Gastrolearning XIV lezione Indicazioni e controindicazioni al trapianto di fegato - Prof. M. Angelico (Università di Roma)

1. Mario Angelico

2. • 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 strategies
Prognostic models to assist organ allocation and ethics
Transplant benefit and MELD exceptions

3. The success of LiverThe success of Liver
Transplantation (LT) requires aTransplantation (LT) requires a
strong multisciplinary effortstrong multisciplinary effort
A synergistic collaboration between the
Transplant Hepatologist and the Transplant
Surgeon is mandatory !

4. The Liver Transplant UnitThe Liver Transplant Unit
TransplantTransplant
SurgeonsSurgeons
TransplantTransplant
SurgeonsSurgeons
Anesthesiologist
Intensivists
Anesthesiologist
Intensivists
Others...Others...Others...Others...
HistopathologistsHistopathologists
Interv. RadiologistsInterv. Radiologists
HistopathologistsHistopathologists
Interv. RadiologistsInterv. Radiologists
MicrobiologistsMicrobiologists
VirologistsVirologists
LaboratoryLaboratory
MicrobiologistsMicrobiologists
VirologistsVirologists
LaboratoryLaboratory
Nephrologists
Oncologists
Nephrologists
Oncologists
TransplantTransplant
HepatologistsHepatologists
TransplantTransplant
HepatologistsHepatologists

5. Who should be evaluated for liverWho should be evaluated for liver
transplantation ?transplantation ?
•LT should be consideredbe 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 cirrhosis
Complications of cirrhosis whose clinical significance is not
reflected in disease-severity scores*
Special conditions in the absence of chronic liver disease**

6. 100%
80%
60%
40%
20%
0
Years from diagnosis
After first episode ofAfter first episode of
decompensationdecompensation
Fattovich Gastroenterology 1997
Survival
probability
CompensatedCompensated
diseasedisease
Natural history of cirrhosisNatural history of cirrhosis
1 2 3 4 5 6 7 8 9 100
Deaths
Liver related (70%)
All causes (30%)

7. The worst complication of liverThe worst complication of liver
transplantationtransplantation
is................................................is................................................
....................................................................................................
....................................................................................................
....................................................................................................
.......is to die before liver.......is to die before liver
transplantationtransplantation
HenryHenry
BismuthBismuth

8. The worst complication of liverThe worst complication of liver
transplantationtransplantation
is................................................is................................................
....................................................................................................
....................................................................................................
....................................................................................................
.......is to die before liver.......is to die before liver
transplantationtransplantation
HenryHenry
BismuthBismuth

9. The sickest first principleThe sickest first principle
• Prima trapiantare il paziente più grave !Prima trapiantare il paziente più grave !
• Rischio di mortalitàRischio di mortalità dei pazienti in lista di attesa comedei pazienti in lista di attesa come
fattore principalefattore principale per l’attribuzione di priorità alper l’attribuzione di priorità al
trapiantotrapianto
• Il rischio di mortalità si calcola attraverso l’uso diIl rischio di mortalità si calcola attraverso l’uso di
scores prognostici validati:scores prognostici validati:
– Child Turcotte Pugh (Child Turcotte Pugh (CTP scoreCTP score))
– MELDMELD (Model for for End-stage Liver Disease)(Model for for End-stage Liver Disease)

10. Sopravvivenza ad uno e due anni sulla baseSopravvivenza 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
Sopravvivenza%

11. 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
INRINR
BilirubinaBilirubina
CreatininaCreatinina
Kim NEJM, 2008: MELD NaKim NEJM, 2008: MELD Na

12. 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

13. Key questions about MELD-basedKey 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

14. MELD is a clinical oversimplification and inMELD 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)

15. Indications for Liver Transplantation notIndications 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

16. Controversial indications LiverControversial indications Liver
TransplantationTransplantation
•Acute alcoholic hepatitis
•Coexisting HIV and hepatitis C
•Cholangiocarcinoma (highly selective protocols)
•Sickle-cell hepatopathy
•Metastatic disease (e.g. neuroendocrine)

