Mario Angelico

• General indications and contraindications to LT and timing for listing

• Evolution of LT in Europe Recipients characteristics Donor issues

• Peculiarities of LT in Italy Insights from the liver Match Study

• Disease-specific issues in LT

• Allocation and prioritization strategiesPrognostic models to assist organ allocation and ethicsTransplant benefit and MELD exceptions

The success of Liver The success of Liver Transplantation (LT) requires a Transplantation (LT) requires a

strong multisciplinary effortstrong multisciplinary effort

A synergistic collaboration between the Transplant Hepatologist and the Transplant

Surgeon is mandatory !

The Liver Transplant UnitThe Liver Transplant Unit

Transplant Transplant SurgeonsSurgeons

Transplant Transplant SurgeonsSurgeons

AnesthesiologistIntensivists

AnesthesiologistIntensivists

Others...Others...Others...Others...

HistopathologistsHistopathologistsInterv. RadiologistsInterv. RadiologistsHistopathologistsHistopathologists

Interv. RadiologistsInterv. Radiologists

MicrobiologistsMicrobiologistsVirologistsVirologistsLaboratoryLaboratory

MicrobiologistsMicrobiologistsVirologistsVirologistsLaboratoryLaboratory

NephrologistsOncologists

NephrologistsOncologists

Transplant Transplant HepatologistsHepatologistsTransplant Transplant

HepatologistsHepatologists

Who should be evaluated for liver Who should be evaluated for liver transplantation ?transplantation ?

•LT should be considered be considered in all patients with ESLD aged < 65…… or………<70…. years

•The broad indications to LT are the following:Acute liver Failure (ALF)ESLD patients that can be assessed by disease-severity scores (e.g. MELD)HCC complicating cirrhosisComplications of cirrhosis whose clinical significance is not reflected in disease-severity scores*Special conditions in the absence of chronic liver disease**

100%

80%

60%

40%

20%

0

Years from diagnosis

After first episode ofAfter first episode ofdecompensationdecompensation

Fattovich Gastroenterology 1997

Survivalprobability

Compensated Compensated diseasedisease

Natural history of cirrhosisNatural history of cirrhosis

1 2 3 4 5 6 7 8 9 100

DeathsLiver related (70%)All causes (30%)

The worst complication of liver The worst complication of liver transplantation transplantation

is............................................is......................................................................................................................................................................................................................................................................................................................................

....................is to die before ....................is to die before liver transplantationliver transplantation

Henry BismuthHenry Bismuth

The worst complication of liver The worst complication of liver transplantation transplantation

is............................................is......................................................................................................................................................................................................................................................................................................................................

....................is to die before ....................is to die before liver transplantationliver transplantation

Henry BismuthHenry Bismuth

The sickest first principleThe sickest first principle • Prima trapiantare il paziente più grave ! Prima trapiantare il paziente più grave !

• Rischio di mortalità Rischio di mortalità dei pazienti in lista di attesa come dei pazienti in lista di attesa come fattore principale fattore principale per l’attribuzione di priorità al trapiantoper l’attribuzione di priorità al trapianto

• Il rischio di mortalità si calcola attraverso l’uso di scores Il rischio di mortalità si calcola attraverso l’uso di scores prognostici validati:prognostici validati:– Child Turcotte Pugh (Child Turcotte Pugh (CTP scoreCTP score))– MELD MELD (Model for for End-stage Liver Disease)(Model for for End-stage Liver Disease)

Sopravvivenza ad uno e due anni sulla base Sopravvivenza ad uno e due anni sulla base dello score CTP alla diagnosidello score CTP alla diagnosi di cirrosidi cirrosi

D’Amico et al, J Hepatol 2006; 44:217-231

Sopr

avvi

venz

a %

Model for End-Stage Liver Disease (MELD) Model for End-Stage Liver Disease (MELD) nell’allocazione degli organi donatinell’allocazione degli organi donati

Wiesner et al. Gastroenterology; 2003; 124:91-95

INRINRBilirubinaBilirubinaCreatininaCreatinina

Kim NEJM, 2008: MELD NaKim NEJM, 2008: MELD Na

The MELD score in patients awaiting liver transplant: The MELD score in patients awaiting liver transplant: strengths and weaknesses (UNOS data base)strengths and weaknesses (UNOS data base)

Bernardi et al. J Hep, 2011

Waiting time

Wait list mortality

Key questions about MELD-based Key questions about MELD-based organ allocationorgan allocation

• Did MELD allocation reduce waiting time and mortality before transplantation (in USA) ? YES

• Did MELD allocation result in sicker transplant candidates? YES

• Did MELD Allocation Complicate the Transplant Procedure? MODERATELY

• Did MELD Allocation Increase Postoperative Morbidity? SLIGHTLY

• Did MELD Allocation Lead to Poor Patient and Graft Survival? SLIGHTLY

• Did MELD Allocation Increase Cost? YES

MELD is a clinical oversimplification and in MELD is a clinical oversimplification and in addition has several limitationsaddition has several limitations

Variability of the laboratory determinations

• Direct bilirubin more accurate then total bilirubin. (Kamath Hepatology 2007)

• Accuracy of INR questionable.Coagulopathy in cirrhosis affects different sites of the coagulation(Kamath Hepatology 2007)

• INR affected by the use of anticoagulants (Heuman LT 2007)

• Different laboratory assays for creatinine may lead to inequities in the prioritization. (Cholongitas LT 2007)

• Female have a lower GFR than male, MELD modified by gender (Huo Transplantation 2007)

