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