17. Absolute contraindications to LiverAbsolute 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

19. The Evolution of LiverThe Evolution of Liver
Transplantation in EuropeTransplantation in Europe
EUROPEAN LIVER TRANSPLANT REGISTRYEUROPEAN LIVER TRANSPLANT REGISTRY
25 countries - 147 institutions
100,542 transplantations - 90,257 patients
From May 1968 to December 2010
www.eltr.org

20. 7 10 7 5 3 6 4 10 22 22 15 21 22 44 70 73
158
285
531
813
1255
1695
2117
2511
2759
2991
3333
3631
3761
4058
4352
4668
4950
5137
5356
5326
5660
5781
5861
61206139
5915
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 LiverEvolution 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
*

21. Patient Survival according to thePatient 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 22 44 7073
158
285
531
813
1255
1695
2117
2511
2759
2991
3333
3631
3761
4058
4352
4668
4950
5137
5356
5326
5660
5781
5861
6120
6139
5915
4941
68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 2000 2002 2004 2006 2008 2010

22. Patient and Graft SurvivalPatient and Graft Survival
following Liver Transplantationfollowing Liver Transplantation
05/1968 – 12/201005/1968 – 12/2010

23. * Others : Budd Chiari : 744 Benign liver tumors or Polycystic diseases : 1093
Parasitic diseases : 77 Other liver diseases : 1190
Primary Diseases leading to LiverPrimary Diseases leading to Liver
Transplantion in EuropeTransplantion in Europe
01/1988 - 12/201001/1988 - 12/2010

24. EUROPEAN LIVER TRANSPLANT REGISTRYEUROPEAN LIVER TRANSPLANT REGISTRY
25 countries - 147 institutions
100,542 transplantations - 90,257 patients
05/1968 - 12/2010
781
2281
4504
1192
839
18538
14080
14662
469
696
12324
11
2084
825
1553
1734
229163
17081
2294
1577
2492
16
36
12
66

25. Primary Diseases leading to Liver Transplantion by CountryPrimary Diseases leading to Liver Transplantion by Country
01/1988 - 12/201001/1988 - 12/2010

26. Primary Diseases leading to LiverPrimary Diseases leading to Liver
Transplantation in Adult RecipientsTransplantation in Adult Recipients
01/1988 - 12/201001/1988 - 12/2010

27. Evolution of Primary Diseases leadingEvolution of Primary Diseases leading
to Liver Transplantation in Europeto Liver Transplantation in Europe
05/1968 - 12/201005/1968 - 12/2010

28. Patient Survival according to thePatient Survival according to the
IndicationIndication
01/1988 - 12/201001/1988 - 12/2010

29. Liver Transplantation in EuropeLiver Transplantation in Europe
Indications of CirrhosisIndications of Cirrhosis
01/1988 - 12/201001/1988 - 12/2010

30. Evolution of Indications for CirrhosisEvolution of Indications for Cirrhosis
in Europein Europe

31. Survival of Patients with CirrhosisSurvival of Patients with Cirrhosis
as the First Indication (1)as the First Indication (1)
01/1988 - 12/201001/1988 - 12/2010

32. Primary Indications of Liver TransplantationPrimary Indications of Liver Transplantation
For Virus related Cirrhosis in EuropeFor Virus related Cirrhosis in Europe
01/1988 - 12/201001/1988 - 12/2010

33. Survival of Patients with Virus relatedSurvival of Patients with Virus related
Cirrhosis as the First IndicationCirrhosis as the First Indication
01/1988 - 12/201001/1988 - 12/2010

34. Liver Transplantation in EuropeLiver Transplantation in Europe
Indications in Hepato-Biliary CancersIndications in Hepato-Biliary Cancers
01/1988 - 12/201001/1988 - 12/2010

35. Evolution of Indications for Hepato-BiliaryEvolution of Indications for Hepato-Biliary
Cancers in EuropeCancers in Europe
05/1968 - 12/201005/1968 - 12/2010

36. Survival of Patients with Liver CancerSurvival of Patients with Liver Cancer
as the First Indicationas the First Indication
01/1988 - 12/201001/1988 - 12/2010

37. Primary Indications of Liver TransplantationPrimary Indications of Liver Transplantation
in Patients with Cholestatic Diseasesin Patients with Cholestatic Diseases
01/1988 - 12/201001/1988 - 12/2010

