PATHOGENESIS AND MANAGEMENT OF PORTAL

HYPERTENSION

PATHOGENESIS AND MANAGEMENT OF PORTAL

HYPERTENSION

Dr. S.K.Sarin, MD, DM

Professor and Head

Dept. of Gastroenterology, G.B.Pant Hospital

University of Delhi, India

Dr. S.K.Sarin, MD, DM

Professor and Head

Dept. of Gastroenterology, G.B.Pant Hospital

University of Delhi, India

Hemodynamic Assessment of Portal Hypertension

IVC

Sinusoid

Hepaticvein

Portal vein

Splenic vein

Pre-hepatic

Post-hepatic

Pre-sinusoidal

Post-sinusoidal

Sinusoidal

Hepatic vein P Gradient Portal P

N N

N N

N

N

Pre-sinusoidal “Portal Hypertension”Pre-sinusoidal “Portal Hypertension”

Portal/splenic vein thrombosis Non-cirrhotic Portal Fibrosis Granulomatosis Schistosomiasis Idiopathic portal fibrosis Nodular regenerative hyperplasia

Portal/splenic vein thrombosis Non-cirrhotic Portal Fibrosis Granulomatosis Schistosomiasis Idiopathic portal fibrosis Nodular regenerative hyperplasia

IVC

Sinusoid

Hepaticvein

Portal vein

Splenic vein

NCPF

EHPVO

SPLEENSMV

Non-Cirrhotic Portal Hypertension

Non-cirrhotic Portal Hypertension, predominantly presents with bleed

G.B.Pant Hospital (1983 - 1995)

Non-cirrhotic Portal Hypertension, predominantly presents with bleed

G.B.Pant Hospital (1983 - 1995)

Bleeder 53.0%(1133)

Bleeder 53.0%(1133)

NB 47.0%(1004)

NB 47.0%(1004)

Bleeder 84.5%(207)

Bleeder 84.5%(207)

NB 15.50%(32)

NB 15.50%(32)

NB 5.50%(13)

NB 5.50%(13)

Bleeder 94.5%(223)

Bleeder 94.5%(223)

Total Patients(n=2137)

Total Patients(n=2137)

NCPF(n=207)NCPF

(n=207)EHPVO(n=236)EHPVO(n=236)

Digestion 1998

NORMAL NCPF

Hepatic vein Hepatic vein

Sinusoid

Portal veinPortal vein

Sinusoid

Increased Resistance

NCPF : PATHOLOGY

NCPF : PATHOLOGY

Thickening of portal venules

Increased collagen in portal vein wall

Animal Models of IPH, NCPHAnimal Models of IPH, NCPH

E.coli + anti E.coli into P.V. (Okuda)

Indwelling cannulation rabbit model

E.coli (Sarin 1998)

Splenic extract (Yoshikawa, Sarin 1998)

Murine chronic arsenic feeding (Sarin 1992)

Umbilical sepsis model (Sarin)

E.coli + anti E.coli into P.V. (Okuda)

Indwelling cannulation rabbit model

E.coli (Sarin 1998)

Splenic extract (Yoshikawa, Sarin 1998)

Murine chronic arsenic feeding (Sarin 1992)

Umbilical sepsis model (Sarin)

