Consensus conference: Indications for Liver Transplantation, January 19 and 20, 2005, Lyon-Palais Des Congrès

Text of recommendations (long version)

Abstract

Sponsors: Association française de chirurgie hépatobiliaire et de transplantation hépatique; and Association française pour l'étude du foie

Cosponsors: Établissement français des greffes

Associates: Académie de chirurgie; Académie de médecine; Association française de chirurgie; Association nationale de prévention en alcoologie et addictologie; Collège national universitaire des enseignants en addictologie; Société de pathologie infectieuse de langue française; Société de réanimation de langue française; Société française d'alcoologie; Société française d'anesthésie et de réanimation; Société française de pathologie; Société francophone de transplantation; Société nationale française de gastro-entérologie; and Société nationale française de médecine interne

Organizing Committee: Karim Boudjema, President, surgeon, Rennes, France; Didier Samuel, Secretary, hepatologist, Villejuif, France; Charles Balabaud, hepatologist, Bordeaux, France; Jacques Belghiti, surgeon, Clichy, France; Henri Bismuth, surgeon, Villejuif, France; Yvon Calmus, hepatologist, Paris, France; Olivier Chazouillères, hepatologist, Paris, France; Daniel Cherqui, surgeon, Créteil, France; Laurence Chiche, surgeon, Caen, France; Sophie Cohen, physician, Établissement Français des Greffes, Paris, France; Patrice Dosquet, physician, Haute Autorité de Santé, Saint-Denis La Plaine, France; Christophe Duvoux, hepatologist, Créteil, France; Christian Jacquelinet, physician, Établissement Français des Greffes, Paris, France; Bernard Launois, surgeon, Rennes, France; Christian LeToublon, surgeon, Grenoble, France; Michel Messner, hepatologist, Rennes, France; Georges-Philippe Pageaux, Hepatologist, Montpellier, France; Christophe Paindavoine, Haute Autorité de Santé, Saint-Denis La Plaine, France; Christian Partensky, surgeon, Lyon, France; Didier Sicard, physician and internist, Paris

Jury: Didier Sicard, President, physician and internist, Paris, France; Amine Benyamina, psychiatrist, Villejuif, France; Alexandre Biosse Duplan, Paris, France; Jean-Pierre Bronowicki, hepatogastroenterologist, Vandouvre-les-Nancy, France; Colette Danet, nurse coordinator, Villejuif, France; Dominique Gendrel, pédiatrician, Paris, France; Maryvonne Hourmant, nephrologist, Nantes, France; Franck Lazorthes, surgeon, Toulouse, France, Guillaume le Loup: général practitionner, Amiens, France; Jean-Luc Nancy, philosoph, Strasbourg, France; Emile Alexandre Pariente, hepatogastroenterologist, Pau, France; Catherine Petitnicolas, journalist, Paris, France; Hugues Rousset, physician and internist, Paris, France; Pierre-Bénite Bernard Tirel, hospital director and professor, École nationale de la santé publique, Rennes, France; Gerard Torpier, Transhépate Association, Lille, France

Experts: Rene Adam, surgeon, Villejuif, France; Daniel Azoulay, surgeon, Villejuif, France; Marina Berenguer, hépatologist, Valencia, Spain; Henri Bismuth, surgeon, Villejuif, France; Olivier Boillot, surgeon, Lyon, France; Karim Boudjema, surgeon, Rennes, France; Yvon Calmus, hepatologist, Paris, France; Carine Camby, General director, Établissement français des greffes, Paris, France; Laurence Chiche, surgeon, Caen, France; Pierre-Alain Clavien, surgeon, Zürich, Switzerland; Jean-Charles Duclos-Vallée, hepatologist, Villejuif, France; Francois Durand, hepatologist, Clichy, France; Christophe Duvoux, hepatologist, Créteil, France; Jean Emond, surgeon, New York, NY, United States; Antoine Hadengue, hepatologist, Genéve, Switzerland; Yves Pierre le Treut, surgeon, Marseille, France; Jan Lerut, surgeon, Bruxelles, Belgium; Pietro Majno, surgeon, Genéve, Switzerland; Phliippe Mathurin, hepatologist, Lille, France; Jean-Philippe Miguet, hepatologist, Besançon, France; Georges Philippe Pageaux, hepatologist, Montpellier, France; Xavier Rogiers, surgeon, Hambourg, Germany; Didier Samuel, hepatologist, Villejuif, France; Alain Sauvanet, surgeon, Clichy, France; Olivier Soubrane, surgeon Paris, France; Christian Trépo, hepatologist, Lyon, France; Philippe Vinceneux, internist, Colombes, France

