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Indicazioni e controindicazioni al trapianto di fegato - Prof. M. Angelico

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

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Indicazioni e controindicazioni al trapianto di fegato - Prof. M. Angelico

  1. 1. Mario Angelico
  2. 2. • General indications and contraindications to LTand 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. 3. The success of LiverThe success of LiverTransplantation (LT) requires aTransplantation (LT) requires astrong multisciplinary effortstrong multisciplinary effortA synergistic collaboration between theTransplant Hepatologist and the TransplantSurgeon is mandatory !
  4. 4. The Liver Transplant UnitThe Liver Transplant UnitTransplantTransplantSurgeonsSurgeonsTransplantTransplantSurgeonsSurgeonsAnesthesiologistIntensivistsAnesthesiologistIntensivistsOthers...Others...Others...Others...HistopathologistsHistopathologistsInterv. RadiologistsInterv. RadiologistsHistopathologistsHistopathologistsInterv. RadiologistsInterv. RadiologistsMicrobiologistsMicrobiologistsVirologistsVirologistsLaboratoryLaboratoryMicrobiologistsMicrobiologistsVirologistsVirologistsLaboratoryLaboratoryNephrologistsOncologistsNephrologistsOncologistsTransplantTransplantHepatologistsHepatologistsTransplantTransplantHepatologistsHepatologists
  5. 5. Who should be evaluated for liverWho should be evaluated for livertransplantation ?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 notreflected in disease-severity scores*Special conditions in the absence of chronic liver disease**
  6. 6. 100%80%60%40%20%0Years from diagnosisAfter first episode ofAfter first episode ofdecompensationdecompensationFattovich Gastroenterology 1997SurvivalprobabilityCompensatedCompensateddiseasediseaseNatural history of cirrhosisNatural history of cirrhosis1 2 3 4 5 6 7 8 9 100DeathsLiver related (70%)All causes (30%)
  7. 7. The worst complication of liverThe worst complication of livertransplantationtransplantationis................................................is...................................................................................................................................................................................................................................................................................................................................................................is to die before liver.......is to die before livertransplantationtransplantationHenryHenryBismuthBismuth
  8. 8. The worst complication of liverThe worst complication of livertransplantationtransplantationis................................................is...................................................................................................................................................................................................................................................................................................................................................................is to die before liver.......is to die before livertransplantationtransplantationHenryHenryBismuthBismuth
  9. 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 comefattore principalefattore principale per l’attribuzione di priorità alper l’attribuzione di priorità altrapiantotrapianto• Il rischio di mortalità si calcola attraverso l’uso diIl rischio di mortalità si calcola attraverso l’uso discores 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. 10. Sopravvivenza ad uno e due anni sulla baseSopravvivenza ad uno e due anni sulla basedello score CTP alla diagnosidello score CTP alla diagnosi di cirrosidi cirrosiD’Amico et al, J Hepatol 2006; 44:217-231Sopravvivenza%