LIVER

PORTAL VEIN

STOMACH

SPLEEN

GASTROSPLENIC VEIN

ANTERIOR MESENTERIC

POSTERIOR MESENTERICSPLENIC TRIBUTARY

SITE OF CANNULATION

ATTACHED TO A THREE WAY STOP COCK

Animal Models of NCPFAnimal Models of NCPF

E.coil

Spleen wt. (g) 0.38+0.1 0.31+0.12

Portal pressure (mm Hg) 7.20+3.6 18.3+7.10*

Splenic Extract

Spleen wt. (g) 0.3+0.1 0.73+0.27*

Portal pressure (mm Hg) 6.4+2.6 16.7+11.0*

E.coil

Spleen wt. (g) 0.38+0.1 0.31+0.12

Portal pressure (mm Hg) 7.20+3.6 18.3+7.10*

Splenic Extract

Spleen wt. (g) 0.3+0.1 0.73+0.27*

Portal pressure (mm Hg) 6.4+2.6 16.7+11.0*

ParameterParameter ControlControl E.coilE.coil

*P<0.05*P<0.05

Rachna et al, 1998Rachna et al, 1998

NCPF

EHPVO

SPLEENSMV

Cavernoma

Porto-porto collateral circulation

Dilated hepatic artery

Portal Vein ThrombosisPathogenesis

Acquired prothrombic disorders

Inheritedprothrombic

disorders

Venous thrombosis

Local precipitating factors

Pathogenesis of NCPHPathogenesis of NCPH

Infection, other agentsInfection, other agents

SevereEARLY, LATE AGESevereEARLY, LATE AGE

Chronic / mildLATE AGEChronic / mildLATE AGE

Portal PyemiaLarge thrombus PVPortal PyemiaLarge thrombus PV

Chronic antigenemiaPhelbosclerosisChronic antigenemiaPhelbosclerosis

Occlusion of Main PV, CavernomaOcclusion of Main PV, Cavernoma

Occlusion of 3, 4 PV branches, RESOcclusion of 3, 4 PV branches, RES

Pre-sinusoidal ResistancePre-sinusoidal Resistance

EHPVOEHPVO NCPFNCPFPHTPHT

Pro-thrombotic State

CIRRHOTIC PORTAL HYPERTENSION

CIRRHOTIC PORTAL HYPERTENSION

Clinical Consequences of CIRRHOTIC Portal Hypertension

Portal hypertensionAscitesHypersplenism

Collateral formation

Encephalopathy

Decreased liver function

Portalgastropathy

Esophago-gastric varices

Altered homeostasis

Hypoxemia, PPS, HPS

Large Oesophageal Varices With Red Signs

Fibrous septaRegenerative nodules

Increased Intra Hepatic Vascular Resistance (IHVR) to portal flow

Portal hypertensionPortal hypertension

Disruption architectureof microcirculation

Increased porto-

collateralresistance

Contraction ofmyofibroblasts

Splanchnicvasodilatation

Increased portalflow

Alcohol, HBV, HCV, autoinmmune, metabolic, Wilson’s disease

Alcohol, HBV, HCV, autoinmmune, metabolic, Wilson’s disease

Pathophysiology of “Cirrhotic” Portal Hypertension.

Increased vascular tone REVERSIBLE

Hepatocyte

Sinusoidal endotheliumSinusoidal endothelium

Space of Disse

HepaticHepatic

Stellate CellStellate Cell

Kupffer CellKupffer Cell

Cells of the Hepatic Sinusoid Cells of the Hepatic Sinusoid

Normal LiverNormal Liver

Basal membrane-like ECM in space of Basal membrane-like ECM in space of Disse Quiescent vitamin A-rich hepatic Disse Quiescent vitamin A-rich hepatic stellate cells Hepatocytic microvilli and stellate cells Hepatocytic microvilli and

sinusoidal fenestrationssinusoidal fenestrations

Liver with chronic Liver with chronic injuryinjury

Fibrillar ECM in space of Disse Fibrillar ECM in space of Disse Activated hepatic stellate cells Activated hepatic stellate cells Loss of hepatocytic microvilli Loss of hepatocytic microvilli and sinusoidal fenestrationsand sinusoidal fenestrations

Capillarization of SinusoidsCapillarization of Sinusoids

Contractile Features of Hepatic Stellate Contractile Features of Hepatic Stellate CellsCells

ETET--1 1 * * ThrombinThrombin **AnngioAnngio--II II **Substance P Substance P Adenosine Adenosine **TxATxA22, PAF , PAF **

Vasopressin Vasopressin **Electric Field Electric Field **

Nitric OxideNitric OxideAdrenomedullinAdrenomedullin

Carbon MonoxideCarbon Monoxide

Actions of Vasoactive Agonists on HSCActions of Vasoactive Agonists on HSC

Pinzani M. et al. J.Clin.Invest. 1992;90:642-646 Pinzani M. et al. J.Clin.Invest. 1992;90:642-646

Hepatic Stellate Cells and the Hepatic Stellate Cells and the RegulationRegulation of Portal Pressureof Portal Pressure

• Regulation of sinusoidal tone in normal Regulation of sinusoidal tone in normal liverliver

• Influence portal pressure in conditions Influence portal pressure in conditions of of developing fibrosis and developing fibrosis and “capillarization of“capillarization of sinusoids” sinusoids”

• Influence portal pressure in cirrhotic Influence portal pressure in cirrhotic liverliver