38. Survival of Patients with CholestaticSurvival of Patients with Cholestatic
Diseases as the First IndicationDiseases as the First Indication
01/1988 - 12/201001/1988 - 12/2010

39. Primary Indications of Liver TransplantationPrimary Indications of Liver Transplantation
In Patients with Acute Hepatic FailureIn Patients with Acute Hepatic Failure
01/1988 - 12/201001/1988 - 12/2010

40. Survival of Patients with AcuteSurvival of Patients with Acute
Hepatic Failure as the First IndicationHepatic Failure as the First Indication
01/1988 - 12/201001/1988 - 12/2010

41. Qualità del donatoreQualità del donatore Gravità del riceventeGravità del ricevente
DurataDurata
dell’ischemia freddadell’ischemia fredda
Difficoltà chirurgicaDifficoltà chirurgica
dell’interventodell’intervento
EsitoEsito
del trapiantodel trapianto
Organ allocationOrgan allocation

42. Key donor issuesKey donor issues
• Donor shortage
• Donor quality
Reduced size, HBiG positive
• Steatotic livers
Need for liver biopsy
• Donor age
• Donor Risk Index (DRI)

43. THE ALLOCATIONS OF LIVERS FORTHE 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

44. THE ALLOCATIONS OF LIVERS FORTHE 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

45. PERCENTAGE OF TITANIC SURVIVORS BY CLASSPERCENTAGE OF TITANIC SURVIVORS BY CLASS
www.titanic.com, 2002
%
%

46. PERCENTAGE OF LIFE-BOATS OCCUPANTS INPERCENTAGE OF LIFE-BOATS OCCUPANTS IN
TITANIC SHIPWRECKTITANIC SHIPWRECK
www.titanic.com, 2002
N.
N.

47. Type of Liver Graft in EuropeType of Liver Graft in Europe
according to the Date of Transplantationaccording to the Date of Transplantation

48. Graft Survival according to theGraft Survival according to the
Type of GraftType of Graft
01/1988 - 12/201001/1988 - 12/2010

49. Gender and Age distribution ofGender and Age distribution of
Liver DonorsLiver Donors
01/1988 - 12/201001/1988 - 12/2010
34.5%

50. Graft Survival according to Donor AgeGraft Survival according to Donor Age
in Elective Liver Transplantationin Elective Liver Transplantation
01/1988 – 12/201001/1988 – 12/2010

51. Impact of Donor Age on Graft Survival in LiverImpact of Donor Age on Graft Survival in Liver TransplantsTransplants
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

52. 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

53. Donor-recipientDonor-recipient
matchingmatching

54. D-MELD FOR OPTIMIZATION OF DONOR/RECIPIENTD-MELD FOR OPTIMIZATION OF DONOR/RECIPIENT
MATCHINGMATCHING
Halldorson et al. Am J Transpl, 2009

55. Balancing Donor and Recipient Risk Factors in LiverBalancing Donor and Recipient Risk Factors in Liver
Transplantation: The Value of D-MELDTransplantation: The Value of D-MELD
Avolio et al, Am J Transpl 2012

56. Avolio et al, Am J Transpl 2012
Predicting unsustainable 5-yearPredicting unsustainable 5-year
survival (survival (waistful outcomewaistful outcome))

57. Liver Transplantation in ItalyLiver Transplantation in Italy

58. Liste di Attesa al 28 Febbraio 2011*Liste di Attesa al 28 Febbraio 2011*
Tempo medio di attesaTempo medio di attesa
dei pazienti in listadei pazienti in lista
Tempo medio di attesaTempo medio di attesa
dei 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 combinazioniIncluse tutte le combinazioniIncluse tutte le combinazioniIncluse tutte le combinazioni
FONTE DATI: Sistema Informativo TrapiantiFONTE DATI: Sistema Informativo Trapianti
FegatoFegatoReneRene
*Dati al 20 Aprile 2011

59. Anno 2010: 21,7Anno 2010: 21,7 Anno 2011: 21,8Anno 2011: 21,8
FONTE DATI: Reports CIRDATI: Reports CIR
Donatori Procurati PMP - 2010 vs 2011Donatori Procurati PMP - 2010 vs 2011
* Dati preliminari al 30 Aprile 2011