  11. 11. Model for End-Stage Liver Disease (MELD)Model for End-Stage Liver Disease (MELD)nell’allocazione degli organi donatinell’allocazione degli organi donatiWiesner et al. Gastroenterology; 2003; 124:91-95INRINRBilirubinaBilirubinaCreatininaCreatininaKim NEJM, 2008: MELD NaKim NEJM, 2008: MELD Na
  12. 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, 2011Waiting timeWait list mortality
  13. 13. Key questions about MELD-basedKey questions about MELD-basedorgan allocationorgan allocation• Did MELD allocation reduce waiting time and mortalitybefore 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 GraftSurvival? SLIGHTLY• Did MELD Allocation Increase Cost? YES
  14. 14. MELD is a clinical oversimplification and inMELD is a clinical oversimplification and inaddition has several limitationsaddition has several limitationsVariability 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 theprioritization. (Cholongitas LT 2007)• Female have a lower GFR than male, MELD modified by gender(Huo Transplantation 2007)
  15. 15. Indications for Liver Transplantation notIndications for Liver Transplantation notaddressed 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, familialhypercholesterolemia, glycogen storage disease, tyrosinemia, Wilson disease
  16. 16. Controversial indications LiverControversial indications LiverTransplantationTransplantation•Acute alcoholic hepatitis•Coexisting HIV and hepatitis C•Cholangiocarcinoma (highly selective protocols)•Sickle-cell hepatopathy•Metastatic disease (e.g. neuroendocrine)
  17. 17. Absolute contraindications to LiverAbsolute contraindications to LiverTransplantationTransplantation•Active extrahepatic malignancy•Hepatic malignancy with intravascular invasion ormetastases•Active and uncontrolled infection outside of thehepatobiliary system•Severe cardiopulmonary or other comorbid conditions•Active substance or alcohol abuse•Some psyco-social factors•Technical or anatomical barriers•Brain death
  18. 18. The Evolution of LiverThe Evolution of LiverTransplantation in EuropeTransplantation in EuropeEUROPEAN LIVER TRANSPLANT REGISTRYEUROPEAN LIVER TRANSPLANT REGISTRY25 countries - 147 institutions100,542 transplantations - 90,257 patientsFrom May 1968 to December 2010www.eltr.org
  19. 19. 7 10 7 5 3 6 4 10 22 22 15 21 22 44 70 731582855318131255169521172511275929913333363137614058435246684950513753565326566057815861612061395915494168 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 2000 2002 2004 2006 2008 2010Evolution of 100,542 LiverEvolution of 100,542 LiverTransplantations in EuropeTransplantations in Europe* The decrease is owed to the fact that some centershad a delay in the updating of their data*
  20. 20. Patient Survival according to thePatient Survival according to theYear of Liver TransplantationYear of Liver Transplantation05/1968 – 12/201005/1968 – 12/20107 10 7 5 3 6 4 10 2222 15 21 22 44 70731582855318131255169521172511275929913333363137614058435246684950513753565326566057815861612061395915494168 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 2000 2002 2004 2006 2008 2010
  21. 21. Patient and Graft SurvivalPatient and Graft Survivalfollowing Liver Transplantationfollowing Liver Transplantation05/1968 – 12/201005/1968 – 12/2010
  22. 22. * Others : Budd Chiari : 744 Benign liver tumors or Polycystic diseases : 1093Parasitic diseases : 77 Other liver diseases : 1190Primary Diseases leading to LiverPrimary Diseases leading to LiverTransplantion in EuropeTransplantion in Europe01/1988 - 12/201001/1988 - 12/2010
  23. 23. EUROPEAN LIVER TRANSPLANT REGISTRYEUROPEAN LIVER TRANSPLANT REGISTRY25 countries - 147 institutions100,542 transplantations - 90,257 patients05/1968 - 12/201078122814504119283918538140801466246969612324112084825155317342291631708122941577249216361266
  24. 24. Primary Diseases leading to Liver Transplantion by CountryPrimary Diseases leading to Liver Transplantion by Country01/1988 - 12/201001/1988 - 12/2010
