Professor Professor AndrewAndrew K K BurroughsBurroughsConsultant Physician and Consultant Physician and HepatologistHepatologist

Professor of Professor of HepatologyHepatology

LiverLiver Transplantation & Transplantation & HepatobiliatyHepatobiliaty UnitUnit

PathogenesisPathogenesis of of chronicchronic liverliver diseasedisease::aetiologyaetiology, , pathologypathology, , epidemiologyepidemiology and and outcomeoutcome

ROYAL FREE & UNIVERSITY COLLEGE MEDICAL SCHOOLROYAL FREE & UNIVERSITY COLLEGE MEDICAL SCHOOL

LICAGE LICAGE –– Newcastle 26Newcastle 26--27 May 200527 May 2005

AetiologyAetiology/Epidemiology of liver diseases/Epidemiology of liver diseasesHCV/HBVHCV/HBV

AlcoholAlcohol

NAFLDNAFLD

biliarybiliary

OthersOthers

Pathogenesis of cirrhosisPathogenesis of cirrhosisComplications of cirrhosisComplications of cirrhosis

NutritionNutritionBleedingBleedingAscitesAscitesHeartHeartEncephalopathyEncephalopathyHCCHCCSpontaneous infectionSpontaneous infection

Prognostic assessmentPrognostic assessment

HBV HBV –– natural historynatural history

Acute HBV Acute HBV infectioninfection

ChronicChronic infectioninfection

InactiveInactivecarrierscarriers

ChronicChronic hepatitishepatitis CIRRHOSISCIRRHOSIS HCCHCC

•• symptomaticsymptomatic99%99%

< 10%< 10%

80%80%

20%20%

1010--15 15 yrsyrs 2525--30%30% 30%30%

99% Acute 99% Acute viralviral hepatitishepatitis1% FHF1% FHF

LAMIVUDINE TREATMENT EFFECTLAMIVUDINE TREATMENT EFFECT75 75 treatedtreated patientspatients notnot candidatescandidates forfor liverlivertransplantationtransplantation

ameliorationamelioration ChildChild--PughPugh scorescore31% 31% ≥≥ 2 2 pointspoints

57% 57% stablestable or < 2 or < 2 pointspoints

12% 12% worseworse

HannHann 20032003

30 30 decompensateddecompensated liverliver diseasedisease

ameliorationamelioration ChildChild--PughPugh score score ≥≥ 2 2 pointspoints, 76%, 76%

ManolakopoulosManolakopoulos 20032003

HEPATITIS C VIRUS (HCV)HEPATITIS C VIRUS (HCV)

Serological testing only available from late 1990 Serological testing only available from late 1990 22--3% world population3% world populationWide differences Wide differences

Egypt 10%+Egypt 10%+Italy 1Italy 1--2% (pockets 32% (pockets 3--4%)4%)UK UK –– NOW 0.05% (post blood screening)NOW 0.05% (post blood screening)

Risk factors as for HBV Risk factors as for HBV (NB surgery (NB surgery –– MeleMele 2001)2001)

Much higher rate of Much higher rate of chronicitychronicity than for HBVthan for HBV

HEPATITIS CHEPATITIS C ((HCV) INFECTIONHCV) INFECTIONOne of the most important causes One of the most important causes morbidity/mortality worldwide morbidity/mortality worldwide –– 170 million170 million

Impairs quality of lifeImpairs quality of life

Major indication for liver transplantation when Major indication for liver transplantation when this is available this is available

Therapy of chronic hepatitis in sustained Therapy of chronic hepatitis in sustained responders prevents the advent of cirrhosis and responders prevents the advent of cirrhosis and its complications including its complications including hepatocellularhepatocellularcarcinomacarcinoma

WORLDWIDE HEPATITIS CWORLDWIDE HEPATITIS C INFECTIONINFECTION

Acute HCV Acute HCV infectioninfection

ChronicChronic infectioninfection

asymptomaticasymptomaticcarrierscarriers

ChronicChronic hepatitishepatitis CirrhosisCirrhosis HCCHCC

•• symptomaticsymptomatic 20%20%•• asymptomaticasymptomatic 80%80%

70%70%--80 %80 %

90%90%

10%10%

1010--15 15 yrsyrs 2525--30%30% 30%30%

HCV HCV –– naural history naural history

0

20

40

60

80

0 3 6 9 12 15

yearsyears followfollow upup

Inci

denc

eIn

cide

nce

HC

C (%

)H

CC

(%)

NONRANDOMIZED OBSERVATIONS OF HCC NONRANDOMIZED OBSERVATIONS OF HCC INCIDENCE IN PATIENTS WITH CHRONIC HCV INCIDENCE IN PATIENTS WITH CHRONIC HCV

HEPATITIS RECEIVING TREATMENT COMPARED TO HEPATITIS RECEIVING TREATMENT COMPARED TO UNTREATED UNTREATED ((ChanderChander 2002)2002)

TREATEDTREATED UNTREATEDUNTREATED

COMPLICATIONS AND CAUSES OF DEATH IN COMPLICATIONS AND CAUSES OF DEATH IN COMPENSATED HCV AND HBV CIRHOSISCOMPENSATED HCV AND HBV CIRHOSIS

((BenvegnuBenvegnu 2004)2004)

N=312 (254 HCV)N=312 (254 HCV)

complication N Deathcomplication N DeathssNon liver related death Non liver related death 13 (4.2%)13 (4.2%)

Liver related deaths Liver related deaths -- 58 (18.6%)58 (18.6%)

-- hepatocellularhepatocellular carcinoma 65 41carcinoma 65 41++ (13%)(13%)