Indications for Liver Transplantation not Indications for Liver Transplantation not addressed by disease-severity scores (e.g. MELD)addressed by disease-severity scores (e.g. MELD)

*In association with cirrhosis*In association with cirrhosis•Diuretic resistant or intolerant ascites•Chronic hepatic encephalopathy•Intractable pruritus in association with cholestatic syndromes•Recurrent cholangitis•Hepatopulmonary syndrome•Portopulmonary hypertension•Cystic fibrosis

**Independent of chronic liver diseases**Independent of chronic liver diseases•Polycystic liver disease•Familial amyloid polyneuropathy•Epithelioid hemangioendothelioma•Giant Hemagiomatosis•Hereditary telangectasia•Range of metabolic/genetic diseases, e.g. primary oxaluria, familial hypercholesterolemia, glycogen storage disease, tyrosinemia, Wilson disease

Controversial indications Liver Controversial indications Liver TransplantationTransplantation

•Acute alcoholic hepatitis

•Coexisting HIV and hepatitis C

•Cholangiocarcinoma (highly selective protocols)

•Sickle-cell hepatopathy

•Metastatic disease (e.g. neuroendocrine)

Absolute contraindications to Liver Absolute contraindications to Liver TransplantationTransplantation

•Active extrahepatic malignancy•Hepatic malignancy with intravascular invasion or metastases•Active and uncontrolled infection outside of the hepatobiliary system•Severe cardiopulmonary or other comorbid conditions•Active substance or alcohol abuse•Some psyco-social factors•Technical or anatomical barriers •Brain death

The Evolution of Liver The Evolution of Liver Transplantation in EuropeTransplantation in Europe

EUROPEAN LIVER TRANSPLANT REGISTRYEUROPEAN LIVER TRANSPLANT REGISTRY

25 countries - 147 institutions100,542 transplantations - 90,257 patients

From May 1968 to December 2010

www.eltr.org

7 10 7 5 3 6 4 10 2222 15 21 2244 7073158

285531

813

1255

1695

2117

25112759

2991

3333

36313761

4058

4352

4668

49505137

53565326

5660

57815861

612061395915

4941

68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 2000 2002 2004 2006 2008 2010

Evolution of 100,542 Liver Evolution of 100,542 Liver Transplantations in EuropeTransplantations in Europe

* The decrease is owed to the fact that some centers had a delay in the updating of their data

*

Patient Survival according to the Patient Survival according to the Year of Liver TransplantationYear of Liver Transplantation

05/1968 – 12/201005/1968 – 12/2010

7 10 7 5 3 6 4 10 2222 15 21 2244 7073158

285531

813

1255

1695

2117

25112759

2991

3333

36313761

4058

4352

4668

49505137

53565326

5660

57815861

612061395915

4941

68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 2000 2002 2004 2006 2008 2010

Patient and Graft Survival Patient and Graft Survival following Liver Transplantationfollowing Liver Transplantation

05/1968 – 12/201005/1968 – 12/2010

* Others : Budd Chiari : 744 Benign liver tumors or Polycystic diseases : 1093Parasitic diseases : 77 Other liver diseases : 1190

Primary Diseases leading to Liver Primary Diseases leading to Liver Transplantion in EuropeTransplantion in Europe

01/1988 - 12/201001/1988 - 12/2010

EUROPEAN LIVER TRANSPLANT REGISTRYEUROPEAN LIVER TRANSPLANT REGISTRY25 countries - 147 institutions

100,542 transplantations - 90,257 patients05/1968 - 12/2010

781

2281

4504

1192

839

18538

14080

14662

469

696

12324

11

2084

825

1553

1734

229163

17081

2294

1577

2492

1636

12

66

Primary Diseases leading to Liver Transplantion by CountryPrimary Diseases leading to Liver Transplantion by Country

01/1988 - 12/201001/1988 - 12/2010

Primary Diseases leading to Liver Primary Diseases leading to Liver Transplantation in Adult RecipientsTransplantation in Adult Recipients

01/1988 - 12/201001/1988 - 12/2010

Evolution of Primary Diseases leading Evolution of Primary Diseases leading to Liver Transplantation in Europeto Liver Transplantation in Europe

05/1968 - 12/201005/1968 - 12/2010

Patient Survival according to the Patient Survival according to the IndicationIndication01/1988 - 12/201001/1988 - 12/2010

Liver Transplantation in EuropeLiver Transplantation in EuropeIndications of CirrhosisIndications of Cirrhosis

01/1988 - 12/201001/1988 - 12/2010

Evolution of Indications for CirrhosisEvolution of Indications for Cirrhosisin Europein Europe

Survival of Patients with CirrhosisSurvival of Patients with Cirrhosisas the First Indication (1)as the First Indication (1)

01/1988 - 12/201001/1988 - 12/2010

Primary Indications of Liver TransplantationPrimary Indications of Liver TransplantationFor Virus related Cirrhosis in EuropeFor Virus related Cirrhosis in Europe

01/1988 - 12/201001/1988 - 12/2010

Survival of Patients with Virus related Survival of Patients with Virus related Cirrhosis as the First Indication Cirrhosis as the First Indication

01/1988 - 12/201001/1988 - 12/2010

Liver Transplantation in EuropeLiver Transplantation in EuropeIndications in Hepato-Biliary CancersIndications in Hepato-Biliary Cancers

01/1988 - 12/201001/1988 - 12/2010

Evolution of Indications for Hepato-BiliaryEvolution of Indications for Hepato-BiliaryCancers in EuropeCancers in Europe