  25. 25. Primary Diseases leading to LiverPrimary Diseases leading to LiverTransplantation in Adult RecipientsTransplantation in Adult Recipients01/1988 - 12/201001/1988 - 12/2010
  26. 26. Evolution of Primary Diseases leadingEvolution of Primary Diseases leadingto Liver Transplantation in Europeto Liver Transplantation in Europe05/1968 - 12/201005/1968 - 12/2010
  27. 27. Patient Survival according to thePatient Survival according to theIndicationIndication01/1988 - 12/201001/1988 - 12/2010
  28. 28. Liver Transplantation in EuropeLiver Transplantation in EuropeIndications of CirrhosisIndications of Cirrhosis01/1988 - 12/201001/1988 - 12/2010
  29. 29. Evolution of Indications for CirrhosisEvolution of Indications for Cirrhosisin Europein Europe
  30. 30. 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
  31. 31. Primary Indications of Liver TransplantationPrimary Indications of Liver TransplantationFor Virus related Cirrhosis in EuropeFor Virus related Cirrhosis in Europe01/1988 - 12/201001/1988 - 12/2010
  32. 32. Survival of Patients with Virus relatedSurvival of Patients with Virus relatedCirrhosis as the First IndicationCirrhosis as the First Indication01/1988 - 12/201001/1988 - 12/2010
  33. 33. Liver Transplantation in EuropeLiver Transplantation in EuropeIndications in Hepato-Biliary CancersIndications in Hepato-Biliary Cancers01/1988 - 12/201001/1988 - 12/2010
  34. 34. Evolution of Indications for Hepato-BiliaryEvolution of Indications for Hepato-BiliaryCancers in EuropeCancers in Europe05/1968 - 12/201005/1968 - 12/2010
  35. 35. Survival of Patients with Liver CancerSurvival of Patients with Liver Canceras the First Indicationas the First Indication01/1988 - 12/201001/1988 - 12/2010
  36. 36. Primary Indications of Liver TransplantationPrimary Indications of Liver Transplantationin Patients with Cholestatic Diseasesin Patients with Cholestatic Diseases01/1988 - 12/201001/1988 - 12/2010
  37. 37. Survival of Patients with CholestaticSurvival of Patients with CholestaticDiseases as the First IndicationDiseases as the First Indication01/1988 - 12/201001/1988 - 12/2010
  38. 38. Primary Indications of Liver TransplantationPrimary Indications of Liver TransplantationIn Patients with Acute Hepatic FailureIn Patients with Acute Hepatic Failure01/1988 - 12/201001/1988 - 12/2010
  39. 39. Survival of Patients with AcuteSurvival of Patients with AcuteHepatic Failure as the First IndicationHepatic Failure as the First Indication01/1988 - 12/201001/1988 - 12/2010
  40. 40. Qualità del donatoreQualità del donatore Gravità del riceventeGravità del riceventeDurataDuratadell’ischemia freddadell’ischemia freddaDifficoltà chirurgicaDifficoltà chirurgicadell’interventodell’interventoEsitoEsitodel trapiantodel trapiantoOrgan allocationOrgan allocation
  41. 41. 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)
  42. 42. THE ALLOCATIONS OF LIVERS FORTHE ALLOCATIONS OF LIVERS FORTRANSPLANTATION:TRANSPLANTATION:A PROBLEM OF TITANIC CONSIDERATIONApril 1912: 2223 passengers and lifeboats capacity of 1178, 32% survivorsApril 1912: 2223 passengers and lifeboats capacity of 1178, 32% survivors
  43. 43. THE ALLOCATIONS OF LIVERS FORTHE ALLOCATIONS OF LIVERS FORTRANSPLANTATION:TRANSPLANTATION:A PROBLEM OF TITANIC CONSIDERATIONApril 1912: 2223 passengers and lifeboats capacity of 1178, 32% survivorsApril 1912: 2223 passengers and lifeboats capacity of 1178, 32% survivorsDecember 2000: 16931 patients waiting liver, 1660 (10%) died waitingDecember 2000: 16931 patients waiting liver, 1660 (10%) died waiting
  44. 44. PERCENTAGE OF TITANIC SURVIVORS BY CLASSPERCENTAGE OF TITANIC SURVIVORS BY CLASSwww.titanic.com, 2002%%
  45. 45. PERCENTAGE OF LIFE-BOATS OCCUPANTS INPERCENTAGE OF LIFE-BOATS OCCUPANTS INTITANIC SHIPWRECKTITANIC SHIPWRECKwww.titanic.com, 2002N.N.