Literature Group: Tarik Asselah, hépatologist, Clichy, France; Pierre-Henri Bernard, hépatologist, Bordeaux France; Michael Bismuth, hépatologist, Montpellier France; Philippe Compagnon, surgeon, Rennes France; Thomas Decaëns, hépatologist, Paris France; Sebastien Dharancy, hépatologist, Lille France; Jerome Dumortier, hépatologist, Lyon France; Emmanuel Jacquet, surgeon, Montpellier France; Elisabeth Kimmoun, hépatologist, Villejuif France; Alexis Laurent, surgeon, Créteil France; Yves le Derf, surgeon, Lyon France; Vincent Leroy, hépatologist, Grenoble, France; Richard Lorho, hépatologist, Rennes, France

QUESTIONS

Question 1. How can medical management be optimized for patients transplanted for viral hepatitis?

Question 2. When is alcoholic cirrhosis an indication for liver transplantation (LT)?

Question 3. Which cancers of the liver can be treated with LT?

Question 4. What is the role of the living donor in LT?

Question 5. What are the expansions of LT indications?

Abbreviations

ANAES, National Agency for Accreditation and Evaluation in Health (l'Agence nationale d'accréditation et d'évaluation en santé); HBIG, hepatitis B immunoglobulins; HCC, hepatocellular carcinoma, LT, liver transplantation; HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus; LDLT, living donor liver transplantation; CDLT, cadaveric donor liver transplantation.

PREFACE

This conference was organized and conducted in accordance with the recommended methodological guidelines of the National Agency for Accreditation and Evaluation in Health (ANAES: l'Agence nationale d'accréditation et d'évaluation en santé).

The conclusions and recommendations presented in this document were expressed exclusively by the conference jury. ANAES is not liable in any way for their content.

INTRODUCTION

The third consensus conference dedicated to indications for LT was a follow-up to the conferences of 1983 in Denver and 1993 in Paris. After the maturation stage of the decade 1984-1993 and the continued improvement of the decade 1993-2003, the current conference focused on expanding indications for LT, with thought given to its general organization and the role of the living donor.

EXPANSION AND/OR OPTIMIZATION OF EXISTING RESOURCES?

There is a strong contrast between:

• the persistent shortage of organ donations and the growing demand, which has been promoted by the progress of screening and imaging and the ever growing prevalence of chronic viral diseases and/or liver tumors;

• the therapeutic approach as implemented by transplant programs and the individualized approach to the patient;

• the constant desire for expanding innovations and the need for an evidence-based approach.

Faced with the shortage of donations, this therapeutic recourse, which is becoming increasingly common, justifies that the indications be founded on:

• more precise epidemiological data, ideally population-based. The number of patients to be transplanted and the true graft needs are not known;

• a better means of presenting the results of LT, allowing better comparison of the different indications and therapeutic strategies in relation to efficacy and economic constraints. This would require an “intention to treat” analysis from the waiting list registration and not from the transplant procedure itself;

• not only would crude survival be studied, but also survival compared to a matched cohort for age, gender, and disease, years of life gained, and the different aspects of the quality of life;

• a better coordination among French centers and between French and European centers. The current difficulties in using shared livers (split techniques) is a striking example;

• better organization in order to reduce the heterogeneity of medical care access and the variable time on the waiting list between centers.

The reinforcement of a dynamic policy of liver donation in brain-dead persons in all regions of France should offset the current regional disparities. This policy should be founded on the motivation of procurement teams, and an improvement in the information and education of the general population regarding organ donation.