Hepatic Sinusoidal BedHepatic Sinusoidal Bed

Cells

Hepatic Stellate Cell

Sinusoidal Endothelial Cell

Kupffer Cells

Cells

Hepatic Stellate Cell

Sinusoidal Endothelial Cell

Kupffer Cells

Paracrine Molecules

NO

ET

CO

Paracrine Molecules

NO

ET

CO

NO-Synthases (NOS)NO-Synthases (NOS)nNOS (NOS1) - “nervous” NOSnNOS (NOS1) - “nervous” NOS

Constitutively present in nervous system. Constitutively present in nervous system.

iNOS (NOS2) - “inducible” NOSiNOS (NOS2) - “inducible” NOS

Synthesized “de novo” in macrophages, SMC, Synthesized “de novo” in macrophages, SMC, hepatocytes and other cell types. Production of hepatocytes and other cell types. Production of large large

amounts of NOamounts of NO independently of independently of hemodynamic/mechanical stimuli. hemodynamic/mechanical stimuli.

eNOS (NOS3) - “endothelial” NOSeNOS (NOS3) - “endothelial” NOS

Found in Found in endothelial cells.endothelial cells. Small amountsSmall amounts produced in response produced in response to endogenous and exogenous stimuli, including shear stress.to endogenous and exogenous stimuli, including shear stress.

Nitric Oxide: Hepatic Vascular BedNitric Oxide: Hepatic Vascular Bed

Endothelial cells NO paracrine

Underlying smooth muscle

stimulates guanylate

cyclase cGMP ed intracellular Ca++

Vasorelaxation

Endothelial cells NO paracrine

Underlying smooth muscle

stimulates guanylate

cyclase cGMP ed intracellular Ca++

Vasorelaxation

Endothelial dysfunctionCirrhosis

TraumaAtherosclerosisHTDefective NO

synthesis

NO vasorelaxation

Intrahepatic vascular resistance (IHVR)

Endothelial dysfunctionCirrhosis

TraumaAtherosclerosisHTDefective NO

synthesis

NO vasorelaxation

Intrahepatic vascular resistance (IHVR)

Normal Vascular BedNormal Vascular Bed Abnormal Vascular BedAbnormal Vascular Bed

Molecular regulation eNOS Molecular regulation eNOS

eNOS geneGolgi

PKB

Hsp90/ Caveolin

arginine NO

citrullineeNOS

caveolae

Relaxation

GTP GMP

PDE PKG CNGPDE PKG CNG

CaCa

Endothelial Cells

Stellate Cell

RegulationShear force, growth factorsLipids, hormones, HMGCoA

reductase inhibitors

Shah 2001

Nitric Oxide (NO)Nitric Oxide (NO)

eNOSeNOS iNOSiNOS

NO NOPost-translational defectin liver

Post-translational defectin liver

NO NO

VasoconstrictionVasoconstriction

In splanchnic veselsHypo-responsivenessTo vasoconstrictors, NE, ET

In splanchnic veselsHypo-responsivenessTo vasoconstrictors, NE, ET

VasodilationVasodilation

Induced by endotoxemiaTNF alphaInduced by endotoxemiaTNF alpha

Caveolin-1CalmodulinCaveolin-1Calmodulin

ShearStressShearStress

NO ET-1

Dilation Angiogensis

Collateral circulation

Splanchnic circulation NO

Dilation

Hepatic circulationHepatic circulation

E.C.E.C.

E.C.E.C.

E.C.E.C.

NO NOCC

CC

PATHOGENESIS OF PORTAL HYEPERTENSION

Molecular regulation of ET-1 Molecular regulation of ET-1

ET-1 gene

AP1/GATAPrepro ET-1

Big ET-1

ECEET-1 eNOS

activation

ET-A ET-B

Contractile cell

Contraction Ca/PKCIP3/DAG

PLC

G-proteins

ET-B

Endothelial Cells

Regulationof ET-1Hormones,

Mechanical forcesGrowth factors

Vasoactive peptides

Shah 2001

Endothelins (ET)Endothelins (ET)

3 isomers, ET – 1 for liver, produced in EC

Receptors – ET-A via Ca++, PKC Contraction

ET-B HSC contraction

EC eNOS activation – NO (Paradoxical)

Stimulus – TFG-

Normal Liver : HSC regulates sinusoidal tone, contraction of distal segment of pre-terminal portal venule

Cirrhotic liver : ET-1 synthesis by HSC, SEC.

ed levels of ET 1 in splanchnic bed HVP (Gerbes 1998)

3 isomers, ET – 1 for liver, produced in EC

Receptors – ET-A via Ca++, PKC Contraction

ET-B HSC contraction

EC eNOS activation – NO (Paradoxical)

Stimulus – TFG-

Normal Liver : HSC regulates sinusoidal tone, contraction of distal segment of pre-terminal portal venule

Cirrhotic liver : ET-1 synthesis by HSC, SEC.

ed levels of ET 1 in splanchnic bed HVP (Gerbes 1998)

NO ET-1

Dilation Angiogensis

Collateral circulation

Splanchnic circulation NO

Dilation

Hepatic circulationHepatic circulation

E.C.E.C.