  46. 46. Type of Liver Graft in EuropeType of Liver Graft in Europeaccording to the Date of Transplantationaccording to the Date of Transplantation
  47. 47. Graft Survival according to theGraft Survival according to theType of GraftType of Graft01/1988 - 12/201001/1988 - 12/2010
  48. 48. Gender and Age distribution ofGender and Age distribution ofLiver DonorsLiver Donors01/1988 - 12/201001/1988 - 12/201034.5%
  49. 49. Graft Survival according to Donor AgeGraft Survival according to Donor Agein Elective Liver Transplantationin Elective Liver Transplantation01/1988 – 12/201001/1988 – 12/2010
  50. 50. Impact of Donor Age on Graft Survival in LiverImpact of Donor Age on Graft Survival in Liver TransplantsTransplantsfor Hepatitis C-related and alcohol-related ESLDfor Hepatitis C-related and alcohol-related ESLDMutimer et al, Transplantation 81: 7-14; 2006HCV: n= 4736ALD: n= 5406ALDHCVRetrospectiveanalysis ofELTR dataset
  51. 51. 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
  52. 52. Donor-recipientDonor-recipientmatchingmatching
  53. 53. D-MELD FOR OPTIMIZATION OF DONOR/RECIPIENTD-MELD FOR OPTIMIZATION OF DONOR/RECIPIENTMATCHINGMATCHINGHalldorson et al. Am J Transpl, 2009
  54. 54. Balancing Donor and Recipient Risk Factors in LiverBalancing Donor and Recipient Risk Factors in LiverTransplantation: The Value of D-MELDTransplantation: The Value of D-MELDAvolio et al, Am J Transpl 2012
  55. 55. Avolio et al, Am J Transpl 2012Predicting unsustainable 5-yearPredicting unsustainable 5-yearsurvival (survival (waistful outcomewaistful outcome))
  56. 56. Liver Transplantation in ItalyLiver Transplantation in Italy
  57. 57. 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 listaTempo 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 combinazioniIncluse tutte le combinazioniIncluse tutte le combinazioniIncluse tutte le combinazioniFONTE DATI: Sistema Informativo TrapiantiFONTE DATI: Sistema Informativo TrapiantiFegatoFegatoReneRene*Dati al 20 Aprile 2011
  58. 58. Anno 2010: 21,7Anno 2010: 21,7 Anno 2011: 21,8Anno 2011: 21,8FONTE DATI: Reports CIRDATI: Reports CIRDonatori Procurati PMP - 2010 vs 2011Donatori Procurati PMP - 2010 vs 2011* Dati preliminari al 30 Aprile 2011
  59. 59. FONTE DATI: Reports CIRDATI: Reports CIROpposizioni alla donazione: 2010 vs 2011Opposizioni alla donazione: 2010 vs 2011* Dati preliminari al 30 Aprile 2011
  60. 60. 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. BurraPartecipating 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. VespasianoCNTCNTLiver MatchLiver Match
  61. 61. Trapianti di FEGATO – Anni 1992/2011Trapianti di FEGATO – Anni 1992/2011Inclusi i trapianti combinatiInclusi i trapianti combinatiFONTE DATI: Reports CIRDATI: Reports CIR * Dati preliminari al 30 Aprile 2011N=1530N=1530LIVERLIVERMATCHMATCHrecruitmentrecruitment
  62. 62. The Liver Match StudyThe Liver Match StudyProspective enrollement of all consecutive LTxRecruitment period: 1.6.2007-31.5.2009Recruitment period: 1.6.2007-31.5.2009N= 1530 adult transplants. Median FU at 30.01.2012 1043 daysN= 1530 adult transplants. Median FU at 30.01.2012 1043 daysData analysis performed by an independent Biostatical BoardCIBS, Tor Vergata Univ, Rome
  63. 63. Indicazioni al trapianto di fegato in ItaliaIndicazioni al trapianto di fegato in ItaliaDati Liver Match, su 1530 trapianti in adulti, 2007-200945,010,36,53,63,42,60,528,1HCCEtohCNT exceptionsCholestaticCriptogenicFHFUnfrequent indications*
  64. 64. Distribution of donor ageLiver Match cohort, Italy 2007-2009Median age: 56 years60 %
  65. 65. Curve di sopravvivenza per patologieCurve di sopravvivenza per patologienella coorte Liver Matchnella coorte Liver Match
  66. 66. Disease specific issuesDisease specific issuesin Liver Transplantationin Liver Transplantation
  67. 67. HBV-relatedHBV-relatedLiver DiseaseLiver Disease
  68. 68. Evolution of survival after liver transplantationEvolution of survival after liver transplantationfor HBV-related liver diseasefor HBV-related liver diseaseKim et al, Liver Transplant 2004; 10: 968-974Kim et al, Liver Transplant 2004; 10: 968-974Liver Match Cohort,Liver Match Cohort,Italy 2007-2009Italy 2007-2009
  69. 69. Epatite colestaticaEpatite colestaticafibrosantefibrosante• 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 soggettiimmunodepressi per altre causeimmunodepressi per altre cause• Rigonfiamento epatocitiRigonfiamento epatociti• Proliferazione duttulareProliferazione duttulareall’interfacciaall’interfaccia• Colangite acuta e fibrosiColangite acuta e fibrosiperiduttulareperiduttulare• Iperplasia istiocitariaIperplasia istiocitaria• Cirrosi assenteCirrosi assente
  70. 70. Optimal treatment of HBV infectionOptimal treatment of HBV infectionbefore liver transplantation isbefore liver transplantation isessentialessential !!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 regardlessof the level of viremia, with potent NUC with high genetic barrier !of the level of viremia, with potent NUC with high genetic barrier !