Consideration of the indications must take into account:

• the expected rise in incidence of hepatitis C and hepatocellular carcinomas (HCC), mainly due to the progress in screening and diagnostic tools;

• the expected detrimental effects of the net decrease in hepatitis B virus (HBV) vaccinations in infants and children in France;

• the social and medical indifference in regards to alcohol dependence, as well as the insufficiencies in psychological, social and medical care which remain encumbered by moral value judgements;

• the insufficiency of policies for primary prevention of infectious risks from intravenous drug use;

• the increase of LT needs related to aging of the population;

• the increase of hepatitis B and C seen in immigrant populations.

The medical management of chronic liver disease due to alcohol or viral hepatitis, which have a long and often fluctuating course, requires an early collaboration between general practitioners and hepatologists. This collaboration will help to achieve better needs assessment and to coordinate the appropriate medical management even before the possible discussion of transplant recourse. This joint approach to the patient should allow for improvement and homogenization of therapeutic results.

The consensus conferences of 1983 and 1993, which touched on these issues, also recommended an evaluation of care and practices; they also favored the existence of a small number of transplantation centers carrying out a large number of LT procedures, which would result in improved team competency. These recommendations were not applied, particularly in France where the number of centers, some of which perform few procedures, has risen.

Better organization and cooperation between centers in terms of organ procurement responsibilities and transplantation procedures are necessary. The modification of the transplant allocation guidelines in order to achieve fairness and to prioritize the most severe patients requires a genuine experimental assessment which would lay the foundation for eventual implementation.

Last, more than the immediate cost of the transplantation, it would be useful to estimate the cost of prevention and long-term treatment strategies both with and without transplantation.

The current number of hepatic grafts in France is about 900 (Etablissement Francais des Greffes, Annual Report; http://www.agence-biomedecine.fr) (5,000 LTs per yr in Europe). At the end of 2003, 57,655 grafts in 51,580 patients had been reported in the European Liver Transplant Registry (http://www.eltr.org). Among the indications for the first graft, chronic liver disease was the main one (69% of indications): from this group, 58% had cirrhosis and 11% had chronic cholestasis. In the cirrhosis group, those linked to alcohol and hepatitis C and B viruses represented, respectively, 18%, 14%, and 3% of graft indications. Cancers represented 12% of all indications (90% being hepatocellular carcinoma or HCC), and retransplantations were about 9%.

QUESTION 1. HOW CAN MEDICAL MANAGEMENT BE OPTIMIZED FOR PATIENTS TRANSPLANTED FOR VIRAL HEPATITIS?

I. What Is the Descriptive Epidemiology of LT Performed for Viral Hepatitis B and C?

In the case of viral hepatitis, LT should be considered for fulminant hepatitis, decompensated cirrhosis, and/or HCC.

Viral hepatitis currently accounts for 20% of LT indications in France, being about 200-250 cases (not including HCC, which is considered in Question 3).

Without accurate epidemiological descriptions, it is not known what percentage of patients affected by end-stage liver failure and/or HCC are currently considered for LT.

The number of indications for viral hepatitis B could increase in the short term due to a rise in the immigrant population coming from countries with strong endemic disease, and in the medium/long term due to the recent decline in the promotion of hepatitis B vaccines in France. If the overall number of LTs does not change, the number of LTs for viral hepatitis C could grow to about 300 transplantations in 2010. This is explained by the epidemiology of hepatitis C virus (HCV) infection in France and the expected increase in mortality, which could reach 4,500 deaths per yr.

The progress and limitations of LT today for viral hepatitis depend primarily on antiviral treatments to control the viremia.

II. What Treatments May Be Offered to Reduce the Risk of Viral Hepatitis B Recurrence in the Graft?

The validity of this indication for LT is no longer an issue today, and the medium and long term survivals are among the best (grade C) (75% at 5 yr and 63% at 10 yr in the European Liver Transplant Registry). The main problem is the prevention of recurrence on the graft, the risk increasing with the pretransplantation viral load (risk being on the order of 80% without prophylactic measures) (grade B).