-- liver failure liver failure 15 (4%)15 (4%)

-- massive GI bleeding 14 massive GI bleeding 14 2 (< 1%) 2 (< 1%)

Liver transplantation Liver transplantation 7 (2.3%)7 (2.3%)

++HCC caused 71% of all deathsHCC caused 71% of all deaths

((BenvegnuBenvegnu 2004)2004)

((BenvegnuBenvegnu 2004)2004)

((BenvegnuBenvegnu 2004)2004)

NAFLD: USA PREVALENCENAFLD: USA PREVALENCE

Nutritional Helath and Nutrition Examination Survey (NHANES III)

-- 19881988--19941994

-- 33--6% American 6% American populationpopulation(850,000(850,000--1.7 1.7 millionmillion))

-- ElevatedElevated transaminasestransaminases

-- exclusionexclusion otherother aetiologiesaetiologiesRuhlRuhl 20032003

NAFLD: ITALIAN PREVALENCENAFLD: ITALIAN PREVALENCE

PopulationPopulation ObesityObesity

AdultsAdults 2.82.8--20%20% 76%76%

ChildrenChildren 2.6%2.6% 52.8%52.8%

FranzeseFranzese 19971997

NAFLD/NASH ASSOCIATIONSNAFLD/NASH ASSOCIATIONS

metabolicmetabolic syndromesyndrome((SyndromeSyndrome X)X)

-- ObesityObesity

-- DiabetesDiabetes

-- DyslipidemiaDyslipidemia

-- HypertensionHypertensionOtherOther metabolicmetabolic syndromessyndromes

-- duodenoduodeno--jejunaljejunal bypassbypass

-- total total parenteralparenteral nutritionnutrition

-- RapidRapid weightweight lossloss

DrugsDrugs//ToxinsToxins

-- CorticosteroidsCorticosteroids

-- TamoxifenTamoxifen

-- AmiodaronAmiodaron

-- SolventsSolvents

HereditaryHereditary lipidlipid disordersdisorders

-- LipodystrophyLipodystrophy

-- aa--ββlipoproteinemialipoproteinemia

NASH IN DIABETIC PATIENTSNASH IN DIABETIC PATIENTS

PrevalencePrevalence

Type I diabetes: Type I diabetes: rarerare

Type II Type II diabetesdiabetes: : 45%45%

TypeType II II diabetesdiabetes prevalenceprevalence in NASH: 2in NASH: 2--50%50%

NASH: NATURAL HISTORYNASH: NATURAL HISTORY

DiabetesDiabetes Non Non diabetesdiabetes ppn 42n 42 n 42n 42

AgeAge at at diagnosisdiagnosis 3737±11±11 54 54 ±14±14 .04.04

FemaleFemale sexsex 67%67% 47%47% .02.02

BMIBMI 31 31 ±5±5 29 ±629 ±6 .04.04

TrigliceridesTriglicerides 489 489 ±312±312 226 ±115 .05226 ±115 .05

CirrosisCirrosis 23.9%23.9% 10.6%10.6% .02.02

LiverLiver relatedrelated deathsdeaths 19% 2%19% 2%

AnguloAngulo 19991999

NASH: NATURAL HISTORYNASH: NATURAL HISTORY

•• LiverLiver relatedrelated deathsdeaths” ” –– 2nd cause of death after neoplasms2nd cause of death after neoplasms

•• LiverLiver relatedrelated deathsdeaths -- 11% 11% vsvs 0.95% 0.95% ageage matchedmatched populationpopulation

MatteoniMatteoni 19991999

0

5

10

15

20

25

30

35

40

45

Type I Type 2 Type 3 Type 4

Cirrhosis

Deaths

Liver relatedeaths

%%

histological progression

ALCOHOLIC CIRRHOSIS: MORTALITYALCOHOLIC CIRRHOSIS: MORTALITY

4000/4000/yearyear in U.K. (in U.K. (alcoholalcohol relatedrelated deathsdeaths))36.000/36.000/yearyear in USAin USA

INDICATION FOR LIVER TRANSPLANTATIONINDICATION FOR LIVER TRANSPLANTATION

19% in USA (3000 OLT/19% in USA (3000 OLT/yearyear))up up toto 40% 40% EuropeanEuropean CentresCentres (550 OLT/(550 OLT/yearyear))

ChildChild--PughPugh B or CB or CPersistentPersistent encephalopathyencephalopathy

VaricealVariceal bleedingbleedingwhichwhich are are correlatedcorrelated withwith poorpoor qualityquality of life or of life or

anticipatedanticipated lengthlength of life of life lessless thanthan 1 1 yearyearUSED FOR INDICATIONS FOR TRANSPLANTUSED FOR INDICATIONS FOR TRANSPLANT

FranceFrance and UK and UK modellingmodelling: : anticipatedanticipated survivalsurvival forforpatientspatients withwith alcoholicalcoholic liverliver diseasedisease withoutwithout liverliver transplantationtransplantation

5050--80% at 1 80% at 1 yearyear

PoynardPoynard T, T, etet al. al. HepatologyHepatology 1999;30:11301999;30:1130--11371137

PROGNOSTIC FACTORS RELATED TO MORTALITYPROGNOSTIC FACTORS RELATED TO MORTALITYIN ALCOHOLIC CIRRHOSISIN ALCOHOLIC CIRRHOSIS

