Pathophysiology of Portal Hypertension

Jaime Bosch, M.D.Professor of Medicine, University of Barcelona

Liver Unit, Hospital Clínic-IDIBAPS,Centro de Investigación Biomédica de Enfermedades Hepáticas y

Digestivas (Ciberehd)

Cirrhosis

Impact of Portal HypertensionImpact of Portal Hypertensionin Chronic Liver Diseasesin Chronic Liver Diseases

SplenomegalySplenomegaly

Varices, PHGVarices, PHG

HepatopulmonaryHepatopulmonary SdSdPortopulmonaryPortopulmonary HTHT

Ascites, SBPAscites, SBPHepatorenalHepatorenal sdsd

EdemaEdema

Spider neviSpider nevi

PalmarPalmarerithemaerithema

Encephalopathy Encephalopathy

CardiomyopathyCardiomyopathy

First cause of death and of livertransplantation in cirrhotic patients

Natural Natural HistoryHistory

IncreasedIncreased Portal Portal PressurePressure(HVPG > 10 (HVPG > 10 mmHgmmHg))

DilatationDilatation of Varicesof VaricesAscitesAscites

RuptureRupture of Varicesof Varices(HVPG > 12 (HVPG > 12 mmHgmmHg))

FormationFormation of Varicesof VaricesNaNa retentionretention

untr

eate

d

trea

ted

LocalTreatments

DrugsDrugsTIPSTIPS

Stage 1Stage 111--y mortality: 1%y mortality: 1%

Stage 2Stage 211--y mortality: 3%y mortality: 3%

Stage 3Stage 311--y mortality: 20%y mortality: 20%

Stage 4Stage 411--y mortality: 50%y mortality: 50%

AnAn indirectindirect measurementmeasurement of of thethe portal portal pressurepressure gradientgradientbasedbased onon hepatichepatic veinvein catherisationcatherisation

HVPG: HVPG: whatwhat isis itit??

HVPG = WHVP HVPG = WHVP –– FHVPFHVP

Free Free pressurepressureWedgedWedged pressurepressure

∆ Pressure = Resistance x Blood flow

Hemodynamic factors in thepathophysiology of portal hypertension

1. Increased hepaticvascular resistance

2. Increased portal blood inflow

3. Formation of portosystemic

collaterals

1. Increased Hepatic Resistance

MechanicalArchitectural changes

FibrosisVascular occlusion

DynamicEndothelialdysfunction

↑ Vascular tone

Two different components

Vasodilator / Vasocontrictor Imbalance in thePathogenesis of the Increased Intrahepatic

Vascular Resistance in Cirrhosis

Nitric Oxide

Other ?

Vasodilators

Carbon MonoxideEndothelinAngiotensin

NorepinephrineLeukotrienes

COX2-ProstanoidsOther?

VasoconstrictorsNitricNitric Oxide

Prostaglandins,SH

Vasodilators

Carbon MonoxideEndothelin

Leukotrienes

AngiotensinNorepinephrineNorepinephrine

Other?ThromboxaneThromboxane A2A2

VasoconstrictorsCirrhotic Liver

The Increased Hepatic Vascular Tone: A New Therapeutic Target

2

• Increasing hepatic NO availabilityincreasing liver NO productionreducing NO scavenging

• Selective delivery of NO to the liver (NCX-1000)

Mechanisms for Decreased Hepatic NO Synthesis in Cirrhosis

- Decreased eNOS expression not provennot proven- Decreased eNOS activity well demonstratedwell demonstrated

Intrahepatic Endothelial DysfunctionIntrahepatic Endothelial Dysfunction• Increased Increased caveolincaveolin expression (cholestasis)expression (cholestasis)• Decreased Decreased AktAkt--pp dependent dependent eNOSeNOS phosphorilationphosphorilation

• Decreased production of BHDecreased production of BH44

•• Scavenging of NO by OScavenging of NO by O..(reduced(reduced SOD activity)SOD activity)

• Increased levels of Increased levels of asymetricasymetric--DMADMA

•• statinsstatins••supplementssupplements•• antioxydantsantioxydants

Splanchnic Splanchnic vasodilationvasodilationIncreased NO, CO,Increased NO, CO,

glucagonglucagon, , endocannabinoidsendocannabinoids

Hyperkinetic syndromeHyperkinetic syndrome

2. Increased Portal Inflow

Increased cardiac indexDecreased peripheral resistance

Hypotension & “Effective” hypovolemiaActivation of vasoactive factors

Na retention

β-blockersTerlipressin

Somatostatin New targetsNew targets

How portosystemic collateral blood vesselsdevelop during portal hypertension?

