 6Deaths 10 15
Hepatology 2003 206 A
88 % Child A pts, 53 % Hep C, median follow-up 4.2 yrs
Groszmann et al., N Engl J Med 2005; 353: 2254
Problems with Propranolol for primary prophylaxis
• 40 % are hämodynamic non-responders.• Around 25 % interrupt treatment.• Around 5 % have contraindications.• Lifelong therapy is necessary.
Merkel et al Hepatology 2000; 32:930 Schepke et al Hepatology
Is there a place for ligation ?
Efficacy of primary prophylaxis
n = 589
35 % Placebo
22 % Propranolol
Poynard et al, N Engl J Med 1991; 324:1532
Schepke et al Hepatology 2004
Ligation vs Propranolol : Metaanlysis
Boyer Baveno IV Blackwell 2006
Ligation for primary prophylaxis of variceal bleeding
You can do it !
Baveno consensus suggests
• Consider a non-selective ß-blocker first• Use ligation, if the patient is non-
compliant, does not tolerate the drug or has contraindications
Primary propylaxis in patients with small varices
Nadolol 60 mg (n=83) vsPlacebo (n = 78)
Bleeding risk 12 vs 22 % after 5 years, NNT : 10
Merkel et al Gastroenterology 2004;127:476
Primary prophylaxis in patients with small varices
You may suggest treatment with a non-selective ß-blocker
but you must not !
Further candidates for preprimary prophylaxis and prophylaxis of
bleeding
• Nitrates• AT-1-receptor antagonists• Statins• Interferon• CB1 blockers
Nitrates for primary prophylaxis of bleeding
• Have not proved beneficial in controlled trials
Angiotensin-II-Receptor Antagonists
Effect of Lorsartan on portal pressure
Schneider et al Hepatology 1999; 29 :334
25 mg/d
Effect of Irbesartan on HVPG
Schepke et al Gastroenterology 2001; 121:389
Effect of combined treatment of Irbesartan (270 mg/d)and Propranolol (40 mg/d) on HVPG
HVP
G (m
m H
g)
Irbesartan/Propranolol
0
5
10
15
20
25
Placebo/Propranolol
Base-line
Week8
Base-line
Week8
p = 0.037 p = 0.018
Schepke et al . Bonn 2006
0
100
200
300
Urin
ary
sodi
um e
xcre
tion
(mm
ol/2
4 h)
Irbesartan/Propranolol Placebo/Propranolol
Base-line
Week8
Base-line
Week8
p = 0.045 p = n.s.
Schepke et al Bonn 2006
Effect of combined treatment of Irbesartan andPropranolol on HVPG on sodium excretion
Angiotensin-II-Receptor Antagonists
• Have a modest or no effect on portal pressure
• Increase sodium excretion (J Gastroenterol 2000;95:2905,Hepatology 2002;35:1449)
• Inhibit fibrosis (J Hepatol 2003;38:455)
• May have a role for primary prophylaxis in early stage of liver disease, but we need long-term controlled trials
Statins
Is there a role for Statins in portal hypertension ?
Statins reduce intrahepatic resistance
R
NO
Effects of Atorvastatin feeding on hepatic resistance in bile duct ligated rats
*
*, †
Sham
BDL
BDL+atorvastatin
hepatic resistance
0 -6 -5 -4 -30.0
0.5
1.0
1.5
2.0
B log [methoxamine]
mm
Hg*
min
/ml
Trebicka et, Bonn, al Hepatology under revision
*
*, †
Sham
BDL
BDL+atorvastatin
hepatic resistance
0 -6 -5 -4 -30.0
0.5
1.0
1.5
2.0
B log [methoxamine]
mm
Hg*
min
/ml
Acute effect of statins on portal pressure
Zaffra et al Gastroenterology 2004;126:749
Statins and portal hypertension
• May decrease portal pressure modestly via decrease of intrahepatic resistance
• May reduce fibrosis(J Hepatol 2003;38:564)• Potential candidates for preprimary
prophylaxis but further long-term trials are mandatory
Interferon-alpha
• Decreases liver inflammation together with an antiviral activity
• Has antifibrotic properties• Decreases portal pressure• Further trials are necessary
Rincon et al J Antimicobrial Chemoth 2006; 58 7-12
How to achieve hemostasis ?