05/1968 - 12/201005/1968 - 12/2010

Survival of Patients with Liver CancerSurvival of Patients with Liver Canceras the First Indication as the First Indication

01/1988 - 12/201001/1988 - 12/2010

Primary Indications of Liver TransplantationPrimary Indications of Liver Transplantationin Patients with Cholestatic Diseasesin Patients with Cholestatic Diseases

01/1988 - 12/201001/1988 - 12/2010

Survival of Patients with Cholestatic Survival of Patients with Cholestatic Diseases as the First Indication Diseases as the First Indication

01/1988 - 12/201001/1988 - 12/2010

Primary Indications of Liver TransplantationPrimary Indications of Liver TransplantationIn Patients with Acute Hepatic FailureIn Patients with Acute Hepatic Failure

01/1988 - 12/201001/1988 - 12/2010

Survival of Patients with Acute Survival of Patients with Acute Hepatic Failure as the First Indication Hepatic Failure as the First Indication

01/1988 - 12/201001/1988 - 12/2010

Qualità del donatoreQualità del donatore Gravità del riceventeGravità del ricevente

DurataDurata dell’ischemia freddadell’ischemia fredda

Difficoltà chirurgicaDifficoltà chirurgicadell’interventodell’intervento

EsitoEsito del trapiantodel trapianto

Organ allocationOrgan allocation

Key donor issuesKey donor issues• Donor shortage

• Donor qualityReduced size, HBiG positive

• Steatotic liversNeed for liver biopsy

• Donor age

• Donor Risk Index (DRI)

THE ALLOCATIONS OF LIVERS FOR THE ALLOCATIONS OF LIVERS FOR TRANSPLANTATION:TRANSPLANTATION:

A PROBLEM OF TITANIC CONSIDERATION

April 1912: 2223 passengers and lifeboats capacity of 1178, 32% survivorsApril 1912: 2223 passengers and lifeboats capacity of 1178, 32% survivors

THE ALLOCATIONS OF LIVERS FOR THE ALLOCATIONS OF LIVERS FOR TRANSPLANTATION:TRANSPLANTATION:

A PROBLEM OF TITANIC CONSIDERATION

April 1912: 2223 passengers and lifeboats capacity of 1178, 32% survivorsApril 1912: 2223 passengers and lifeboats capacity of 1178, 32% survivors

December 2000: 16931 patients waiting liver, 1660 (10%) died waitingDecember 2000: 16931 patients waiting liver, 1660 (10%) died waiting

PERCENTAGE OF TITANIC SURVIVORS BY CLASS PERCENTAGE OF TITANIC SURVIVORS BY CLASS

www.titanic.com, 2002

%%

PERCENTAGE OF LIFE-BOATS OCCUPANTS IN PERCENTAGE OF LIFE-BOATS OCCUPANTS IN TITANIC SHIPWRECKTITANIC SHIPWRECK

www.titanic.com, 2002

N.N.

Type of Liver Graft in Europe Type of Liver Graft in Europe according to the Date of according to the Date of

TransplantationTransplantation

Graft Survival according to the Graft Survival according to the Type of GraftType of Graft

01/1988 - 12/201001/1988 - 12/2010

Gender and Age distribution of Gender and Age distribution of Liver DonorsLiver Donors

01/1988 - 12/201001/1988 - 12/2010

34.5%

Graft Survival according to Donor AgeGraft Survival according to Donor Agein Elective Liver Transplantationin Elective Liver Transplantation

01/1988 – 12/201001/1988 – 12/2010

Impact of Donor Age on Graft Survival in Liver Impact of Donor Age on Graft Survival in Liver Transplants Transplants for Hepatitis C-related and alcohol-related ESLDfor Hepatitis C-related and alcohol-related ESLD

Mutimer et al, Transplantation 81: 7-14; 2006

HCV: n= 4736

ALD: n= 5406

ALD

HCV

Retrospective analysis of

ELTR dataset

CHARACTERISTICS ASSOCIATED WITH LIVER GRAFT FAILURE: CHARACTERISTICS ASSOCIATED WITH LIVER GRAFT FAILURE: THE CONCEPT OF A DONOR RISK INDEX (DRI)THE CONCEPT OF A DONOR RISK INDEX (DRI)

Feng et al. Am J Transpl, 2006

Donor-recipient Donor-recipient matchingmatching

D-MELD FOR OPTIMIZATION OF DONOR/RECIPIENT D-MELD FOR OPTIMIZATION OF DONOR/RECIPIENT MATCHINGMATCHING

Halldorson et al. Am J Transpl, 2009

Balancing Donor and Recipient Risk Factors in Liver Balancing Donor and Recipient Risk Factors in Liver Transplantation: The Value of D-MELD Transplantation: The Value of D-MELD

Avolio et al, Am J Transpl 2012

Avolio et al, Am J Transpl 2012

Predicting unsustainable 5-year Predicting unsustainable 5-year survival (survival (waistful outcomewaistful outcome))

Liver Transplantation in ItalyLiver Transplantation in Italy

Liste di Attesa al 28 Febbraio 2011*Liste di Attesa al 28 Febbraio 2011*

Tempo medio di attesaTempo medio di attesadei pazienti in listadei pazienti in lista

Tempo medio di attesaTempo medio di attesadei pazienti in listadei pazienti in lista3,02 anni3,02 anni3,02 anni3,02 anni 2,13 anni2,13 anni2,13 anni2,13 anni