E.C.E.C.

E.C.E.C.

NO NOCC

CC

PATHOGENESIS OF PHT

Nitric Oxide (NO)Nitric Oxide (NO)

eNOSeNOS Inos and eNOSInos and eNOS

NO NOPost-translational defectin liver

Post-translational defectin liver

NO NO

VasoconstrictionVasoconstriction

In splanchnic vesselsHypo-responsivenessTo vasoconstrictors, NE, ET

In splanchnic vesselsHypo-responsivenessTo vasoconstrictors, NE, ET

VasodilationVasodilation

Induced by endotoxemiaTNF alphaInduced by endotoxemiaTNF alpha

Caveolin-1CalmodulinCaveolin-1Calmodulin

ShearStressShearStress

Causes of vascular hyporeactivity in cirrhosis

VasoconstrictorsCatecholamines vasopressin Angiotensin II ET-1

Others?

All Intracellular Ca +

VasodilatorsANPCGRPET-3Others?

Postreceptor Postreceptor mechanismsmechanisms

Postreceptor defect

Central nervous syustem

vasorelaxation

Smooth muscle cell

ProstacyclinNO

Splanchnic overproduction and intrahepatic deficit of endothelial NO. ? = Unknown

Splanchnic overproduction and intrahepatic deficit of endothelial NO. ? = Unknown

Hepatology, 2002

Vascular tone

Decreased vascular tone

VascularNO overproduction

Increased eNOS-derived NO synthesis

reduced eNOS-derived NO synthesis

MicrocirculatoryNO deficiency

IncreasedVascular tone

Hepatic Microvascularture

Splanchnic and systemicvascularture

?

Clinical Consequences of CIRRHOTIC Portal Hypertension

Portal hypertensionAscitesHypersplenism

Collateral formation

Encephalopathy

Decreased liver function

Portalgastropathy

Esophago-gastric varices

Altered homeostasis

Hypoxemia, PPS, HPS

Bleeding GOV1 Varix Bleeding GOV1 Varix

Bleeding Gastric VarixBleeding Gastric Varix

Risk Factors for First Variceal bleedRisk Factors for First Variceal bleed

Intravariceal pressure - >12 mm Hg

Variceal size - >5 mm

Variceal wall thickness and tension La Place’s Law

`Red Color Signs’

Severity of liver disease

Intravariceal pressure - >12 mm Hg

Variceal size - >5 mm

Variceal wall thickness and tension La Place’s Law

`Red Color Signs’

Severity of liver disease

Clinical Predicators of Variceal Hemorrhage

Clinical Predicators of Variceal Hemorrhage

Wall Tension = Transmural Pressure x RadiusWall Thoickness

o High HVPG transmural pressure

o Variceal size radius of the varix

o Red color signs wall thickness

o Liver failure impaired coagulation ?

Pa

tie

nts

wit

h g

oo

d o

utc

om

e

HVPG 20 mmHg

HVPG 20 mmHg

0

20

40

60

80

100

1 2 3 4 5 6 7Days after admission

p<0.0003

Determinants of Variceal BleedDeterminants of Variceal Bleed

Severity of blood loss Child’s Score - A-5%, B-25%, C-50% Infection Time to control bleed/ success HVPG > 16 mm Hg Active bleeding at the time of endoscopy

Severity of blood loss Child’s Score - A-5%, B-25%, C-50% Infection Time to control bleed/ success HVPG > 16 mm Hg Active bleeding at the time of endoscopy

MANAGEMENT OF VARICEAL BLEEDINGMANAGEMENT OF VARICEAL BLEEDING

Determinants Acute Bleeding Secondary Prophylaxis Primary Prophylaxis Prevention size (Early Primary Prophylaxis) Prevention of development of varices

(Pre-primary prophylaxis)

Determinants Acute Bleeding Secondary Prophylaxis Primary Prophylaxis Prevention size (Early Primary Prophylaxis) Prevention of development of varices