60. FONTE DATI: Reports CIRDATI: Reports CIR
Opposizioni alla donazione: 2010 vs 2011Opposizioni alla donazione: 2010 vs 2011
* Dati preliminari al 30 Aprile 2011

61. 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

62. Trapianti di FEGATO – Anni 1992/2011Trapianti di FEGATO – Anni 1992/2011
Inclusi i trapianti combinatiInclusi i trapianti combinati
FONTE DATI: Reports CIRDATI: Reports CIR * Dati preliminari al 30 Aprile 2011
N=1530N=1530
LIVERLIVER
MATCHMATCH
recruitmentrecruitment

63. The Liver Match StudyThe Liver Match Study
Prospective 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 Board
CIBS, Tor Vergata Univ, Rome

64. Indicazioni al trapianto di fegato in ItaliaIndicazioni al trapianto di fegato in Italia
Dati Liver Match, su 1530 trapianti in adulti, 2007-2009
45,0
10,3
6,5
3,6
3,4
2,6
0,5
28,1
HCC
Etoh
CNT exceptions
Cholestatic
Criptogenic
FHF
Unfrequent indications*

65. Distribution of donor age
Liver Match cohort, Italy 2007-2009
Median age: 56 years
60 %

66. Curve di sopravvivenza per patologieCurve di sopravvivenza per patologie
nella coorte Liver Matchnella coorte Liver Match

67. Disease specific issuesDisease specific issues
in Liver Transplantationin Liver Transplantation

68. HBV-relatedHBV-related
Liver DiseaseLiver Disease

70. 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

71. Epatite colestaticaEpatite colestatica
fibrosantefibrosante
• Variante rapidamente progressivaVariante 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 soggettiOsservabile anche in soggetti
immunodepressi per altre causeimmunodepressi per altre cause
• Rigonfiamento epatocitiRigonfiamento epatociti
• Proliferazione duttulareProliferazione duttulare
all’interfacciaall’interfaccia
• Colangite acuta e fibrosiColangite acuta e fibrosi
periduttulareperiduttulare
• Iperplasia istiocitariaIperplasia istiocitaria
• Cirrosi assenteCirrosi assente

72. Optimal treatment of HBV infectionOptimal treatment of HBV infection
before liver transplantation isbefore liver transplantation is
essentialessential !!
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 regardlessTreat 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 !

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

74. ConclusionsConclusions
•91% patients underwent loss of HBsAg after 2 years91% patients underwent loss of HBsAg after 2 years
•98.8% achieved undetectable HBV DNA levels98.8% 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 forAn 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 HepatitisEntecavir Monotherapy Is Effective in Suppressing Hepatitis
B Virus AfterB Virus After Liver TransplantationLiver Transplantation
Fung et al. Gastroenterology 2011;141:1212–1219
•26% had undetectable HBV DNA+ at LTx
•No graft losses due to HBV recurrence !

75. HCV-related disease and liverHCV-related disease and liver
transplantationtransplantation

76. HCV kinetics during and after OLTHCV 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 hrs
Peak valuePeak value
at month 3-6at month 3-6
Steroids increase
HCV-RNA levels
100% reinfection !100% reinfection !

77. Incidence of cirrhosis afterIncidence of cirrhosis after
transplant in HCV positivetransplant in HCV positive
recipientsrecipients
Post-transplant
0%
10%
20%
30%
40%
50%
0 1 2 3 4 5
Years Posttransplant
%ofpatientswithCirrhosis
Berenguer,2002
Sanchez-Fueyo,2002
Prieto,1999
Gane,1996
Berlin,2004

78. Curve di sopravvivenza dell’organo in relazioneCurve di sopravvivenza dell’organo in relazione
all’età del donatore nei riceventi HCV negativiall’età del donatore nei riceventi HCV negativi
(sinistra) and HCV positivi (destra)(sinistra) and HCV positivi (destra)
Liver Match data-base, 2007-2009

79. Fibrosis progression after OLT in the Mayo cohortFibrosis progression after OLT in the Mayo cohort
of HCV+ patientsof HCV+ patients (1991-2000)(1991-2000)
Charlton, LT 9:535-7; 2003
Donor Age
p<0.0001p<0.0001
Fibrosisprogressionrate/yr
0.6/yr0.6/yr
2.7/yr2.7/yr