  71. 71. Importance of HBIg in the initial prophylaxisImportance of HBIg in the initial prophylaxis
  72. 72. 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 forpatients with hepatitis Bpatients with hepatitis BEntecavir Monotherapy Is Effective in Suppressing HepatitisEntecavir Monotherapy Is Effective in Suppressing HepatitisB Virus AfterB Virus After Liver TransplantationLiver TransplantationFung et al. Gastroenterology 2011;141:1212–1219•26% had undetectable HBV DNA+ at LTx•No graft losses due to HBV recurrence !
  73. 73. HCV-related disease and liverHCV-related disease and livertransplantationtransplantation
  74. 74. HCV kinetics during and after OLTHCV kinetics during and after OLTGarcia Retortillo et al, Hepatology 2002; 35: 680-687Hours after OLT Weeks after OLTHCV-RNAHCV-RNA>>2/3 log drop2/3 log dropDoubling time = 13 hrsDoubling time = 13 hrsPeak valuePeak valueat month 3-6at month 3-6Steroids increaseHCV-RNA levels100% reinfection !100% reinfection !
  75. 75. Incidence of cirrhosis afterIncidence of cirrhosis aftertransplant in HCV positivetransplant in HCV positiverecipientsrecipientsPost-transplant0%10%20%30%40%50%0 1 2 3 4 5Years Posttransplant%ofpatientswithCirrhosisBerenguer,2002Sanchez-Fueyo,2002Prieto,1999Gane,1996Berlin,2004
  76. 76. Curve di sopravvivenza dell’organo in relazioneCurve di sopravvivenza dell’organo in relazioneall’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
  77. 77. Fibrosis progression after OLT in the Mayo cohortFibrosis progression after OLT in the Mayo cohortof HCV+ patientsof HCV+ patients (1991-2000)(1991-2000)Charlton, LT 9:535-7; 2003Donor Agep<0.0001p<0.0001Fibrosisprogressionrate/yr0.6/yr0.6/yr2.7/yr2.7/yr
  78. 78. Graft survival is worse in HCV positive femaleGraft survival is worse in HCV positive femalerecipients of a graft from a male donorrecipients of a graft from a male donorLiver Match data-base, 2007-2009Cox H.R: 2.13 (1.26-3.58)
  79. 79. Multivariable analyses to evaluate the association betweenMultivariable analyses to evaluate the association betweendonor–recipient gender mismatch and graft loss, stratified bydonor–recipient gender mismatch and graft loss, stratified byrecipient HCV-statusrecipient HCV-statusNon-HCV (n= 18159) HCV (n= 9403)HR (95% CI) p-Value HR (95% CI) p-ValueM→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) 0.39F→M mismatch 0.96 (0.88–1.05) 0.35 0.92 (0.83–1.03) 0.14M→F mismatch 0.93 (0.85–1.02) 0.12 1.23 (1.10–1.38) <0.001J. C. Lai, S. Feng, J. P. Roberts and N. A. TerraultAmerican Journal of Transplantation 2011; 11: 296–302
  80. 80. Black holes in HCV andBlack holes in HCV andTransplantationTransplantation• HCV+ recipients should ideally not receivegrafts from elder donors• If possible, all cirrhotic patients with favorablepredictors who are candidates totransplantation should be treated withantivirals before transplantbefore transplant !– CTP A, young, G 2 and 3, IL28b C/C, RVR– The advent of DAA in this setting is eagerly awaited
