aetiology, pathology, epidemiology and outcome · 2014. 1. 22. · tips for portal vein thrombosis...
TRANSCRIPT
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