80. Graft survival is worse in HCV positive femaleGraft 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)

81. Multivariable analyses to evaluate the association betweenMultivariable analyses to evaluate the association between
donor–recipient gender mismatch and graft loss, stratified bydonor–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. Terrault
American Journal of Transplantation 2011; 11: 296–302

82. Black holes in HCV andBlack 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 transplantbefore transplant !
– CTP A, young, G 2 and 3, IL28b C/C, RVR
– The advent of DAA in this setting is eagerly awaited

83. 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

84. Alcoholic Liver DiseaseAlcoholic Liver Disease

85. ETHICAL ISSUES in LT for ALCOHOLICETHICAL 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

86. 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%

87. ETHICAL and PRACTICAL ISSUES in LT forETHICAL 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

88. The burden of HCCThe burden of HCC

89. 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 cm3 nodules < 3 cm
Advantage Removal of the diseased liver together with the tumor
Disadvantage Long waiting lists

90. Mazzaferro, New Engl J Med, 1996
Sopravvivenza dopo trapianto perSopravvivenza dopo trapianto per
HCC entro i “criteri di Milano”HCC entro i “criteri di Milano”
Non invasione vascolare o linfonodaleNon invasione vascolare o linfonodale
Nodulo singoloNodulo singolo ≤≤ 5 cm5 cm; oppure sino a; oppure sino a 3 noduli3 noduli ≤≤ 3 cm3 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 !

91. The rise of liver transplantations for HCC in the USThe rise of liver transplantations for HCC in the US
IntroductionIntroduction
of 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 allof 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 !

92. The evolution of the fast tracking conceptThe 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 centerto be decided by each center

94. Intention–to-treatIntention–to-treat
datadata

95. 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 ?

96. Increasing liver Tx for HCCIncreasing liver Tx for HCC
Liver Match cohort, June 2007 -May, 2009
Median MELD = 9 Median MELD = 17

97. Graft survival in recipients with HCC in relation to theirGraft 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 pos662 patients transplanted for HCC, of whom 290 HCV neg and 372 HCV pos
HCV -HCV - HCV +HCV +

98. Il trapianto di fegato per pazienti con tumoreIl 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 cm
Assenza di localizzazioni tumorali extraepatiche
Assenza di invasione vascolare

99. RESEZIONERESEZIONE TRAPIANTOTRAPIANTO ABLAZIONEABLAZIONE
BARCELONABARCELONA

100. Barcelona Clinic Liver Cancer (BCLC)Barcelona Clinic Liver Cancer (BCLC)
staging classificationstaging classification
Llovet JM et al. J Natl Cancer Inst 2008;100: 698 – 711
HCC
Stage 0Stage 0
PST 0, Child-Pugh APST 0, Child-Pugh A
Stage A-CStage A-C
PST 0-2, Child-Pugh A-BPST 0-2, Child-Pugh A-B
Stage DStage D
PST>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
Terminal
stage (D)
Very early stage (0)
Single < 2 cm
Carcinoma in situ
Single 3 nodules ≤ 3 cm
Portal
pressure/bilirubin
Normal No Yes
Associated
diseases
Increased
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

101. [Pomfret, Liver Transpl 2010]
Risk of drop-out from waiting list for candidatesRisk of drop-out from waiting list for candidates
within Milan Criteria at entrywithin Milan Criteria at entry

102. How many transplants were performedHow many transplants were performed
within Milan criteria in Italy ?within Milan criteria in Italy ?
TransplantTransplant
recipientrecipient
Median WaitingMedian Waiting
time (months)time (months)
Median MELD atMedian MELD at
transplantationtransplantation
HCC T1, n= 121HCC T1, n= 121 4.5 (0-79)4.5 (0-79) 13 (7-39)13 (7-39)
HCC T2, n= 413HCC T2, n= 413 4 (0-55)4 (0-55) 11 (6-40)11 (6-40)
HCC T3, n = 84HCC T3, n = 84 3 (0-35)3 (0-35) 12 (7-40)12 (7-40)