Primary Biliary CirrhosisPrimary Biliary Cirrhosis

Usually females (90%), middle agedUsually females (90%), middle aged

Symptoms: pruritus and lethargySymptoms: pruritus and lethargy

Biochemistry: cholestasisBiochemistry: cholestasis

Immunology: IgM and AMAImmunology: IgM and AMA

Liver histology: granulomatous Liver histology: granulomatous

cholangitischolangitis

Role of liver biopsy Role of liver biopsy -- not indicated in not indicated in

classical casesclassical cases

PBCPBC--Prevalence and IncidencePrevalence and Incidence

Reported prevalence varies from 19Reported prevalence varies from 19--400/million 400/million

populationpopulation

Reported incidence 1Reported incidence 1--40/million/year40/million/year

Increased familial riskIncreased familial risk

Commoner in North Europe/North AmericaCommoner in North Europe/North America

Clustering (no evidence for rural/urban concentration)Clustering (no evidence for rural/urban concentration)

PBCPBC--Natural HistoryNatural History

Symptomatic:Symptomatic: ‘classical PBC’: progress to ‘classical PBC’: progress to

End Stage Liver Disease in 5End Stage Liver Disease in 5--10 years10 years

Decompensated: Decompensated: presents with ascites or GI presents with ascites or GI

bleeding: survival 2bleeding: survival 2--5 years5 years

PRIMARY SCLEROSING CHOLANGITISPRIMARY SCLEROSING CHOLANGITIS

117 Italian patients 117 Italian patients ((OkolicsanyiOkolicsanyi 1996) 1996) 74% 74%

small duct PSC better long term survivalsmall duct PSC better long term survival 90%90%

compared to classic PSC compared to classic PSC ((AnguloAngulo 2002)2002) 74%74%

305 Swedish patients305 Swedish patients asymptomaticasymptomatic 78%78%

(Broome 1996)(Broome 1996) symptomaticsymptomatic 50%50%

Risk of Risk of CholangiocarcinomaCholangiocarcinoma 8%8%

Duct involvement influences prognosis (Duct involvement influences prognosis (PonsioenPonsioen 2002)2002)

survivalsurvival at 10 at 10 yearsyears

HAEMOCROMATOSISHAEMOCROMATOSISORGANS ORGANS

INVOLVEDINVOLVED HEART: HEART: cardiomyopathycardiomyopathyPANCREAS: PANCREAS: diabetesdiabetes mellitusmellitusJOINTS: JOINTS: degenerative degenerative arthritsarthritsGONADS: GONADS: hypogonadismhypogonadismLIVERLIVERfibrosisfibrosis ⇒⇒ cirrhosiscirrhosis ⇒⇒ hepatocarcinomahepatocarcinoma

symptomssymptomsweaknessweakness

articulararticular painpainabdominalabdominal painpain

impotenceimpotence//amenorrhoeaamenorrhoea

HaemochromatosisHaemochromatosis -- ClassificationClassification

Primary iron overload Primary iron overload

Hereditary Hereditary hemochromatosishemochromatosis (HH)(HH)HFEHFE--associated HH (C282Y) (AR)associated HH (C282Y) (AR)Non HFENon HFE--associated HHassociated HH

TfR2 mutations (AR)TfR2 mutations (AR)FerroportinFerroportin mutations (AD)mutations (AD)Other mutations...Other mutations...

Juvenile HJuvenile HSolomon Islands HH (AD)Solomon Islands HH (AD)

African (SubAfrican (Sub--SaharianSaharian) H) HHeredity not yet characterisedHeredity not yet characterised

CONSEQUENCES OF DEVELOPING PROGRESSIVECONSEQUENCES OF DEVELOPING PROGRESSIVEHEPATIC FIBROSISHEPATIC FIBROSIS

intrahepaticintrahepatic resistanceresistancestructuralstructural & & functionalfunctional

decreaseddecreased intrahepaticintrahepatic NO productionNO production⇑⇑ splanchnicsplanchnic bloodblood flowflow

((cirrhosiscirrhosis))HCCHCC

portalportal hypertensionhypertension

varicealvariceal bleedingbleeding

hepatichepatic encephalopathyencephalopathy

pulmonarypulmonary hypertensionhypertension

hepatopulmonaryhepatopulmonary syndromesyndrome

portosystemicportosystemic collateralscollaterals

systemicsystemichyperdynamichyperdynamic circulationcirculation

ascitesascites

spontaneousspontaneousbacterialbacterial peritonitisperitonitis

⇑ cardiac output cardiomyopathy

NO (eNOS)prostacyclinCOendocannabinoids

decrease centralvolumeRAS activation

ROLE OF NO IN PORTAL HYPERTENSIONROLE OF NO IN PORTAL HYPERTENSION

portalportal hypertensionhypertension

portosystemicportosystemic shuntshunt

cardiaccardiac output output ⇑⇑shearshear stress stress ⇑⇑

cytokinescytokines ⇑⇑LPS LPS ⇑⇑

iNOSiNOS eNOSeNOS

portosystemicportosystemic shuntshunt

biochemicalbiochemicalstimulationstimulation

mechanicalmechanical stimulationstimulationbacterialbacterial traslocationtraslocation

systemicsystemic vasodilatationvasodilatation ⇑⇑splancnicsplancnic bloodblood flowflow ⇑⇑

MANIPULATON OF NO WITHIN THE CIRRHOTIC LIVERMANIPULATON OF NO WITHIN THE CIRRHOTIC LIVER

PHARMACOLOGICAL VECTORSPHARMACOLOGICAL VECTORS°° VIRAL VIRAL VECTORS*VECTORS*

hepatichepatic ““vascularvascular”” cellcell

⇑⇑ NONO

NO NO releaserelease eNOeNO releaserelease

decreasedecrease portalportal pressurepressure

relaxationrelaxation

°° gene transfer (gene transfer (VanVan de de CasteeleCasteele 2002); 2002); * V* V--PYRRO/NO (PYRRO/NO (MoalMoal 2000), NCX2000), NCX--1000 (1000 (FiorucciFiorucci 2001)2001)