(Pre-primary prophylaxis)

Acute Variceal Bleed Acute Variceal Bleed Balloon

SBT, Zimmon’s Drugs

Vasopressin / with nitroglycerin Glypressin Somatostatin Octreotide, Vapreotide

Endoscopy Ligation Sclerotherapy Glue

Combination

TIPS / 0LT

Balloon SBT, Zimmon’s

Drugs Vasopressin / with nitroglycerin Glypressin Somatostatin Octreotide, Vapreotide

Endoscopy Ligation Sclerotherapy Glue

Combination

TIPS / 0LT

00

00

11 22 33 44 55 66 77

2525

5050

7575

100100

DaysDays

67%67%

68%68%

NSNS SclerotherapySclerotherapy

TerlipressinTerlipressin

Acute Variceal Bleed: TEST STUDYProbability of Remaining Bleed Free

Hepatology Sept. 2000

75%75%

82%82%

NSNS

00

00

77 1414 2121 2828 3535 4242

2020

4040

6060

100100

DaysDays

SclerotherapySclerotherapy

TerlipressinTerlipressin

8080

Acute Variceal Bleed: TEST STUDYProbability of Survival

IntravaricealSclerotherapyAlcohol, EO

IntravaricealSclerotherapyAlcohol, EO

Endoscopic Variceal LigationEndoscopic Variceal Ligation

Meta-analysis of Treatments of Acute Variceal BleedingMeta-analysis of Treatments of Acute Variceal Bleeding

0.5 1.0 1.5Pooled odds ratio

a) Better b) Bettera) Sclerotherapy Vs.b) Balloon tamponade

a) Sclerotherapy Vs.b) Vasopressin / terlipr

a) Sclerotherapy Vs.b) Somatostatin

a) Sclerotherapy Vs.b) Octreotide

a) Band ligation Vs.b) Sclerotherapy

a) EST or EVL + drugs Vs.b) Sclerotherapy

No. of Trials

5/1

4

3

3

14

5

Failure to controlbleeding

Mortality

Summary StatementAcute Variceal Bleeding

Summary StatementAcute Variceal Bleeding

VASOACTIVE

DRUGS (60%)

VASOACTIVE

DRUGS (60%)EVL (60-70%)EVL (60-70%)

PharmacologicalPharmacological EndoscopicEndoscopic

Combination (70-80%)Combination (70-80%)

TIPS in Acute Variceal BleedTIPS in Acute Variceal Bleed

MANAGEMENT OF VARICEAL BLEEDING

MANAGEMENT OF VARICEAL BLEEDING

Determinants Acute Bleeding Secondary Prophylaxis (Prevent Rebleed) Primary Prophylaxis Prevention size (Early Primary Prophylaxis) Prevention of development of varices

(Pre-primary prophylaxis)

Determinants Acute Bleeding Secondary Prophylaxis (Prevent Rebleed) Primary Prophylaxis Prevention size (Early Primary Prophylaxis) Prevention of development of varices

(Pre-primary prophylaxis)

SIGNIFICANCE OF HEPATIC GRADIENTSIGNIFICANCE OF HEPATIC GRADIENT

510121520

25

30

35

0 1 2 3 45

Esophageal Varices

NORMALNORMAL

BLEEDERS NON-BLEEDERS

HE

PA

TIC

GR

AD

IEN

T

(mm

Hg)

100

50

00 25 50 75 100

SurvivalNS

Rebleed 40%

Control

Co

ntr

ol

Meta-Anlaysis of Beta Blockers for Secondary Prophylaxis (Luketic GCNA, 2000)

0.5 1.5 1Treated Better Treated Worse

Recurrent bleedingMortality

Sclerotherapy Vs.non active treatment

Sclerotherapy Vs.-Blockers

Sclerotherapy + -Blockers Vs.sclerotherapy

Banding Vs.Sclerotherapy

No. Trials(Patients)

10 1259

9 752

10 600

13 1091

Meta-analysis of Treatments for Preventionof Variceal Rebleeding

Non-Selective Beta-Blockers in Preventing Variceal Non-Selective Beta-Blockers in Preventing Variceal RebleedRebleed

As effective, as EVL Can be associated with endoscopic therapy Optimal results when HVPG is reduced by at least

20% and/or <12 mmHg* ...