103. The “up-to-7” criteria could be a reasonable starting pointThe “up-to-7” criteria could be a reasonable starting point
for prospective clinical trials on expansion of Milan Criteriafor prospective clinical trials on expansion of 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.org
Predicting survival after liver transplantation in patients with HCCPredicting survival after liver transplantation in patients with HCC
beyond the Milan Criteria: a retrospective, exploratory analysisbeyond the Milan Criteria: a retrospective, exploratory analysis

104. Months
SurvivalProbability
0 12 24 36 48 60 72 84 96 108 120
0.00.20.40.60.81.0
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 (“up-to-7”)Proving the existence of a good outcome group (“up-to-7”)
outside the Conventional Milan Criteriaoutside the Conventional Milan Criteria
[Mazzaferro et al, Lancet Oncology 2009 ]
www.hcc-olt-metroticket.org
Predicting survival after liver transplantation in patients with HCC
beyond the Milan Criteria: a retrospective, exploratory analysis

105. Annal Surg. 2003; volume 238, Number 6,
The concept of Salvage OLTThe concept of Salvage OLT

106. Salvage OLTSalvage OLT
Il trapianto come scialuppa di salvataggioIl trapianto come scialuppa di salvataggio
Da utilizzare solo quando non sonoDa utilizzare solo quando non sono
possibili valide alternative di curapossibili valide alternative di cura

107. Allocation and prioritizationAllocation and prioritization
strategiesstrategies

108. PROGNOSTIC MODELS TO ASSIST ORGANPROGNOSTIC MODELS TO ASSIST ORGAN
ALLOCATION AND MEDICAL ETHICSALLOCATION 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

109. The concept ofThe concept of
transplant benefittransplant benefit

110. WHAT IS THE REAL GAIN AFTER LIVERWHAT IS THE REAL GAIN AFTER LIVER
TRANSPLANTATION?TRANSPLANTATION?
Neuberger J. Liver Transpl, 2009
Transplant benefit
Transplant benefit

111. Merion et al. Am J Transpl; 2005
Schaubel et al. Am J Transpl, 2009
SURVIVAL BENEFIT-BASED DECEASED DONORSURVIVAL BENEFIT-BASED DECEASED DONOR
LIVER ALLOCATIONLIVER ALLOCATION

112. 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 trapiantatiMortalità ad un anno dei pazienti trapiantati
rispetto alla mortalità dei candidati nonrispetto alla mortalità dei candidati non
trapiantati che rimangono in lista di attesatrapiantati che rimangono in lista di attesa
Zona di transizioneZona di transizione

113. Merion et al. Am J Transpl; 2005
• The survival benefit model has identified a minimuma minimum
value of MELD score (>15) justifying LTvalue of MELD score (>15) justifying LT
• High-MELD patients may have survival benefit even wheneven 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

115. Consensus Conference on Outcome Measures in
Liver Transplantation in Italy: Second Step
Gruppo di lavoro
Eccezioni al MELD
P. Burra, D. Pinna
Proposta Statements

116. 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 senzaEccezioni 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 conference
Eccezioni al MELDEccezioni al MELD
Palermo, 25maggio 2013Palermo, 25maggio 2013

117. GRUPPO A - ECCEZIONI AL MELD
A1. Condizioni con end point mortalita'
1.1 Ascite refrattaria e sindrome epato-renale
1.2 Encefalopatia epatica
1.3 Deficit nutrizionali
1.4 Rendu Osler
1.5 Malattie da accumulo
1.6 Sindrome epato-polmonare ed ipertensione porto-
polmonare
1.7 Ritrapianto
1.8 Epatite fulminante
1.9 Trapianto in HIV

118. GRUPPO A - ECCEZIONI AL MELD
A2. Condizioni con end point rischio di trasformazione
neoplastica e/o progressione della neoplasia
2.1 Emangioendoteliomi, emangiopericitomi,
emangiosarcomi
2.2 Tumori neuroendocrini, adenomatosi, carcinoma
fibrolamellare, epatoblastoma
2.3 Colangiocarcinoma
2.4 Metastasi da neoplasia colon-retto

119. GRUPPO A - ECCEZIONI AL MELD
A3. Condizioni con end point qualita' di vita
3.1 Fegato policistico
3.2 Prurito nelle malattie colestatiche

120. 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
646 635 652 794 709 744 712 702 728 723
256 227 250 252 283 265 296 312 345 352
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