% mortalità in lista% mortalità in lista% mortalità in lista% mortalità in lista1,6 %1,6 %1,6 %1,6 % 6,9 %6,9 %6,9 %6,9 %

Incluse tutte le combinazioni Incluse tutte le combinazioni Incluse tutte le combinazioni Incluse tutte le combinazioni

FONTE DATI: Sistema Informativo TrapiantiFONTE DATI: Sistema Informativo Trapianti

FegatoFegatoRene Rene

*Dati al 20 Aprile 2011

Anno 2010: 21,7 Anno 2010: 21,7 Anno 2011: 21,8Anno 2011: 21,8

FONTE DATI: Reports CIR DATI: Reports CIR

Donatori Procurati PMP - 2010 vs 2011Donatori Procurati PMP - 2010 vs 2011

* Dati preliminari al 30 Aprile 2011

FONTE DATI: Reports CIR DATI: Reports CIR

Opposizioni alla donazione: 2010 vs 2011Opposizioni alla donazione: 2010 vs 2011

* Dati preliminari al 30 Aprile 2011

Liver Match Coordinating Group:Liver Match Coordinating Group:• M. Angelico (coordinator)M. Angelico (coordinator)• AISFAISF: U.Cillo, S.Fagiuoli, A.Gasbarrini, D.Prati, M.Strazzabosco: U.Cillo, S.Fagiuoli, A.Gasbarrini, D.Prati, M.Strazzabosco• CNTCNT: A. Nanni Costa, P. Burra: A. Nanni Costa, P. Burra

Partecipating Centers & investigatorsPartecipating Centers & investigators::• Torino (M. Salizzoni, R. Romagnoli, G. Bertolotti, D.Patrono)Torino (M. Salizzoni, R. Romagnoli, G. Bertolotti, D.Patrono)• Milano Niguarda (L. De Carlis, J.M.E. Mangoni)Milano Niguarda (L. De Carlis, J.M.E. Mangoni)• Milano Policlinico (L. Caccamo, B. Antonelli)Milano Policlinico (L. Caccamo, B. Antonelli)• Milano Tumori (V. Mazzaferro, E. Regalia, C. Sposito) Milano Tumori (V. Mazzaferro, E. Regalia, C. Sposito) • Bergamo (M. Colledan, V. Corno, F. Tagliabue, S. Marin)Bergamo (M. Colledan, V. Corno, F. Tagliabue, S. Marin)• Padova (U. Cillo, E. Gringeri)Padova (U. Cillo, E. Gringeri)• Verona (Donataccio, D. Donataccio)Verona (Donataccio, D. Donataccio)• Udine (F. Bresadola, D. Lorenzin) Udine (F. Bresadola, D. Lorenzin) • Genova (U. Valente, M. Gelli)Genova (U. Valente, M. Gelli)• Modena (G.E. Gerunda, G. Rompianesi) Modena (G.E. Gerunda, G. Rompianesi) • Bologna (A. Pinna, G.L. Grazi, A. Cucchetti)Bologna (A. Pinna, G.L. Grazi, A. Cucchetti)• Ancona (A. Risaliti, M. G. Faraci),Ancona (A. Risaliti, M. G. Faraci),• Roma Tor Vergata (G. Tisone, D. Sforza)Roma Tor Vergata (G. Tisone, D. Sforza)• Roma Gemelli (S. Agnes, M. Di Mugno) Roma Gemelli (S. Agnes, M. Di Mugno) • Roma POIT (G.M. Ettorre, L. Miglioresi)Roma POIT (G.M. Ettorre, L. Miglioresi)• Roma Sapienza (P.Berloco. M. Rossi, S. Ginanni, A. Molinaro)Roma Sapienza (P.Berloco. M. Rossi, S. Ginanni, A. Molinaro)• Napoli (F. Calise, V. Scuderi, O. Cuomo, G. Arenga) Napoli (F. Calise, V. Scuderi, O. Cuomo, G. Arenga) • Bari (L. Lupo, G. Notarnicola) Bari (L. Lupo, G. Notarnicola) • Palermo (B. Gridelli, S. Li Petri) Palermo (B. Gridelli, S. Li Petri) • CagliariCagliari (F. Zamboni, G. Carbotta, S. Dedola) (F. Zamboni, G. Carbotta, S. Dedola)

Data Collection and Verification & BiostatisticsData Collection and Verification & Biostatistics• T. Marianelli, A. Nardi, C. Gavrila, A. Ricci, F. VespasianoCNTCNT

Liver MatchLiver Match

Trapianti di FEGATO – Anni 1992/2011Trapianti di FEGATO – Anni 1992/2011Inclusi i trapianti combinatiInclusi i trapianti combinati

FONTE DATI: Reports CIR DATI: Reports CIR * Dati preliminari al 30 Aprile 2011

N=1530N=1530

LIVER LIVER MATCH MATCH

recruitmentrecruitment

The Liver Match StudyThe Liver Match StudyProspective enrollement of all consecutive LTx

Recruitment period: 1.6.2007-31.5.2009Recruitment period: 1.6.2007-31.5.2009

N= 1530 adult transplants. Median FU at 30.01.2012 1043 daysN= 1530 adult transplants. Median FU at 30.01.2012 1043 days

Data analysis performed by an independent Biostatical BoardCIBS, Tor Vergata Univ, Rome

Indicazioni al trapianto di fegato in ItaliaIndicazioni al trapianto di fegato in ItaliaDati Liver Match, su 1530 trapianti in adulti, 2007-2009