…but only achieved in 30% of pts

Select better the patients we treat

measure HVPG measure HVPG responseresponse

Treat better thepatients we select

new drug(s)new drug(s)

or

andand

MANAGEMENT OF VARICEAL BLEEDING

MANAGEMENT OF VARICEAL BLEEDING

Determinants Acute Bleeding Secondary Prophylaxis Primary Prophylaxis (Prevent FIRST Bleed) Prevention size (Early Primary Prophylaxis) Prevention of development of varices

(Pre-primary prophylaxis)

Determinants Acute Bleeding Secondary Prophylaxis Primary Prophylaxis (Prevent FIRST Bleed) Prevention size (Early Primary Prophylaxis) Prevention of development of varices

(Pre-primary prophylaxis)

Child-Pugh Class ASmall varices Large varices

Child-Pugh Class B+CSmall varices Large varices

1 year: 5% 1 year: 13%

6 years:19% 6 years: 44%

Bleeding 1 year: 16% 1 year = 26%

6 years:19% 6 years = 66%

11%

1 year:22%2 years:31%

B:15% C:50%

1 year:43%2 years:62%

42-daydeaths

Rebleeding

INCIDENCE OF VARICEAL BLEED

PROPHYLAXIS FOR FIRST VARICEAL BLEED

PROPHYLAXIS FOR FIRST VARICEAL BLEED

Large ‘High Risk’ Varices - Primary Prophylaxis

Small Varices - Early Primary Prophylaxis

No Varices - Pre-primary prophylaxis

Large ‘High Risk’ Varices - Primary Prophylaxis

Small Varices - Early Primary Prophylaxis

No Varices - Pre-primary prophylaxis

Primary Prophylaxis of Oesophageal Variceal Bleeding

Primary Prophylaxis of Oesophageal Variceal Bleeding

Pharmacotherapy : Beta-blockersNitrovasodilators

Combination

Surgery

Endoscopic therapy

Endoscopic sclerotherapy (EST)

Endoscopic variceal band ligation (EVL)

B-blocker + EVL

Pharmacotherapy : Beta-blockersNitrovasodilators

Combination

Surgery

Endoscopic therapy

Endoscopic sclerotherapy (EST)

Endoscopic variceal band ligation (EVL)

B-blocker + EVL

Problems With Beta-blocker TherapyProblems With Beta-blocker Therapy

Non-response (HPVG) : 67% >12 mm Hg Contraindications : CHF, DM, COPD,

Asthma peripheral vascular dis.

Side-effects (40%) : Asthenia, sexual dysfunction, HE

(2%) Non-compliance : Alcoholics Rebleed on stopping (Cales ‘90)

How long to treat ? Life long ??

Non-response (HPVG) : 67% >12 mm Hg Contraindications : CHF, DM, COPD,

Asthma peripheral vascular dis.

Side-effects (40%) : Asthenia, sexual dysfunction, HE

(2%) Non-compliance : Alcoholics Rebleed on stopping (Cales ‘90)

How long to treat ? Life long ??

How long to continue BB ?? (Abraczinskas et al. Heepatology 2001)How long to continue BB ?? (Abraczinskas et al. Heepatology 2001)

>4 yr Follow-up after stopping BB Bleeding risk same or high as untreated patients Mortality significantly higher (48% vs. 21%,

p<0.05) in the Propranolol group vs. untreated. Continue BB life-long !!! Is it viable, cost-effective or advisable !!!

>4 yr Follow-up after stopping BB Bleeding risk same or high as untreated patients Mortality significantly higher (48% vs. 21%,

p<0.05) in the Propranolol group vs. untreated. Continue BB life-long !!! Is it viable, cost-effective or advisable !!!

Problems With NitrovasodilatorsProblems With Nitrovasodilators

Given alone have no benefit over placebo ( GE 2001)

Being NO donors, enhance vasodilatory syndrome specially in cirrhosis with ascites (Salmeron 1993; Groszmann 1997, Pietrosi 1999)

liver failure and mortality in >50 yr. (Angelico 1997)

Titration of dose/side-effects/tolerance

Given alone have no benefit over placebo ( GE 2001)

Being NO donors, enhance vasodilatory syndrome specially in cirrhosis with ascites (Salmeron 1993; Groszmann 1997, Pietrosi 1999)

liver failure and mortality in >50 yr. (Angelico 1997)

Titration of dose/side-effects/tolerance

META-ANALYSIS OF EVL IN PR. PROPHYLAXISMETA-ANALYSIS OF EVL IN PR. PROPHYLAXIS

EVL vs. Control : 5 trials (n=601) the RR of bleed, bleed related mortality ed 0.36 and 0.20.