Hyperkinetic syndrome in cirrhosis

Portal hypertension

Hepatorenal syndrome

Hepatic encephalopathy

Hepatopulmonary syndrome

Cirrhotic cardiomyopathy

HVPG ↑

GFR ↓

RBF ↓

CBF?TLCO↓

PO2↓CO ↑

Contr↓

Systemic vasoconstrictionSystemic vasoconstriction

• Sympathetic nervous system

• Renin-angiotensin-aldosterone system

• Arginine vasopressin• Endothelin

Epstein et al. Am J Med 1970

Pathophysiology of HRS

Incidence of Incidence of HepatorenalHepatorenal SyndromeSyndrome

234 patients 234 patients withwith cirrhosiscirrhosis andand ascites: ascites: 54 54 hepatorenalhepatorenal syndromesyndromeOccurrence Occurrence atat 1 1 yearyear

18%18%Occurrence Occurrence atat 5 5 yearyear

39%39%

Ginès et al Gastroenterology 1993;105:229-36.

HepatorenalHepatorenal SyndromeSyndrome

PrognosisPrognosis

RegressionRegression: 2 cases (0.4%): 2 cases (0.4%)DeathDeath: 52 cases: 52 casesMedianMedian survivalsurvival time: 1.7 time: 1.7 weeksweeks

GinèsGinès et al. et al. GastroenterologyGastroenterology 1993;105:2291993;105:229--3636..

Type of HRSType of HRS

Type IRapidly progressive reduction of renal function• Doubling of S-Creatinine

>2.5 mg/dL or:• 50% reduction of 24-h Cr

Cl < 20 mL/min in less than 2 weeks

Type IISlowly progressive course

0

0,2

0,4

0,6

0,8

1

%

PROBABILITY OF SURVIVAL IN PATIENTS WITH HRS

2 4 86 months

A. Gines et al. Lancet 2003 ; 362 : 1819-1827.

10 12

P < 0.001

Type 2 HRS

Type 1 HRS

0

0,2

0,4

0,6

0,8

1%

PROBABILITY OF SURVIVAL IN PATIENTS WITH HRS PROBABILITY OF SURVIVAL IN PATIENTS WITH HRS TREATED WITH TIPS OR CONVENTIONAL MEDICAL TREATED WITH TIPS OR CONVENTIONAL MEDICAL

THERAPY (CMT)THERAPY (CMT)

13 39 104

With TIPS

With CMT

P < 0.001

65 days

K.A. Brensing et al. Gut 2000 ; 47 : 288-995.

26 52 78 91

0

0,25

0,5

0,75

1%

PROBABILITY OF SURVIVAL WITH TYPE 1 HRS PROBABILITY OF SURVIVAL WITH TYPE 1 HRS TREATED WITH TERLIPRESSIN ACCORDING TO TREATED WITH TERLIPRESSIN ACCORDING TO

THE CHILDTHE CHILD--PUGH SCOREPUGH SCORE

15 60 180

Child-Pugh < 11

Child-Pugh > 11

P < 0.0025

90 days

R. Moreau et al. Gastroenterology 2002 ; 122 : 923-930.

Decreased effectivearterial blood volume

Cerebralvasoconstriction

Brachial/femoralvasoconstriction

Renalvasoconstriction

Maintenance ofeffective arterial

blood volume

HEPATORENALSYNDROME

Cirrhosis

Portal hypertensionSplanchnic vasodilatation

Vasoconstrictor systems

PATHOGENESIS OF HEPATORENAL SYNDROME

Liver transplantationTIPS

Vasoconstrictors

Albumin

Therapeutic options

0

0,2

0,4

0,6

0,8

1%

RECOVERY OF RENAL FUNCTIONRECOVERY OF RENAL FUNCTIONWITH TERLIPRESSIN AND ALBUMINWITH TERLIPRESSIN AND ALBUMIN

2 4 10 12

Terlipressin plus albumin

Terlipressin

P < 0.05

6 8 days

R. Ortega et al. Hepatology 2002 ; 36 : 941-948.

0

0,25

0,5

0,75

1%

PROBABILITY OF SURVIVAL WITH HRS TREATED WITH PROBABILITY OF SURVIVAL WITH HRS TREATED WITH EXTRACORPOREAL ALBUMIN DIALYSIS (MARS)EXTRACORPOREAL ALBUMIN DIALYSIS (MARS)

5 10 20

MARS

Conventional medical treatment

P < 0.025

15 days

SR. Mitzner et al. Liver Transpl. 2000 ; 6 : 277-286.