Ligate the patient if ever possible !
Apply adjuvant vasoactive drugs that reduce portal inflow and variceal pressure (flow) !
Metaanalysis: de Franchis 2004
Use adjuvant antibiotics !
Bernard et al Hepatology 1999;29 :1655
Refractory bleeding
What to do ?
Local treatment of uncontrolled bleeding
Lethal complications 5 %
Refractory variceal bleeding : Stents?
Hubmann et al Endoscopy 2006;38:896
Results
• 20 patients with refractory massive variceal bleeding
• Bleeding stopped in every patient• Stents remained in the patient for 2 - 14
days and allowed rescue• There was no rebleeding
Hubmann et al Endoscopy 2006;38:896
Early decompression by TIPS placement
Monescillo et al Hepatology 2004; 40 : 793
Rebleeding prophylaxis is necessary since 60 to 70 % rebleed after acute hemostasis
Hemodynamic monitoring of the response
Combination
Rescue
Prevention of rebleeding : Ligation vs ligation and ß-blockers
Verknüpfung mit neue seite.jpg.lnk
Lo GH et al Hepatology 2000; 32 : 461-5 and de La Pena etal Hepatology 2005; 41:572.
Summary
• The future lies in preprimary prophylaxis to prevent portal hypertension and variceal bleeding as well as other complications (new indication for established drugs).
• Improvements in management of acute bleeding have been achieved.
• Ligation and Propranolol should be combined for rebleeding prophylaxis before considering shunts.
Antibiotic prophylaxis vs. on-demand treatment in patients with vriceal hemorrhage
Hou et al Hepatology 2004;39:746
Rebleeding
Increase of CB1 receptors and its ligands in portal hypertension and cirrhosis
This may modulate intrahepatic resistance
Kunos et al Nature Medicine 2006,12:608
Pleiotropic effects of Statins
• Increase eNOS activity via reduction of the endogenous endothelial cholesterol pool
• Increase eNOS expression and NOavailability via inhibition of Rho activation
• Possibly decrease intrahepatic resistance
Review : Abraldes et al Kluwer 2004
MLCP
P-MLCcontracted
relaxedMLC
MLCK
Moesin
P-Moesin
P-VASP
ROK-II
HMG-CoA-R
Acetyl-CoA
statin
VASP
eNOS
eNOSP
PKG cGMP NO
RhoA↓ Stability
of
eNOS-mRNA
RhoA
Farnesyl-PP
Cholesterol
Geranylgeranyl-PP
vasoconstrictors
G-protein
Interferon and portal hypertension
Rincon et al J Antimicobrial Chemoth 2006; 58 7-12
Interferon-Alpha and portal hypertension
Further trials are mandatory
CB1 receptor and portal hypertension
Batkai et al., Nature Med. 7, 827 (2001)
CB1-receptor blockers
Their role should be evaluated for thetreatment of portal hypertension !
Primary prophylaxis : Ligation vs Propranolol
Jutabha et al Gastroenterology 2005;128:870
Cannabinoid-1(CB1) receptors and portal hypertension
• CB1 receptors are induced in fibrogenic cells (and other cells) in chronic liver disease
• Endogenous ligands are increased in cirrhosis
Kunos et al Nature Medicine 2006,12:608
CB1-receptor blockers may modulate intrahepatic resistance and portal hypertension.
TIPS = Transjugulärer intrahepatischer portosystemischer Shunt
Treatments of varices
Ligation
InjectionPortal decompression
Escorsell and Bosch, Kluwer 2004