45,0

10,36,5

3,63,42,6

0,5

28,1

HCC

Etoh

CNT exceptions

Cholestatic

Criptogenic

FHF

Unfrequent indications*

Distribution of donor age Liver Match cohort, Italy 2007-2009

Median age: 56 years

60 %

Curve di sopravvivenza per patologie Curve di sopravvivenza per patologie nella coorte Liver Matchnella coorte Liver Match

Disease specific issues Disease specific issues in Liver Transplantationin Liver Transplantation

HBV-relatedHBV-related Liver Disease Liver Disease

Evolution of survival after liver transplantationEvolution of survival after liver transplantation for HBV-related liver diseasefor HBV-related liver disease

Kim et al, Liver Transplant 2004; 10: 968-974Kim et al, Liver Transplant 2004; 10: 968-974

Liver Match Cohort, Liver Match Cohort, Italy 2007-2009Italy 2007-2009

Epatite colestatica Epatite colestatica fibrosantefibrosante

• Variante rapidamente progressiva Variante rapidamente progressiva (insufficienza epatica) di infezione (insufficienza epatica) di infezione (neo- o recidiva) da virus B (e C(neo- o recidiva) da virus B (e C

• Osservabile anche in soggetti Osservabile anche in soggetti immunodepressi per altre causeimmunodepressi per altre cause

• Rigonfiamento epatocitiRigonfiamento epatociti• Proliferazione duttulare Proliferazione duttulare

all’interfacciaall’interfaccia• Colangite acuta e fibrosi Colangite acuta e fibrosi

periduttulareperiduttulare• Iperplasia istiocitariaIperplasia istiocitaria• Cirrosi assenteCirrosi assente

Optimal treatment of HBV infection Optimal treatment of HBV infection before liver transplantation is before liver transplantation is

essential essential !!

Keep HBV-DNA as low as possible !Keep HBV-DNA as low as possible !(less is more, none is better)(less is more, none is better)

Treat all wait-listed cirrhotics who have detectable HBV DNA regardless Treat all wait-listed cirrhotics who have detectable HBV DNA regardless of the level of viremia, with potent NUC with high genetic barrier !of the level of viremia, with potent NUC with high genetic barrier !

Importance of HBIg in the initial prophylaxisImportance of HBIg in the initial prophylaxis

ConclusionsConclusions•91% patients underwent loss of HBsAg after 2 years 91% patients underwent loss of HBsAg after 2 years •98.8% achieved undetectable HBV DNA levels 98.8% achieved undetectable HBV DNA levels n•22.5% were HBsAg positive at their last visit, 17 with udetectable HBV DNA22.5% were HBsAg positive at their last visit, 17 with udetectable HBV DNA•An HBIG-free regimen using ETV monotherapy is effective after liver transplantation for An HBIG-free regimen using ETV monotherapy is effective after liver transplantation for patients with hepatitis Bpatients with hepatitis B

Entecavir Monotherapy Is Effective in Suppressing Hepatitis Entecavir Monotherapy Is Effective in Suppressing Hepatitis B Virus After B Virus After Liver Transplantation Liver Transplantation

Fung et al. Gastroenterology 2011;141:1212–1219

•26% had undetectable HBV DNA+ at LTx

•No graft losses due to HBV recurrence !

HCV-related disease and liver HCV-related disease and liver transplantationtransplantation

HCV kinetics during and after OLT HCV kinetics during and after OLT Garcia Retortillo et al, Hepatology 2002; 35: 680-687

Hours after OLT Weeks after OLT

HCV-RNAHCV-RNA

>>2/3 log drop2/3 log drop

Doubling time = 13 hrsDoubling time = 13 hrsPeak valuePeak value

at month 3-6at month 3-6

Steroids increase HCV-RNA levels

100% reinfection !100% reinfection !

Incidence of cirrhosis after Incidence of cirrhosis after transplant in HCV positive transplant in HCV positive

recipientsrecipients

Post-transplant

0%

10%

20%

30%

40%

50%

0 1 2 3 4 5Years Posttransplant

% o

f pati

ents

with

Cirr

hosi

s Berenguer,2002

Sanchez-Fueyo,2002

Prieto,1999

Gane,1996

Berlin,2004

Curve di sopravvivenza dell’organo in relazione Curve di sopravvivenza dell’organo in relazione all’età del donatore nei riceventi HCV negativi all’età del donatore nei riceventi HCV negativi

(sinistra) and HCV positivi (destra) (sinistra) and HCV positivi (destra) Liver Match data-base, 2007-2009

Fibrosis progression after OLT in the Mayo cohort Fibrosis progression after OLT in the Mayo cohort of HCV+ patients of HCV+ patients (1991-2000)(1991-2000)

Charlton, LT 9:535-7; 2003

Donor Age

p<0.0001p<0.0001

Fib

ros

is p

rog

ress

ion

ra

te/y

r

0.6/yr0.6/yr

2.7/yr2.7/yr

Graft survival is worse in HCV positive female Graft survival is worse in HCV positive female recipients of a graft from a male donorrecipients of a graft from a male donor

Liver Match data-base, 2007-2009

Cox H.R: 2.13 (1.26-3.58)

Multivariable analyses to evaluate the association between Multivariable analyses to evaluate the association between donor–recipient gender mismatch and graft loss, stratified by donor–recipient gender mismatch and graft loss, stratified by

recipient HCV-statusrecipient HCV-status

Non-HCV (n= 18159) HCV (n= 9403)

HR (95% CI) p-Value HR (95% CI) p-Value

M→M match 1.00 (ref) 1.00 (ref)