25

Mortality from Mortality from varicealvariceal bleeding in bleeding in a single centre a single centre ((CarbonellCarbonell 2004)2004)

Child Pugh A/B

Child Pugh C

PROSPECTIVE STUDY OF UPPER GI PROSPECTIVE STUDY OF UPPER GI BLEEDING IN CIRRHOTICS BLEEDING IN CIRRHOTICS (D(D’’AmicoAmico 2003)2003)

9.6%9.6%P=0.019P=0.01919%19%RebleedRebleed ≤ 6w≤ 6w

14.9%14.9%P=0.16P=0.1620.8%20.8%Deaths ≤ 6 wDeaths ≤ 6 w

5.3%5.3%P=0.18P=0.189.2%9.2%Deaths ≤ 5dDeaths ≤ 5d

1.8%1.8%4.8%4.8%RebleedRebleed ≤ 5d≤ 5d7%7%P=0.03P=0.0314.6%14.6%5 day failure5 day failure114114336336patientspatients

NonNon--varicealvaricealvaricesvaricescirrhoticscirrhotics

ACUTE VARICEAL BLEEDING ACUTE VARICEAL BLEEDING PROPHYLACTIC ANTIBIOTICS AND MORTALITYPROPHYLACTIC ANTIBIOTICS AND MORTALITY

Diagnosis of upper GI bleeding in cirrhosis Diagnosis of upper GI bleeding in cirrhosis

• endoscopy as soon as resuscitation adequate

• it is a high risk endoscopy

adequate support staff (suction)

assess risk of aspiration

pulse oximetry - nasal oxygen

may need endotracheal intubation

• look at fundus, other lesions

TRANSVENOUS (JUGULAR) ROUTE : THE KEY TO TRANSVENOUS (JUGULAR) ROUTE : THE KEY TO PORTAL HYPERTENSION PORTAL HYPERTENSION -- ONE STOP LIVER SHOPONE STOP LIVER SHOP

((VlachogiannakosVlachogiannakos 2000)2000)

hepatic hepatic venographyvenography

hepatic venous hepatic venous

pressure(HVPG)pressure(HVPG)

transjugulartransjugular liver biopsyliver biopsy

transhepatictranshepatic portal pressureportal pressure

COCO22 portographyportography

direct direct portographyportography

IVC pressures IVC pressures

balloon angioplasty balloon angioplasty hephep. webs . webs

hepatic vein hepatic vein stentsstents

TIPSTIPS

balloon angioplasty IVC websballoon angioplasty IVC webs

IVC IVC stentsstents

transtrans--venous renal biopsyvenous renal biopsy

All as day case single visit

THE KEY HOLE TO THE LIVER WORLD

MONITORING HAEMODYNAMIC RESPONSE MONITORING HAEMODYNAMIC RESPONSE FOLLOWING VARICEAL BLEEDING FOLLOWING VARICEAL BLEEDING (Villanueva 2004)(Villanueva 2004)

132 132 cirrhoticscirrhotics -- nadololnadolol and and isosorbideisosorbide mononitratemononitrate

64 responders (48%) at 164 responders (48%) at 1--3 months3 months-- less less ascitesascites-- less encephalopathyless encephalopathy-- improved CP scoreimproved CP score-- less transplantationless transplantation-- less mortalityless mortality-- more abstentionmore abstention

81% of 64 maintained response (1281% of 64 maintained response (12--18m)18m)

RELATIONSHIP BETWEEN LIVER FUNCTION AND PORTAL PRESSURERELATIONSHIP BETWEEN LIVER FUNCTION AND PORTAL PRESSUREWHAT COMES FIRST, THE CHICKEN OR THE EGG? WHAT COMES FIRST, THE CHICKEN OR THE EGG? ((VillaneuvaVillaneuva 2005)2005)

ChildChild--Pugh score unchanged or worse (n=31)Pugh score unchanged or worse (n=31)

Response to Response to nsBBnsBB/ISMN non responders /ISMN non responders respondersresponders

Patients 20 Patients 20 1111

RebleedingRebleeding 55% 9%55% 9%

AscitesAscites 60% 18%60% 18%

HRS 20% HRS 20% 9%9%

Transplant 25% Transplant 25% 0%0%

Death 35% Death 35% 18%18%

PORTAL PRESSURE MEASUREMENTS and PORTAL PRESSURE MEASUREMENTS and SURVIVALSURVIVAL

published studies and number of patients all studies show statistical significance

previous variceal bleeding

Vinel 1986 72Viola 1987 290Gluud 1988 53Tage-Jensen 1988 81Merkel 1992 129

no bleeding

Arroyo 1981 31Vinel 1982* 89Groszmann 1990 84Barrett 1990 101Urbain 1993* 99Vorobioff 1994 30

n multiple or Cox regression used * not stated

TIPS FOR PORTAL VEIN THROMBOSIS AT RFHTIPS FOR PORTAL VEIN THROMBOSIS AT RFHSenzoloSenzolo etet al 2005al 2005

26 patients portal vein thrombosis 26 patients portal vein thrombosis -- 12 with cirrhosis12 with cirrhosis

TotalTotal Complete PVTComplete PVT CavernomaCavernoma

SuccessfulSuccessful 65% 61% 65% 61% 62%62%

ComplicationsComplications 0 0 -- --

MechanicalMechanicalthrombectomythrombectomy 53%53%

* * VaricealVariceal bleedingbleeding in 14, in 14, prepre OLT 3, OLT 3, BuddBudd Chiari 2, Chiari 2, AscitesAscites 5, 5,

portalportal biliopathybiliopathy 22

SenzoloSenzolo etet al 2005al 2005

TIPS BEFORE ABDOMINAL SURGERY IN PATIENTS WITH TIPS BEFORE ABDOMINAL SURGERY IN PATIENTS WITH CIRRHOSIS AND SEVERE PORTAL HYPERTENSIONCIRRHOSIS AND SEVERE PORTAL HYPERTENSION

Gastrointestinal surgery in patients with liver cirrhosisGastrointestinal surgery in patients with liver cirrhosisleads to a 10%leads to a 10%--57% mortality57% mortality

to date 12 patients reported undergoing 2to date 12 patients reported undergoing 2--step procedure step procedure (TIPS before abdominal surgery or minimally gastric (TIPS before abdominal surgery or minimally gastric invasive procedures)invasive procedures)