II.1. Prior to Transplantation

An attempt must be made to reduce the viremia to less than 10⁵ copies/mL using lamivudine or adefovir (interferon is contraindicated in decompensated cirrhosis) in all patients with detectable viremia (grade D, expert opinion). If the viremia is ≥10⁵ copies/mL, the liver transplant is considered controversial.

Lamivudine is rapidly effective, is well tolerated, and has the benefit of many years of experience, but it causes frequent resistance, the incidence of which increases over time (10% at 1 yr, 30% at 2 yr, and 50% at 4 yr) (grade C).

Adefovir probably has similar efficacy, is well tolerated (particularly for renal function at a dosage of 10 mg/day), and causes less resistance (about 1-5% at 3 yr and 10-15% at 4 yr); however, there is less experience with its use (grade C).

An effective antiviral treatment can improve hepatic function from Class C to class B, and even A, of the Child-Turcotte-Pugh classification scale. The question then becomes: 1) whether to maintain the transplant indication due to the risk of the occurrence of viral resistance to antiviral therapy (which could induce rapid deterioration of hepatic function); or 2) have the patient taken off the LT waiting list. Since the availability of adefovir, the second option seems consensual.

These difficulties warrant that antiviral treatment modalities be discussed with the LT team before their initiation in all cirrhotic patients with potential for transplant. They should also provoke thought regarding the potential dangers of a too early initiation of long-term antiviral therapy, particularly of adefovir, in patients having relatively mild hepatic lesions; indeed, there is the risk of the emergence of viral escape mutants at the time of LT. The jury recommends that studies be performed regarding this issue.

II.2. During the First 2 yr Posttransplantation

The long-term routine administration of high doses of intravenous anti-hepatitis B surface antigen immunoglobulins (HBIG) reduces the risk of recurrence (defined as the reappearance of hepatitis B surface antigen in serum) from 80% to 25% at 2 yr (grade C). The success of immunoglobulins in preventing recurrence is better in patients with low viremia (<10⁵ copies) before transplantation; the rate of relapse remains high in patients with viremia >10⁵/mL before transplantation (grade B).

The association of lamivudine with immunoglobulins strongly reduces the risk of recurrence in patients (5-20% at 1-2 yr, grade C). It is probable (expert opinion) that adefovir given with immunoglobulins has a similar efficacy and a lower risk of viral breakthrough. Antiviral combination therapy has not been tested for this indication, justifying the need for comparative studies. The jury recommends the routine association of an antiviral to the immunoglobulins (grade B).

The use of intramuscular HBIG is possible and is less costly but it is uncomfortable for the patient; however, no randomized comparisons have been done and some cases of viral recurrence have been described.

II.3. After the First 2 yr Posttransplantation

Immunoglobulin and antiviral therapy should continue uninterrupted for the length of the patient's life, except when spontaneous anti-hepatitis B surface antigen seroconversion is suspected, on the basis of the anti-hepatitis B surface antigen titer not decreasing between 2 HBIG injections.

However, recent reports with a short follow-up have suggested good results after HBIG withdrawal and replacement by antivirals or vaccine. The withdrawal or reduction of immunoglobulins while continuing the use of antivirals should be carried out in large randomized trials for a sufficient duration; the jury recommends that this be quickly implemented due to the very high cost of lifelong treatment with HBIG.

III. What Treatments May Be Offered to Reduce the Risk of Viral Hepatitis C Recurrence in the Graft?

The validity of hepatitis C as an indication for LT is not modified by the current medium/long term results. These results are related to:

• the early reinfection of the graft;

• the accelerated evolution towards cirrhosis on the graft (10 to 40% at 5 yr), followed by a very high risk of decompensation (40% 1 yr after diagnosis), and an increase in mortality from 10 to 20% after 5-10 yr of follow-up compared to other LT indications. The 5-yr survival in the European Registry is 62% for cirrhosis and 89% in the absence of cirrhosis;

• the increasing age of patients and donors.

III.1. Prior to LT

LT may be performed even in those subjects who remain viremic after antiviral treatment. There is no threshold of viral load that disqualifies a patient from LT. However, patient and graft survival are lower when viral load is greater than 10⁶ mEq/mL than below. There are no limitations for LT according to genotype.