F→F match 0.77 (0.69–0.85) <0.001 1.06 (0.93–1.21) 0.39

F→M mismatch 0.96 (0.88–1.05) 0.35 0.92 (0.83–1.03) 0.14

M→F mismatch 0.93 (0.85–1.02) 0.12 1.23 (1.10–1.38) <0.001

J. C. Lai, S. Feng, J. P. Roberts and N. A. TerraultAmerican Journal of Transplantation 2011; 11: 296–302

Black holes in HCV and Black holes in HCV and TransplantationTransplantation

• HCV+ recipients should ideally not receive grafts from elder donors

• If possible, all cirrhotic patients with favorable predictors who are candidates to transplantation should be treated with antivirals before transplant before transplant !– CTP A, young, G 2 and 3, IL28b C/C, RVR – The advent of DAA in this setting is eagerly awaited

A look to the near futureA look to the near future• 2nd generation DAAs should enter the transplant

arena as soon as possible !!!! – The safety of current and new DAAs should be tested in

decompensated cirrhotic patients to be listed for LT– Patients should ideally be transplanted with undetectable

viremia– IFN-free regimens are eagerly awaited in this setting !

• Availability of new DAAs will likely result into dramatic favorable changes:

– in reducing the number of transplant candidates– in the preparation of patients to be transplanted– in the treatment of recurrent disease

Alcoholic Liver DiseaseAlcoholic Liver Disease

ETHICAL ISSUES in LT for ALCOHOLIC ETHICAL ISSUES in LT for ALCOHOLIC CIRRHOSISCIRRHOSIS

• Self-inflicted disease

• Controversial views of the public

• Difficult to predict the rate of recidivism

• Risk of poor compliance

SHORTAGE OF DONOR ORGANS

Platz KP, Transpl Int 2000;13:S127-S130

““THE 6 MONTH RULE” (pro)THE 6 MONTH RULE” (pro)

Duration of abstinence prior to transplantation

Incidence of recurrence of alcoholic liver disease

Severe recurrence of alcoholic liver disease

<6 months 66.4% 84.7%

6-12 months 14.3% 60%

1-2 years 13.9% 40%

>2 years 5.6% 100%

ETHICAL and PRACTICAL ISSUES in LT for ETHICAL and PRACTICAL ISSUES in LT for ALCOHOLIC CIRRHOSISALCOHOLIC CIRRHOSIS

• The 6-month abstinence rule:

– Permits some patients to recover from their liver disease and obviate the need of LT

– Identifies subsets of patients likely to maintain abstinence after LT

• However, the utility of the 6-month rule as a predictor of long-term sobriety are controversial

• A role for early LT in the treatment of severe alcoholic hepatitis not responding to medical therapy ? A controversial issue

SHORTAGE OF DONOR ORGANS

The burden of HCCThe burden of HCC

Liver Transplantation fo HCCLiver Transplantation fo HCC

Illustration Copyright © 2007 Nucleus Medical Art,All rights reserved. www.nucleusinc.com.

5-year survival 70% 5-year survival 70% Recurrence rate < 15%Recurrence rate < 15%

Bruix J, Sherman M. Hepatology 2005; 42: 1208-1236; Llovet JM. J Gastroenterol 2005; 40: 225-235;Mazzaferro V et al. N Engl J Med 1996; 334: 693-699

Optimal candidates:Optimal candidates:

• BCLC Stage A diseaseBCLC Stage A disease

• No vascular invasionNo vascular invasion

• No metastasesNo metastases

• Fulfill the Milan criteriaFulfill the Milan criteria

– Solitary tumor < 5 cm orSolitary tumor < 5 cm or

– ≤≤ 3 nodules < 3 cm 3 nodules < 3 cm

Advantage Removal of the diseased liver together with the tumor

Disadvantage Long waiting lists

Mazzaferro, New Engl J Med, 1996

Sopravvivenza dopo trapianto per Sopravvivenza dopo trapianto per HCC entro i “criteri di Milano”HCC entro i “criteri di Milano”

Non invasione vascolare o linfonodaleNon invasione vascolare o linfonodaleNodulo singolo Nodulo singolo 5 cm 5 cm; oppure sino a; oppure sino a 3 noduli 3 noduli 3 cm 3 cm..

75%83%

Necessità di attribuzione di punti MELD aggiuntivi Per i pazienti con HCC T2 ! Necessità di attribuzione di punti MELD aggiuntivi Per i pazienti con HCC T2 !

The rise of liver transplantations for HCC in the USThe rise of liver transplantations for HCC in the US

IntroductionIntroductionof MELD with extraof MELD with extra

points for HCCpoints for HCC

Thuluvath et al Liver Transpl 2009; 15:754-762

8.8%8.8%of all LTof all LT

21.7%21.7%of all of all LTLT

27% of T1 and 45% of T2 received LT within 30 days !27% of T1 and 45% of T2 received LT within 30 days !

The evolution of the fast tracking concept The evolution of the fast tracking concept for liver transplantation in HCCfor liver transplantation in HCC

• 2002, USA2002, USA– HCC T2: 29 MELD points– HCC T1: 24 MELD points

• 2005, USA2005, USA

– HCC T2: 24 MELD points, then 22 MELD points– HCC T1: no additional points

• Italy, CNT recommendationsItaly, CNT recommendations– 2007: HCC T2: 22 MELD points – 2010: HCC T2: extra points to be decided by each center to be decided by each center

Intention–to-treatIntention–to-treatdatadata

Changing indications for Liver Transplantation in ItalyChanging indications for Liver Transplantation in Italy

59.5%59.5%

18%18% 45%45%

Too many transplants performed for HCC ?Too many transplants performed for HCC ?