-- 10 underwent surgery10 underwent surgery-- median interval 1 month after TIPSmedian interval 1 month after TIPS-- 3 required blood transfusion during surgery3 required blood transfusion during surgery-- 1 died1 died

MoulinMoulin 1995, 1995, GuglielmiGuglielmi 1999, 1999, AzoulayAzoulay 2001, 2001, GilGil 20042004

SystemicSystemic circulationcirculation

Plasma Plasma valumevalume ⇑⇑Total Total bloodblood volume volume ⇑⇑CentralCentral and and arterialarterial bloodblood volume volume ⇓⇓ ⇑⇑CardiacCardiac output output ⇑⇑ArterialArterial pressurepressure ⇓⇓CardiacCardiac frequencyfrequency ⇑⇑SystemicSystemic vascularvascular resistanceresistance ⇓⇓

LIVER CIRRHOSISLIVER CIRRHOSIS ⇑⇑ sympatheticsympathetic activityactivity⇑⇑ bloodblood volumevolumearterioarterio--venousvenous shuntsshunts

HYPERDYNAMICHYPERDYNAMICCIRCULATIONCIRCULATION

CIRRHOTIC CARDIOMYOPATHYCIRRHOTIC CARDIOMYOPATHY

CARDIAC VOLUMESCARDIAC VOLUMES

ContrastingContrasting data: data: normalnormal volumevolumeincreasedincreased volume (volume (hypertrophyhypertrophy//eccentriceccentric))

EDVEDVESVESV

outputoutputstrokestroke volumevolumearterialarterial pressurepressurebloodblood volumevolume

CARDIAC PRESSURESCARDIAC PRESSURES

NormalNormal at at restrest

PhysicalPhysical or or pharmacologicalpharmacological stressstress--⇑⇑ EDVEDV--⇓⇓ LV LV ejectionejection fractionfraction--⇓⇓ strokestroke indexindex

WongWong, , HepatologyHepatology 19941994RectorRector, , GastroenterologyGastroenterology 19881988PerelloPerello, J , J HepatolHepatol 20002000

correlate correlate withwith

PRE ASCITIC CIRRHOSISPRE ASCITIC CIRRHOSIS

•• normalnormal cardiaccardiac functionfunction•• abnormalabnormal ANP ANP secretionsecretion ((increasedincreased cardiaccardiac stiffnessstiffness))•• abnormalabnormal stress stress responseresponse

ASCITIC CIRRHOSISASCITIC CIRRHOSIS

•• ⇑⇑⇑⇑ ANPANP•• ventricularventricular hypertrophyhypertrophy•• diastolicdiastolic and and systolicsystolic abnormalityabnormality

LaVillaLaVilla, , HepatologyHepatology 19921992IwaoIwao, J , J HepatolHepatol 20002000Valeriano, Valeriano, AmAm J J GastroenterolGastroenterol 20002000

⇓⇓ cardiaccardiacfunctionfunction

VasodilatationVasodilatation

⇓⇓ ouputouput

⊕⊕

ASCITESASCITESHEPATO RENAL SYNDROMEHEPATO RENAL SYNDROME

CARDIAC RESPONSE AND ASCITESCARDIAC RESPONSE AND ASCITES

VasoconstrictionVasoconstriction cardiaccardiac output output ==PWCPPWCP ⇑⇑

⇑⇑ venousvenous returnreturn

= = cardiaccardiac outputoutput

TIPSTIPS Plasma Plasma expandersexpanders

restoringrestoring normalnormal afterloadafterload or or effectiveeffectiveplasma volume plasma volume -- cardiaccardiac failurefailure can can occurroccurr

ElizaldeElizalde, J , J HepatolHepatol 19881988KelbaekKelbaek, , ClinClin PhysiolPhysiol 19871987LebrecLebrec, J , J HepatolHepatol 19961996

NHNH33

glutamineglutamine

ureaurea

GlutamateGlutamate glutamineglutamine

NHNH33

GlutamineGlutamine synthetasesynthetase

7%7%

50%50%

14%14%

AmmoniaAmmonia metabolismmetabolism

> 165%> 165%

CEREBRAL EFFECT OF AMMONIACEREBRAL EFFECT OF AMMONIA

NHNH33

AlzheimerAlzheimertypetype II II changeschanges in in

astrocytesastrocytes

↓↓ ATP productionATP productionalteredaltered mitochondrialmitochondrial functionfunction

↑↑ glutamineglutamine astrocyteastrocyte swellingswelling

neutralneutral AAAAAA

OssindolOssindol((neuroinhibitorsneuroinhibitors))

FalseFalseneurotransmittersneurotransmitters

↑↑ AAA AAA aromaticaromatictryptophantryptophan

NeurosteroidsNeurosteroids((GABArGABAr modulationmodulation))

EndogenousEndogenous ligandsligands

↑↑ BDZ BDZ receptorsreceptors

↑↑ MAOMAO--A A degradingdegrading serotoninserotonin

PrognosticPrognostic valuevalue of of hepatichepatic encephalopathyencephalopathy

•• earlyearly studiesstudies ((’’5050--8080’’): ): 1 1 yearyear survivalsurvival 20%20%--40%40%

3 3 yearyear survivalsurvival 15% 15%

((SaundersSaunders 1981, 1981, ChristensenChristensen 1989)1989)

survivalsurvival

1 1 yearyear 2 2 yearsyears 3 3 yearsyears 5 5 yearsyears

BustamanteBustamante 19991999 42%42% 23%23%

YoneimadaYoneimada 20042004 59%59% 48%48% 22%22%

PROGNOSIS HCC WITHOUT PROGNOSIS HCC WITHOUT TREATMENT TREATMENT ((LlovetLlovet 1999)1999)