HCV eradication is difficult though not impossible in Child-Turcotte-Pugh A or B patients. Eradication is more questionable in Child-Turcotte-Pugh C patients, because of the contraindications regarding interferon use. A sustained viral response can be attained in about 20% of patients using the combination of pegylated interferon and ribavirin:

• especially in patients with viral genotypes 2 or 3 (grade C);

• as long as doses are not reduced excessively and are taken in conjunction with growth factors.

The results of studies of “long-term” interferon treatment in nonresponders with the goal of reducing liver-related complications are not yet available.

III.2. After LT

The following factors may increase the risk of developing cirrhosis on the graft: very high viremia (>10⁶ mEq/mL), early recurrence before 1 yr, donors over age 50, poor quality grafts, retransplantation, and perhaps living donor grafts. HCV genotypes do not seem to have a clear effect.

Liver biopsy is necessary in the case of early graft dysfunction in order to make a differential diagnosis between hepatitis C and rejection (helping to avoid overuse of antirejection treatment, which promotes the evolution of hepatitis C), and to screen for cases of hepatitis, which are severe from the start, justifying early treatment.

The optimal treatment period for recurrent viral hepatitis C seems to be after 1 yr (grade D, expert opinion), when lesions are at least A1F1 (Metavir classification), predictive of an increased risk of developing cirrhosis (grade C).

When using the combination therapy of interferon and ribavirin (at optimal dosage, taken concurrently with growth factors), a sustained viral response can be expected in about 1 in 3 patients (expert opinion).

However, side effects, dose reduction, and premature discontinuation of treatment are more frequent than in nontransplanted patients (grade C). While an increased risk of rejection has not been observed under antiviral treatment, it would be prudent to avoid reducing immunosuppression too extensively during hepatitis C treatment (expert opinion). Antiviral treatment should be continued if possible for at least 6 months after viral clearance by polymerase chain reaction. In the absence of viral clearance, treatment should be discontinued. The potential benefit of adding amantadine has not been assessed after transplantation.

Transplantation results for viral hepatitis C have progressively declined over the last decades, though the cause remains unknown. Possible reasons include the higher age of donors, the utilization of living donors and the use of more potent immunosuppressive regimens. It is currently recommended that immunosuppressive treatment be restricted to an anticalcineurin agent, that corticosteroid boluses and anti-OKT3 be avoided, and that corticosteroid therapy only be gradually decreased (due to the risk of immune rebound in case of rapid withdrawal) (grade D, expert opinion).

The reduction of the cofactors aggravating cirrhotic evolution (alcohol, metabolic syndrome, or tobacco) is necessary (expert opinion).

IV. Should LT Be Considered in Patients with Human Immunodeficiency Virus (HIV) Coinfection?

The 1993 consensus conference stated that acquired immunodeficiency syndrome was a formal contraindication to transplant and HIV infection (before the acquired immunodeficiency syndrome stage) was a relative contraindication due to the generally unfavorable prognosis of HIV infection and fear of the effect of immunosuppressive treatment on HIV disease progression.

The introduction of highly active antiretroviral therapy in 1996 considerably modified the prognosis of HIV disease by greatly increasing life expectancy.

In 2004, viral hepatitis became a major concern in the care of HIV-infected patients, 30% of whom are HCV-positive (90% of those being infected by drug use), and 10% being chronic carriers of hepatitis B surface antigen (Source Institut National de Veille Sanitaire, INVS, France). Viral liver disease has become the main cause of death in HIV-infected patients.

Prevention, screening, and treatment of viral hepatitis are imperative today for HIV-infected patients.

IV.1. HIV-HBV Coinfection

The progression of hepatitis B lesions can be delayed with the use of hepatitis B antiviral agents (interferon, lamivudine, adefovir, or tenofovir), with the chances of attaining a sustained viral response being weaker than in non-coinfected patients. The use of HBV antivirals should be considered thoroughly and discussed between infectious disease specialists and hepatologists in order not to jeopardize future treatment possibilities in either disease. Hepatitis B treatment should not be started too early; it requires an assessment of liver injury (grade D, expert opinion) and the association of 2 antivirals to reduce the risk of viral escape mutants.