EVL vs. beta-blocker: 4 trials (n=283) RR of 1st bleed 0.48 ed , no change in mortality

Prophylactic EVL recommended for intolerant to BB

EVL vs. Control : 5 trials (n=601) the RR of bleed, bleed related mortality ed 0.36 and 0.20.

EVL vs. beta-blocker: 4 trials (n=283) RR of 1st bleed 0.48 ed , no change in mortality

Prophylactic EVL recommended for intolerant to BB

Imeriale and Chalasani 2001, Heyes 2002

Approach to Primary Prophylaxis for EVApproach to Primary Prophylaxis for EV

High risk varicesHigh risk varices

Drug therapyDrug therapy

Propranolol+

ISMN

Propranolol+

ISMN

PropranololPropranololBeta-Blockerscontraindicated/

Side-effects

Beta-Blockerscontraindicated/

Side-effects

EVLEVL

HVPGHVPG

> 12mmHg> 12mmHg < 12mmHg< 12mmHg

EVLEVL Continue drug RXContinue drug RX

Management of Variceal BleedingManagement of Variceal Bleeding

Acute Bleeding

Prevention of rebleeding (Secondary Prophylaxis)

Prevention of first bleed (Primary Prophylaxis)

Prevention of in size (Early Primary Prophylaxis)

Prevention of development of varices(Pre-primary prophylaxis)

Acute Bleeding

Prevention of rebleeding (Secondary Prophylaxis)

Prevention of first bleed (Primary Prophylaxis)

Prevention of in size (Early Primary Prophylaxis)

Prevention of development of varices(Pre-primary prophylaxis)

0

2

4

6

8

10

12

Control Propranolol

0

4

8

12

16

Control Propranolol

mm

Hg

mm

Hg

Portal PressurePortal Pressure Portal systemic shuntingPortal systemic shunting

* ** *

**

Murine Schistosomiasis model

Sarin et al , JCI 1991

Pre-primary Prophylaxis

EVL + PROPRANOLOL VS. EVL ALONE An Interim Analysis (n=187)

EVL + PROPRANOLOL VS. EVL ALONE An Interim Analysis (n=187)

Actuarial Probability

Combination EVL alone

Bleed 10.5% 15.8%

Survival 90% 92%

Recurrence 4.5% 17% (0.06)

Actuarial Probability

Combination EVL alone

Bleed 10.5% 15.8%

Survival 90% 92%

Recurrence 4.5% 17% (0.06)

SEVERE = Red Marks of any type

MILD = Mosaic Pattern of any type

GASTRIC ANTRAL VASCULAR ECTASIAGASTRIC ANTRAL VASCULAR ECTASIA

Portal Hypertensive GastropathyPortal Hypertensive Gastropathy

Vasoactive agents – SMT Propranolol Argon Plasma Laser TIPS Shunt No Devascularization

Vasoactive agents – SMT Propranolol Argon Plasma Laser TIPS Shunt No Devascularization

SUMMARY:Cirrhotic Portal Hypertension HVPG

(mmHg)

varices

BLEEDING ASCITES

PHG SBP

HE

0

5

1210

subclinical portal hypertension

HRS

URINE OUTPUT

MEAN ARTERIAL PR.

GFR

SPLANCH NIC VASODILATION

-NO, PC, GLUCAGON

RENAL VASOCONSTRICTION

-RAAS, SNS, ENDOTHELINS

CHILD’S A CHILD’S B CHILD’S C

HEPATORENAL SYNDROME

ROLE OF ENDOTOXINS: The Vallance Moncada hypothesis for the Role of NO in the hyperdynamic circulation in cirrhosis

ROLE OF ENDOTOXINS: The Vallance Moncada hypothesis for the Role of NO in the hyperdynamic circulation in cirrhosis

Cirrhosis

Portal hypertension

Endotoxaemia cytokines

iNOS

NO

AscitesSodium & water retention

Effective blood volume

ResistanceBlood flow

Cardiac outputBlood pressure

PHT: Renal Hemodynamic ChangesPHT: Renal Hemodynamic Changes

Splanchnic Vasodilation

Effective Blood Volume

Renal Vasoconstriction

GFR

Renal Hypoperfusion (Cortical) (80%) RAS, SNS

HRS Salt and Water retention (15%)