54 cirrhotics with HCC not suitable for radical 54 cirrhotics with HCC not suitable for radical therapies with at least one of:therapies with at least one of:

PerformacePerformace status 1/2status 1/2Constitutional syndromeConstitutional syndromePortal thrombosisPortal thrombosisExtrahepaticExtrahepatic spreadspread

Median survival = 5.4 months Median survival = 5.4 months 1 year survival = 29%1 year survival = 29%

DISCRIMINATION ABILITY FOR DEATH AT 1, 3, AND 5 YEARS, DISCRIMINATION ABILITY FOR DEATH AT 1, 3, AND 5 YEARS, EVALUATED BY EVALUATED BY ROC CURVE AREAROC CURVE AREA, ,

OF OF OKUDA, CLIP AND BCLC SCORESOKUDA, CLIP AND BCLC SCORES

GriecoGrieco, , GutGut 20052005

1 1 yearyear 3 3 yearyear 5 5 yearyear

OKUDAOKUDA 0.7020.702 0.6840.684 0.6690.669

CLIPCLIP 0.7820.782 0.7300.730 0.7260.726

BCLCBCLC 0.8160.816 0.7790.779 0.7310.731

Radiofrequency Ablation for HCCRadiofrequency Ablation for HCC

Often needs general anaestheticOften needs general anaestheticFelt to be superior than alcohol for nodules > 3 cm diameterFelt to be superior than alcohol for nodules > 3 cm diameter2 randomized trials versus alcohol injection2 randomized trials versus alcohol injection

Livraghi 1999

Total necrosis complicationsPEI

RFA

(44)

(42)

80%

90%

0%

10%

Lencioni 2003 (Milan Criteria)

Survival

PEI (50)

RFA (52) 98%

88%82%

91%

26%

29%

( single nodule ≤≤ <3cm)

1y 2y

96%

100%

- -

- -

Cumulative Meta-analysis of TACE /TAERCT for HCC 2 year survival

PROGNOSTIC VALUE OF NUTRITION INPROGNOSTIC VALUE OF NUTRITION INPATIENTS WITH LIVER CIRRHOSISPATIENTS WITH LIVER CIRRHOSIS

-- ProteinProtein calorie calorie malnutritionmalnutrition assessedassessed withwith handhand--gripgrip

strength correlates with risk of developing strength correlates with risk of developing

complications (65% complications (65% vsvs 12%), but not with mortality 12%), but not with mortality

((AlvaresAlvares--dada--SilvaSilva 2005)2005)

-- Subjective global assessment adds independentlySubjective global assessment adds independently

to Childto Child--Pugh and MELD score Pugh and MELD score ((GunsarGunsar 2003)2003)

YEAR1

'01-'04'97-'00'93-'96'89-'92

% cir

rhotic

s adm

itted t

o ICU

100

90

80

70

60

50

40

30

20

10

0

OUTCOME

died

alive

54616582

46

3935

18

Year of admission

SOFA=12 SOFA=12 SOFA=11 SOFA=9Median:

P=0.005

18%

35%39%

46%

82% 65% 61% 54%

MORTALITY IN ITU ACCORDING TO ADMISSION MORTALITY IN ITU ACCORDING TO ADMISSION YEAR YEAR -- RFH EXPERIENCE RFH EXPERIENCE ((CholongitasCholongitas 2005)2005)

FOS

3 or more FOS2 FOS1 FOSno orga n fa iling

% cir

rhotic

s adm

itted t

o ICU

100

90

80

70

60

50

40

30

20

10

0

OUTCOME

died

alive

906545

10

35

55

96

P<0.001

Number of failing organ systems (FOS)

4%

96%45%

55%

35%

10%

65% 90%

70 patients

8 patients

MORTALITY IN ITU ACCORDING TO FAILING MORTALITY IN ITU ACCORDING TO FAILING ORGAN SYSTEMS ORGAN SYSTEMS ((CholongitasCholongitas 2005)2005)

PROGNOSTIC MODELS IN LIVER DISEASEPROGNOSTIC MODELS IN LIVER DISEASE

-- ChildChild--Pugh score (CPS)Pugh score (CPS)

-- Model End Stage Liver Disease (MELD)Model End Stage Liver Disease (MELD)

-- Disease specific scoresDisease specific scores

PBC scores (MAYO, ROYAL FREE, PBC scores (MAYO, ROYAL FREE, EuropeanEuropean))

HCC scores (CLIP, BLCG HCC scores (CLIP, BLCG etcetc))

competingcompeting riskrisk

Model for predicting survival in PBCModel for predicting survival in PBC(Christensen 1985)(Christensen 1985)

2.51 x log serum bilirubin (2.51 x log serum bilirubin (ìmol/lìmol/l))++ log e (age (years)log e (age (years)--20)/1020)/10++ 0.88 (if cirrhosis present)0.88 (if cirrhosis present)-- 0.05 x serum albumin (0.05 x serum albumin (g/lg/l))++ 0.68 (if central cholestasis)0.68 (if central cholestasis)++ 0.52 (if not treated with azathioprine)0.52 (if not treated with azathioprine)

Prediction of Survival in PBCPrediction of Survival in PBC

FLUID RETENTION IN PBC: The Goodness of Fit of Royal Free Ascites stage model(Chan 2005)