Opening of pre- existing blood vessels (increased pressure)

Growth of new blood vessels (angiogenesis)

3. Formation of portal-systemic collaterals and varices

Development of varices is lower in patients with a baseline HVPG <10 and an HVPG reduction >10%

Baseline HVPG<10mmHg and ↓HVPG>10%

0

0.2

0.4

0.6

0.8

1

0 12 24 36 48 60 72 84 Months of Follow-up

Baseline HVPG<10mmHg alone

Baseline HVPG≥10mmHg alone

Free

of V

aric

es (

%)

Baseline HVPG is the strongest predictor of the development of varices

VEGFR-2 blockade by SU5416 decreases theformation of portosystemic collaterals in portal

hypertensive rats

Fernández et al, Gastroenterology (2004)

Increased splanchnic arteriolar

vasodilatation

Increased splanchnic blood flow

Increased splanchnic neovascularization

(angiogenesis)

Mechanisms of increased splanchnic blood flow in portal hypertension

VEGFR-2 blockade by SU5416 decreases mesentericand intestinal blood flows in portal hypertensive rats

Fernández et al, J Hepatol (2005)

Vasodilatation Angiogenesis

Mechanisms of increased splanchnic blood flow in portal hypertension

Initiation(adaptative responses)

Maintenance(chronic scenario)

Rx: vasoconstrictors + antiRx: vasoconstrictors + anti--angiogenicsangiogenics

maturationPDGF

VEGFformation

c

RapamycinRapamycin

cGleevecGleevec

Combined VEGF and PDGF blockade reduces portal pressure, SMA blood flow and portosystemic collaterals

Fernández et al, Hepatology 2007

Increased portal pressure

Dilation of pre-existing vessels

Local anatomical factors

Enhanced angiogenic factors(VEGF, PDGF, NO, CO)

Formation of new vessels(Venous and Arterial)

Collaterals and Varices Splanchnic hyperemia

Cirrhosis of the liverIncreased resistance Liver dysfunction

Structural abnormalities + Increased hepatic vascular tone

x x x

xMultiMulti--targettargetantianti--angiogenicangiogenic

agentsagents

New Therapeutic Perspectives in Portal Hypertension

Ascites

4. Dilation and Rupture of Varices

VarixP

Flow

Repeat brisk increases inportal pressure and collateral blood flow causedby meals, alcohol, , exercise and increasedintra-abdominal pressure

WT= WT= ΔΔP x rP x r

* H = Defects in hemostasis

SeveritySeverity of of BleedingBleeding Portal Portal PressurePressure x x AreaArea of of VarixVarix RentRentBlood viscosity

xx H*H*

FactorsFactors InfluencingInfluencing thethe SeveritySeverity of of Variceal Variceal BleedingBleeding

==

(partly correctable by rFVIIa)

Failure toControl AVB

Early Rebleeding 1-year Mortality0%

20%

40%

60%

23%0%

p <0.01

12%20%

p <0.01 p <0.01

0

5

10

15

20

Transfusions (UU) Days in ICU Days in Hospital

p <0.01 p <0.02

p <0.02

HVPG > 20 mmHg HVPG < 20 mmHg

Moitinho et al, Gastroenterology 1999

HVPG Determines HVPG Determines thethe Prognosis of Prognosis of Variceal Variceal BleedingBleeding

50%64%

Factors Influencing the Outcome ofFactors Influencing the Outcome ofVariceal Hemorrhage

Abnormal Hemostasis

Unstable clot

Blood in GI Tract

Portal Pressure

Variceal Pressurepersistentpersistentbleedingbleeding

SomatostatinOctreotide

rF-VIIa

infectionsenhancedfibrinolysis

AcknowledgementsAcknowledgementsStaff & fellows Hepatic Hemodynamic Lab

Juan Carlos GarcJuan Carlos Garcííaa--PagPagáánnJuan GJuan G--AbraldesAbraldes

MercedesMercedes FernFernáándezndezAinaAina RodriguezRodriguez

Annalisa Berzigotti Annalisa Berzigotti SebastiSebastiáán n RaffaRaffaCarolina TianiCarolina Tiani

Filippo Filippo ScheppisScheppisEva EriceEva EriceElbaElba LlopLlop

Andrea De Gottardi Andrea De Gottardi Angels Angels BaringoBaringo Laura Laura RocabertRocabert Rosa Rosa SaezSaez

Hepatology, September 2007

Δ Portal Pressure = Resistance x Blood Flow

Increased Portal PressureIncreased Portal Pressure

IncreasedBlood Flow

(splanchnic vasodilation)

IncreasedResistance

(dynamic / mechanic)

Pathophysiology of Portal HypertensionPathophysiology of Portal Hypertension

Currenttreatments

β-blockersTerlipressinSomatostatin

TIPSNew targets

AssessmentAssessment of Portal of Portal PressurePressure by HVPGby HVPG

HepaticVenousPressureGradient

Equivalent toPortal Pressure Gradient

“Gold standard” in the assessment of portal hypertension*, the most

common and lethal complication of cirrhosis

* defined by an HVPG > 5 mmHg

TypicalTypical measurementmeasurement of HVPG of HVPG usingusing a a balloonballoon cathetercatheter

0

20

30

10

mmHg

FHVP

WHVP WHVP

HVPG= 24 mmHg