  81. 81. A look to the near futureA look to the near future• 2nd generation DAAs should enter the transplantarena as soon as possible !!!!– The safety of current and new DAAs should be tested indecompensated cirrhotic patients to be listed for LT– Patients should ideally be transplanted with undetectableviremia– IFN-free regimens are eagerly awaited in this setting !• Availability of new DAAs will likely result intodramatic favorable changes:– in reducing the number of transplant candidates– in the preparation of patients to be transplanted– in the treatment of recurrent disease
  82. 82. Alcoholic Liver DiseaseAlcoholic Liver Disease
  83. 83. ETHICAL ISSUES in LT for ALCOHOLICETHICAL ISSUES in LT for ALCOHOLICCIRRHOSISCIRRHOSIS• Self-inflicted disease• Controversial views of the public• Difficult to predict the rate of recidivism• Risk of poor complianceSHORTAGE OF DONOR ORGANS
  84. 84. Platz KP, Transpl Int 2000;13:S127-S130““THE 6 MONTH RULE” (pro)THE 6 MONTH RULE” (pro)Duration ofabstinence prior totransplantationIncidence ofrecurrence of alcoholicliver diseaseSevere recurrence ofalcoholic liverdisease<6 months 66.4% 84.7%6-12 months 14.3% 60%1-2 years 13.9% 40%>2 years 5.6% 100%
  85. 85. ETHICAL and PRACTICAL ISSUES in LT forETHICAL and PRACTICAL ISSUES in LT forALCOHOLIC CIRRHOSISALCOHOLIC CIRRHOSIS• The 6-month abstinence rule:– Permits some patients to recover from their liver disease and obviate the needof 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 sobrietyare controversial• A role for early LT in the treatment of severe alcoholic hepatitis notresponding to medical therapy ? A controversial issueSHORTAGE OF DONOR ORGANS
  86. 86. The burden of HCCThe burden of HCC
  87. 87. Liver Transplantation fo HCCLiver Transplantation fo HCCIllustration 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 cmAdvantage Removal of the diseased liver together with the tumorDisadvantage Long waiting lists
  88. 88. Mazzaferro, New Engl J Med, 1996Sopravvivenza dopo trapianto perSopravvivenza dopo trapianto perHCC entro i “criteri di Milano”HCC entro i “criteri di Milano”Non invasione vascolare o linfonodaleNon invasione vascolare o linfonodaleNodulo 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 !
  89. 89. The rise of liver transplantations for HCC in the USThe rise of liver transplantations for HCC in the USIntroductionIntroductionof MELD with extraof MELD with extrapoints for HCCpoints for HCCThuluvath et al Liver Transpl 2009; 15:754-7628.8%8.8%of all LTof all LT21.7%21.7%of allof allLTLT27% of T1 and 45% of T2 received LT within 30 days !27% of T1 and 45% of T2 received LT within 30 days !
  90. 90. The evolution of the fast tracking conceptThe evolution of the fast tracking conceptfor 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
  91. 91. Intention–to-treatIntention–to-treatdatadata
  92. 92. Changing indications for Liver Transplantation in ItalyChanging indications for Liver Transplantation in Italy59.5%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 ?