Which priority should be given to HCC to respect equity and justice ?Which priority should be given to HCC to respect equity and justice ?

Increasing liver Tx for HCCIncreasing liver Tx for HCCLiver Match cohort, June 2007 -May, 2009

Median MELD = 9 Median MELD = 17

Graft survival in recipients with HCC in relation to their Graft survival in recipients with HCC in relation to their Age and HCV statusAge and HCV status

Liver Match cohort study, Italy, June 2007-May 2009

662 patients transplanted for HCC, of whom 290 HCV neg and 372 HCV pos 662 patients transplanted for HCC, of whom 290 HCV neg and 372 HCV pos

HCV -HCV - HCV +HCV +

Il trapianto di fegato per pazienti con tumore Il trapianto di fegato per pazienti con tumore primitivo del fegato (HCC)primitivo del fegato (HCC)

Freeman et al. AJT 2006

n=9379n=9379

n=2057n=2057

Necessità di attribuzione di punti MELD aggiuntivi ai pazienti con HCC T2 !

Criteri di trapiantabilità per HCC (criteri di Milano) (T2)Nodulo singolo < 5 cm di diametro oppure , sino a 3 noduli ciascuno non superiore a 3 cmAssenza di localizzazioni tumorali extraepaticheAssenza di invasione vascolare

RESEZIONERESEZIONE TRAPIANTOTRAPIANTO ABLAZIONEABLAZIONE

BARCELONABARCELONA

Barcelona Clinic Liver Cancer (BCLC) Barcelona Clinic Liver Cancer (BCLC) staging classification staging classification

Llovet JM et al. J Natl Cancer Inst 2008;100: 698 – 711

HCC

Stage 0Stage 0PST 0, Child-Pugh APST 0, Child-Pugh A

Stage A-CStage A-CPST 0-2, Child-Pugh A-BPST 0-2, Child-Pugh A-B

Stage DStage DPST>2, Child-Pugh CPST>2, Child-Pugh C

Early stage (A)Single <5 cm or 3

nodules< 3 cm, PS 0

Intermediate stage (B)Multinodular, PS 0

Advanced stage (C)Portal invasion,N1, M1, PS 1-2

Terminalstage (D)

Very early stage (0)Single < 2 cm

Carcinoma in situ

Single 3 nodules 3 cm

Portalpressure/bilirubin

Normal No Yes

AssociateddiseasesIncreased

Resection Liver TransplantationLiver Transplantation(CLT/LDLT)(CLT/LDLT) PEI/RF Chemoembolization Medical treatment

(sorafenib)

Curative Treatments (30%)5-yr survival: 50-70%

Randomized controlled trials (50%)3 yr survival: 20-40%

Symptomatic ttc (20%)1 yr survival: 10-20%

ttc: treatment

[Pomfret, Liver Transpl 2010]

Risk of drop-out from waiting list for candidates Risk of drop-out from waiting list for candidates within Milan Criteria at entrywithin Milan Criteria at entry

How many transplants were performed How many transplants were performed within Milan criteria in Italy ?within Milan criteria in Italy ?

Transplant Transplant recipientrecipient

Median Median Waiting time Waiting time

(months)(months)

Median MELD Median MELD at at

transplantationtransplantation

HCC T1, n= HCC T1, n= 121121

4.5 (0-79)4.5 (0-79) 13 (7-39)13 (7-39)

HCC T2, n= HCC T2, n= 413413

4 (0-55)4 (0-55) 11 (6-40)11 (6-40)

HCC T3, n = HCC T3, n = 8484

3 (0-35)3 (0-35) 12 (7-40)12 (7-40)

The “up-to-7” criteria could be a reasonable The “up-to-7” criteria could be a reasonable starting pointstarting point

for prospective clinical trials on expansion of for prospective clinical trials on expansion of Milan Criteria Milan Criteria

The “up-to-7 Criteria”The “up-to-7 Criteria”

mVI absent

[Mazzaferro et al, Lancet Oncology 2009]

www.hcc-olt-metroticket.orgwww.hcc-olt-metroticket.orgPredicting survival after liver transplantation in Predicting survival after liver transplantation in patients with HCC beyond the Milan Criteria: a patients with HCC beyond the Milan Criteria: a retrospective, exploratory analysisretrospective, exploratory analysis

Months

Sur

viva

l Pro

babi

lity

0 12 24 36 48 60 72 84 96 108 120

0.0

0.2

0.4

0.6

0.8

1.0

73%

71%

48%

70%58%

33%

Exceeding “Up-to-7” criteria (N=829)

Beyond Milan – “Up-to-7” criteria (N=283)

Milano IN (N=444)

Median follow-up: 53 months

Proving the existence of a good outcome group Proving the existence of a good outcome group (“up-to-7”)(“up-to-7”)

outside the Conventional Milan Criteriaoutside the Conventional Milan Criteria

[Mazzaferro et al, Lancet Oncology 2009 ]

www.hcc-olt-metroticket.orgPredicting survival after liver transplantation in patients with HCC beyond the Milan Criteria: a retrospective, exploratory analysis

Annal Surg. 2003; volume 238, Number 6,

The concept of Salvage The concept of Salvage OLTOLT

Salvage OLTSalvage OLT

Il trapianto come scialuppa di salvataggioIl trapianto come scialuppa di salvataggio