0.2

5.5

.75

1S

urvi

val p

roba

bilit

y

0 2 4 6 8Survival time

95% CI Survivor functionPredicted from model

Overall goodness of fit

(years)

Predicted from Royal Free Ascites stage model

Model Model toto predictpredict survivalsurvival in in patientspatientswithwith EndEnd--Stage Stage LiverLiver DiseaseDisease (MELD)(MELD)

KathmanKathman PS, PS, HepatologyHepatology 2001;33:4642001;33:464--470470

MortalityMortality 3 3 monthsmonths

MELDMELD ≤≤ 99 1010--1919 2020--2929 3030--3939 ≥≥4040

HospitalHospital 4%4% 27%27% 76%76% 85%85% 100%100%OutpatientsOutpatients nonnon--CC 2%2% 5.6%5.6% 50%50% -- --OutpatientsOutpatients PBCPBC 1%1% 13%13% 0%0% -- --Historical Historical groupgroup 8%8% 26%26% 56%56% 66%66% 100%100%

MELD/PELDMELD/PELD

MELD: (0.957 x MELD: (0.957 x lnln ((creatininecreatinine) + 0.378 x ) + 0.378 x lnln ((bilirubinbilirubin) ) +1.12 x +1.12 x lnln (INR) +0.643) x 10(INR) +0.643) x 10

Capped at 40Capped at 40

PELD: (0.436 x Age)PELD: (0.436 x Age)--(0.687 x log(albumin))+(0.480 x (0.687 x log(albumin))+(0.480 x log(bilirubinlog(bilirubin))+ (1.857 x log(INR))+(0.667 x growth ))+ (1.857 x log(INR))+(0.667 x growth failure) x 10failure) x 10

Age < 1 year = 1, Age >1year = 0Growth failure =1, no growth failure =0

MELD VS CP SCORE FOR ELECTIVE TIPSMELD VS CP SCORE FOR ELECTIVE TIPS

SchepheSchephe (2001)(2001) 162162 0.710.71/0.73/0.73 0.720.72/0.67/0.67 NS/NS/NSNS

Cejna (2002)Cejna (2002) 349 349 -- /0.78 /0.78 -- /0.67 /0.67 -- /NS/NS

Salerno (2002)Salerno (2002) 140140 0.840.84/0.78/0.78 0.700.70/0.67/0.67 0.038/NS0.038/NS

Angermayer (2003)Angermayer (2003) 475475 0.720.72/0.69/0.69 0.700.70/0.66/0.66 NS/NS/NSNS

FerralFerral (2004)(2004) 166166 0.760.76/0.66/0.66 0.780.78/0.66/0.66 NS/NS/NSNS

authorauthor ((yearyear) ) cohortcohort MELD CPS PMELD CPS P

3m and 12m 3m and 12m mortalitymortality –– area under ROC curve area under ROC curve -- c statistic c statistic --

MELD AND CP SCORES SURVIVAL OF CIRRHOTICS MELD AND CP SCORES SURVIVAL OF CIRRHOTICS ON WAITING LIST FOR LIVER TRANSPLANTATIONON WAITING LIST FOR LIVER TRANSPLANTATION

3m 3m survivalsurvival –– area under ROC curve area under ROC curve -- c statistic c statistic --

WeisnerWeisner (2003)(2003) 34733473 0.830.83 0.760.76 < 0.001< 0.001

Kim (2001)Kim (2001) 706706 0.850.85 0.720.72 < 0.001< 0.001

Abovassi (2001)Abovassi (2001) 140140 0.660.66 0.660.66 NSNS

LiadoLiado (2002)(2002) 7070 0.860.86 0.810.81 NSNS

HeumanHeuman (2003)(2003) 69586958 0.760.76 0.770.77 NSNS

authorauthor ((yearyear) ) cohortcohort MELD CPS PMELD CPS P

MELD AND CHRONIC LIVER DISEASE (MELD AND CHRONIC LIVER DISEASE (SaidSaid 2004)2004)

•• 1161 1 1161 1 yearyear survivalsurvival ((SaidSaid 2004)2004)

•• no no differencedifference withwith CPS CPS forfor: :

-- non non alcoholicalcoholic liverliver diseasedisease

-- compensatedcompensated cirrhosiscirrhosis

-- alcoholicalcoholic hepatitishepatitis

•• 129 (129 (BottaBotta 2003)2003)

-- no difference with CPSno difference with CPS

SUMMARYSUMMARY•• HBV/HCV HBV/HCV mostmost importantimportant causescauses worldwideworldwide

•• AlcoholAlcohol/NASH /NASH increasingincreasing rapidlyrapidly in the Westin the West

•• preventionprevention of of cirrhosiscirrhosis

-- antiviralsantivirals

-- identificationidentification haemochromatosishaemochromatosis

-- abstentionabstention

-- antifibroticantifibrotic drugsdrugs ? ?

-- preventsprevents HCCHCC

•• better “medical management”better “medical management”

-- antibiotics for antibiotics for varicealvariceal bleedingbleeding

-- renal failure renal failure –– glypressinglypressin and albuminand albumin

-- ITU careITU care

-- liver support devices ?liver support devices ?

SUMMARYSUMMARY

•• improvingimproving survivalsurvival in in cirrhoticscirrhotics

-- better management portal hypertensionbetter management portal hypertension

-- HCC still a problem (early diagnosis)HCC still a problem (early diagnosis)

•• better prognostic systemsbetter prognostic systems

-- identify timing for liver transplantationidentify timing for liver transplantation

-- ITU scores for ITU scores for cirrhoticscirrhotics

-- disease specific scores for long term therapydisease specific scores for long term therapy