  93. 93. Increasing liver Tx for HCCIncreasing liver Tx for HCCLiver Match cohort, June 2007 -May, 2009Median MELD = 9 Median MELD = 17
  94. 94. Graft survival in recipients with HCC in relation to theirGraft survival in recipients with HCC in relation to theirAge and HCV statusAge and HCV statusLiver Match cohort study, Italy, June 2007-May 2009662 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 posHCV -HCV - HCV +HCV +
  95. 95. Il trapianto di fegato per pazienti con tumoreIl trapianto di fegato per pazienti con tumoreprimitivo del fegato (HCC)primitivo del fegato (HCC)Freeman et al. AJT 2006n=9379n=9379n=2057n=2057Necessità 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
  96. 96. RESEZIONERESEZIONE TRAPIANTOTRAPIANTO ABLAZIONEABLAZIONEBARCELONABARCELONA
  97. 97. Barcelona Clinic Liver Cancer (BCLC)Barcelona Clinic Liver Cancer (BCLC)staging classificationstaging classificationLlovet JM et al. J Natl Cancer Inst 2008;100: 698 – 711HCCStage 0Stage 0PST 0, Child-Pugh APST 0, Child-Pugh AStage A-CStage A-CPST 0-2, Child-Pugh A-BPST 0-2, Child-Pugh A-BStage DStage DPST>2, Child-Pugh CPST>2, Child-Pugh CEarly stage (A)Single <5 cm or 3nodules< 3 cm, PS 0Intermediate stage (B)Multinodular, PS 0Advanced stage (C)Portal invasion,N1, M1, PS 1-2Terminalstage (D)Very early stage (0)Single < 2 cmCarcinoma in situSingle 3 nodules ≤ 3 cmPortalpressure/bilirubinNormal No YesAssociateddiseasesIncreasedResection 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
  98. 98. [Pomfret, Liver Transpl 2010]Risk of drop-out from waiting list for candidatesRisk of drop-out from waiting list for candidateswithin Milan Criteria at entrywithin Milan Criteria at entry
  99. 99. How many transplants were performedHow many transplants were performedwithin Milan criteria in Italy ?within Milan criteria in Italy ?TransplantTransplantrecipientrecipientMedian WaitingMedian Waitingtime (months)time (months)Median MELD atMedian MELD attransplantationtransplantationHCC 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)
  100. 100. The “up-to-7” criteria could be a reasonable starting pointThe “up-to-7” criteria could be a reasonable starting pointfor prospective clinical trials on expansion of Milan Criteriafor prospective clinical trials on expansion of Milan CriteriaThe “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 patients with HCCPredicting survival after liver transplantation in patients with HCCbeyond the Milan Criteria: a retrospective, exploratory analysisbeyond the Milan Criteria: a retrospective, exploratory analysis
  101. 101. MonthsSurvivalProbability0 12 24 36 48 60 72 84 96 108 1200.00.20.40.60.81.073%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 monthsProving 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.orgPredicting survival after liver transplantation in patients with HCCbeyond the Milan Criteria: a retrospective, exploratory analysis
  102. 102. Annal Surg. 2003; volume 238, Number 6,The concept of Salvage OLTThe concept of Salvage OLT
  103. 103. Salvage OLTSalvage OLTIl trapianto come scialuppa di salvataggioIl trapianto come scialuppa di salvataggioDa utilizzare solo quando non sonoDa utilizzare solo quando non sonopossibili valide alternative di curapossibili valide alternative di cura
  104. 104. Allocation and prioritizationAllocation and prioritizationstrategiesstrategies
  105. 105. PROGNOSTIC MODELS TO ASSIST ORGANPROGNOSTIC MODELS TO ASSIST ORGANALLOCATION AND MEDICAL ETHICSALLOCATION AND MEDICAL ETHICS• EQUITY: the need to equitably distribute the available therapeuticresources• INDIVIDUAL JUSTICE: the duty to promote the best interest ofindividual patients• Medical urgency• UTILITY: the duty to strive to obtain the best results for the correctpopulation therapeutic use of the resource• Post transplant outcomes: maximize graft and patient survival