Splanchnic Vasodilation

Effective Blood Volume

Renal Vasoconstriction

GFR

Renal Hypoperfusion (Cortical) (80%) RAS, SNS

HRS Salt and Water retention (15%)

ANF, ET-1

Systemic hemodynamics in cirrhosis with ascites

Systemic hemodynamics in cirrhosis with ascites

MAP (mmHg) 87±3 82±2 69±5

Plasma volume

(mL/Kg)

44±2 66±2 59±4

Cardiac index

(L/min m3)

3.0±0.2 5.7±0.2 5.5±0.5

P<0.001 for all values (ANOVA)

Healthy Cirrhosis with ascites Subjects no HRS HRS

STRATEGIES FOR HEPATO-RENAL SYNDROMESTRATEGIES FOR HEPATO-RENAL SYNDROME

TIPS:

improves renal function

TRANSPLANT

Tt of choice

•SPLANCHNIC CIRC. VASOCONSTRICTORS

-ALFA ADR. AGENT

-TERLIPRESSIN

•-NORADRENALINERAAS

SNS

RENAL BLD. FLOW

Ml/24 hMl/24 h

p <0.05

Group A, n=12Group A, n=12

Group B, n=12Group B, n=12

HRS: Creatinine clearance (ml/min) at baseline, day-4, day-8, day-15 in group A(Terlipressin) and group B (placebo) patients. (Solanki 2003)

HRS: Creatinine clearance (ml/min) at baseline, day-4, day-8, day-15 in group A(Terlipressin) and group B (placebo) patients. (Solanki 2003)

HRS: TERLIPRESSIN

Ml/24 hMl/24 h

p <0.05

Group AGroup A

Group BGroup B

HRS: 24 hour urine output (ml) at baseline, day-4, day-8, day-15 in group A(Terlipressin) and group B (placebo) patients.

HRS: 24 hour urine output (ml) at baseline, day-4, day-8, day-15 in group A(Terlipressin) and group B (placebo) patients.

HRS: TERLIPRESSIN

HRS: New OptionsHRS: New Options

Terlipressin

Noradrenaline

TNF – alpha ab Pentoxyphylline Infleximab

Terlipressin

Noradrenaline

TNF – alpha ab Pentoxyphylline Infleximab

GOV1GOV1 GOV2GOV2

IGV1IGV1 IGV2IGV2

Gastro Oesophageal Varices (GOV)Gastro Oesophageal Varices (GOV)

Isolated Gastric Varices (IGV)Isolated Gastric Varices (IGV)

Classification of GVClassification of GV

Based on locationBased on location

Based on presentationBased on presentation

PrimarySecondary

PrimarySecondary

Am J Gastroenterol 1989

GOV2GOV1

IGV 1

Gastric Varices : Summary of ProfileGastric Varices : Summary of Profile

Prevalence 70% 21% 6.7%

Association with large EV 92% 50% -

Disapp. after EV eradication 62% 23% -

Frequency of bleeding 11.8% 55% 78%

Prevalence 70% 21% 6.7%

Association with large EV 92% 50% -

Disapp. after EV eradication 62% 23% -

Frequency of bleeding 11.8% 55% 78%

GOV 1GOV 1 GOV 2GOV 2 IGV 1IGV 1

Bleeding gastric varixBleeding gastric varix

Glue injectionGlue injection

SUMMARY:Cirrhotic Portal Hypertension HVPG

(mmHg)

varices

BLEEDING ASCITES

PHG SBP

HE

0

5

1210

subclinical portal hypertension

HRS

Splanchnic overproduction and intrahepatic deficit of endothelial NO. ? = Unknown

Splanchnic overproduction and intrahepatic deficit of endothelial NO. ? = Unknown

Hepatology, 2002

Vascular tone

Decreased vascular tone

VascularNO overproduction

Increased eNOS-derived NO synthesis

reduced eNOS-derived NO synthesis

MicrocirculatoryNO deficiency

IncreasedVascular tone

Hepatic Microvascularture

Splanchnic and systemicvascularture

?

NO ET-1

Dilation Angiogensis

Collateral circulation

Splanchnic circulationNOS inhibitors, Antibiotic

Vasoconstictora

NO

Dilation

Hepatic circulationHepatic circulation

E.C.E.C.

E.C.E.C.

E.C.E.C.

NO NOCC

CC

Over express NOSETA Receptor Antagonist

PATHOGENESIS TO THERAPY OF PHT