Da utilizzare solo quando non Da utilizzare solo quando non sono possibili valide alternative sono possibili valide alternative

di curadi cura

Allocation and prioritization Allocation and prioritization strategiesstrategies

PROGNOSTIC MODELS TO ASSIST ORGAN PROGNOSTIC MODELS TO ASSIST ORGAN ALLOCATION AND MEDICAL ETHICS ALLOCATION AND MEDICAL ETHICS

• EQUITY: the need to equitably distribute the available therapeutic resources

• INDIVIDUAL JUSTICE: the duty to promote the best interest of individual patients

• Medical urgency

• UTILITY: the duty to strive to obtain the best results for the correct population therapeutic use of the resource

• Post transplant outcomes: maximize graft and patient survival

The concept of The concept of transplant benefittransplant benefit

WHAT IS THE REAL GAIN AFTER LIVER WHAT IS THE REAL GAIN AFTER LIVER TRANSPLANTATION?TRANSPLANTATION?

Neuberger J. Liver Transpl, 2009

Transplant benefit

Transplant benefit

Merion et al. Am J Transpl; 2005Schaubel et al. Am J Transpl, 2009

SURVIVAL BENEFIT-BASED DECEASED DONOR SURVIVAL BENEFIT-BASED DECEASED DONOR LIVER ALLOCATIONLIVER ALLOCATION

Il survival benefit del trapianto di fegatoIl survival benefit del trapianto di fegato Merion et al. Am J Transplantation 2005; 5:307-313

Mortalità ad un anno dei pazienti trapiantati Mortalità ad un anno dei pazienti trapiantati rispetto alla mortalità dei candidati non rispetto alla mortalità dei candidati non

trapiantati che rimangono in lista di attesatrapiantati che rimangono in lista di attesa

Zona di transizioneZona di transizione

Merion et al. Am J Transpl; 2005

• The survival benefit model has identified a minimum a minimum value of MELD score (>15) justifying LTvalue of MELD score (>15) justifying LT

• High-MELD patients may have survival benefit even when even when they received a high DRI organ !they received a high DRI organ !

• Low-MELD patients have limited or even no survival benefit when transplanted with a high DRI organ.

• Thus the current informal practice of inverse matching of recipient MELD score and liver DRI should be discouraged

• The overall validity and practical applicability of the transplant benefit model must be confirmed prospectively

Consensus Conference on Outcome Measures in Liver Transplantation in Italy: Second Step

Gruppo di lavoro Eccezioni al MELDP. Burra, D. Pinna

Proposta Statements

Gruppo di lavoro Eccezioni al MELDP. Burra, D. Pinna

Proposta Statements

Eccezioni con proposta di prioritizzazione:Eccezioni con proposta di prioritizzazione:

•Emangioma (Kasabach-Merritt syndrome)•Rendu Osler•Amiloidosi•Epatoblastoma•Re-trapianto tardivo•Idrotorace refrattario•Emangioendotelioma•Infezioni ricorrenti•Sindrome epato-polmonare•Ipertensione porto-polmonare•SER tipo I responsiva a tratt. •SER tipo I o II non responsive a tratt. •Ascite refrattaria•M. di Wilson•Tumori neuroendocrini•Adenomiomatosi •Fegato policistico isolato•Prurito

Eccezioni senza Eccezioni senza prioritizzazione:prioritizzazione:

•Malnutrizione•Encefalopatia epatica ricorrente•Emocromatosi•Deficit di α1 antitripsina•HIV•HCC fibrolamellare•Colangiocarcinoma •Metastasi di carcinoma del colon-retto

AISF/SITO Consensus conferenceAISF/SITO Consensus conferenceEccezioni al MELDEccezioni al MELD

Palermo, 25maggio 2013Palermo, 25maggio 2013

GRUPPO A - ECCEZIONI AL MELD

A1. Condizioni con end point mortalita' 1.1 Ascite refrattaria e sindrome epato-renale1.2 Encefalopatia epatica1.3 Deficit nutrizionali 1.4 Rendu Osler1.5 Malattie da accumulo1.6 Sindrome epato-polmonare ed ipertensione porto-

polmonare1.7 Ritrapianto1.8 Epatite fulminante1.9 Trapianto in HIV

GRUPPO A - ECCEZIONI AL MELD

A2. Condizioni con end point rischio di trasformazione neoplastica e/o progressione della neoplasia

2.1 Emangioendoteliomi, emangiopericitomi, emangiosarcomi2.2 Tumori neuroendocrini, adenomatosi, carcinoma fibrolamellare, epatoblastoma2.3 Colangiocarcinoma2.4 Metastasi da neoplasia colon-retto

GRUPPO A - ECCEZIONI AL MELD

A3. Condizioni con end point qualita' di vita

3.1 Fegato policistico

3.2 Prurito nelle malattie colestatiche

6813 6842 6364 6264 6220 6512 6742 6808 7021 6961

1218 1276 1371 1522 1590 1399 1423 1447 1314 1234

Rene

Fegato

Lista di attesa standard

646 635 652 794 709 744 712 702 728 723256 227 250 252 283 265 296 312 345 352

230 194 195 174 212 227 216 226 260 252

Cuore

Polmone

Pancreas

Pazienti iscritti in lista

*Dati al 20 Aprile 2011

• L’unica terapia risolutiva nelle ESLD e nella FHF

• Una terapia con rischi non trascurabili, da riservare solo a chi ne può avere un beneficio

• Una risorsa preziosa, ma limitata e costosa, da utilizzare con equità e trasparenza

• Richiede una totale sinergia tra epatologo e chirurgo dei trapianti