  106. 106. The concept ofThe concept oftransplant benefittransplant benefit
  107. 107. WHAT IS THE REAL GAIN AFTER LIVERWHAT IS THE REAL GAIN AFTER LIVERTRANSPLANTATION?TRANSPLANTATION?Neuberger J. Liver Transpl, 2009Transplant benefitTransplant benefit
  108. 108. Merion et al. Am J Transpl; 2005Schaubel et al. Am J Transpl, 2009SURVIVAL BENEFIT-BASED DECEASED DONORSURVIVAL BENEFIT-BASED DECEASED DONORLIVER ALLOCATIONLIVER ALLOCATION
  109. 109. Il survival benefit del trapianto di fegatoIl survival benefit del trapianto di fegatoMerion et al. Am J Transplantation 2005; 5:307-313Mortalità ad un anno dei pazienti trapiantatiMortalità ad un anno dei pazienti trapiantatirispetto alla mortalità dei candidati nonrispetto alla mortalità dei candidati nontrapiantati che rimangono in lista di attesatrapiantati che rimangono in lista di attesaZona di transizioneZona di transizione
  110. 110. Merion et al. Am J Transpl; 2005• The survival benefit model has identified a minimuma minimumvalue of MELD score (>15) justifying LTvalue of MELD score (>15) justifying LT• High-MELD patients may have survival benefit even wheneven whenthey received a high DRI organ !they received a high DRI organ !• Low-MELD patients have limited or even no survivalbenefit when transplanted with a high DRI organ.• Thus the current informal practice of inverse matching ofrecipient MELD score and liver DRI should be discouraged• The overall validity and practical applicability of thetransplant benefit model must be confirmed prospectively
  111. 111. Consensus Conference on Outcome Measures inLiver Transplantation in Italy: Second StepGruppo di lavoroEccezioni al MELDP. Burra, D. PinnaProposta Statements
  112. 112. 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•PruritoEccezioni senzaEccezioni senzaprioritizzazione:prioritizzazione:•Malnutrizione•Encefalopatia epatica ricorrente•Emocromatosi•Deficit di α1 antitripsina•HIV•HCC fibrolamellare•Colangiocarcinoma•Metastasi di carcinoma del colon-rettoAISF/SITO Consensus conferenceAISF/SITO Consensus conferenceEccezioni al MELDEccezioni al MELDPalermo, 25maggio 2013Palermo, 25maggio 2013
  113. 113. GRUPPO A - ECCEZIONI AL MELDA1. Condizioni con end point mortalita1.1 Ascite refrattaria e sindrome epato-renale1.2 Encefalopatia epatica1.3 Deficit nutrizionali1.4 Rendu Osler1.5 Malattie da accumulo1.6 Sindrome epato-polmonare ed ipertensione porto-polmonare1.7 Ritrapianto1.8 Epatite fulminante1.9 Trapianto in HIV
  114. 114. GRUPPO A - ECCEZIONI AL MELDA2. Condizioni con end point rischio di trasformazioneneoplastica e/o progressione della neoplasia2.1 Emangioendoteliomi, emangiopericitomi,emangiosarcomi2.2 Tumori neuroendocrini, adenomatosi, carcinomafibrolamellare, epatoblastoma2.3 Colangiocarcinoma2.4 Metastasi da neoplasia colon-retto
  115. 115. GRUPPO A - ECCEZIONI AL MELDA3. Condizioni con end point qualita di vita3.1 Fegato policistico3.2 Prurito nelle malattie colestatiche
  116. 116. 6813 6842 6364 6264 6220 6512 6742 6808 7021 69611218 1276 1371 1522 1590 1399 1423 1447 1314 1234ReneFegatoLista di attesa standard646 635 652 794 709 744 712 702 728 723256 227 250 252 283 265 296 312 345 352230 194 195 174 212 227 216 226 260 252CuorePolmonePancreasPazienti iscritti in lista*Dati al 20 Aprile 2011• L’unica terapia risolutiva nelle ESLD e nella FHF• Una terapia con rischi non trascurabili, dariservare solo a chi ne può avere un beneficio• Una risorsa preziosa, ma limitata e costosa, dautilizzare con equità e trasparenza• Richiede una totale sinergia tra epatologo echirurgo dei trapianti

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