IV.2. HIV-HCV Coinfection

A cure for hepatitis C can be achieved in about 1/3 of treated patients (grade B) with the use of interferon and ribavirin combination therapy.

Current epidemiological data showing faster progression to cirrhosis in HIV coinfected patients (grade C) makes the possible recourse to LT an important question in these subjects.

IV.3. LT in Coinfected Patients

Only limited series of transplants are currently available, totaling about 200 patients. They have mainly been performed for decompensated cirrhosis in a very select group of patients for whom HIV infection was controlled by highly active antiretroviral therapy. The follow-up of these studies is short (generally 2-3 yr). Considering these limitations, LT does not seem to accelerate HIV infection. Viremia control and the CD4 count remain unchanged; there does not appear to be an increase in opportunistic infections (provided that strong prophylactic, antibacterial, antiviral, and antiparasitic treatments are implemented, grade C). An extra recommended precaution (expert opinion) in the pretransplantation assessment is the verification of the genotype profile of HIV resistance in the patient. The acute rejection rate does not seem to be diminished by the HIV-related immunodepression. The cancer rate does not seem to increase in the short-term.

• In the case of hepatitis B, the short term evolution does not appear to be worse than in the absence of HIV infection (grade C).The prevention of recurrence is done through the combination of high doses of HBIG with a hepatitis B antiviral chosen based on earlier treatments; there is not sufficient data however, to guarantee its efficacy.

• In the case of hepatitis C, the overall short-term survival seems comparable to that of an HIV-negative population (grade C).

Microvesicular steatosis (a hallmark of mitochondrial toxicity) was observed in 4 out of 10 patients undergoing routine biopsy after 6 months in a series from Paul Brousse Hospital. Several cases of lactic acidosis and acute pancreatitis, which was sometimes fatal, were observed before and after hepatitis C antiviral therapy implementation; for this reason, the nucleoside inhibitors ddI and d4T should be avoided after the graft. In the case of HIV-HCV coinfection, the hepatitis C viral load and especially the fibrosis progression rate are much higher than those seen in noncoinfected patients (4 out of 13 patients had fibrosis ≥F3 6 months post-LT in the Paul Brousse Hospital series). Hepatitis C treatment is therefore a necessary and possible option. With peg interferon and ribavirin however, the Paul Brousse Hospital team only obtained a sustained viral response in 2 out of 14 treated patients, with 1 case of lactic acidosis. Anticalcineurin therapy should be adapted at the moment of highly active antiretroviral therapy reimplementation due to the risk of overdose with the use of protease inhibitors; likewise, anticalcineurin dosage should be increased if protease inhibitors are discontinued.

In conclusion, LT in HIV-infected patients seems feasible, but its benefit-risk ratio in the medium-term is unknown. It can therefore only be currently recommended under the following conditions (grade D):

• stable control of HIV infection (undetectable viral load, without a well-defined CD4 level);

• no history of acquired immunodeficiency syndrome-defining opportunistic illness (except if it occurred before the highly active antiretroviral therapy implementation);

• no general contraindications, which especially implies screening for tumors;

• with the same indications as patients without HIV infection;

• with the provision of a specific prospective validation of the above mentioned recommendations.

Careful organization is required, especially including the availability of infectious disease specialists and the informed consent of the entire team due to the particular risk of accidental blood exposure for the healthcare workers.

The treatment and follow-up are particularly burdensome (probable difficulties in compliance), which justifies intensified support and the anticipation of a more difficult social reintegration than in noncoinfected patients.

QUESTION 2. WHEN IS ALCOHOLIC CIRRHOSIS AN INDICATION FOR LT?

The French Committee of Health Education estimates that the number of people having excessive alcohol consumption in France is 5 million. It is estimated that the number of registered deaths per year in France, which are related to excessive and regular alcohol consumption is 45,000. There are 8,000 to 10,000 annual registered deaths linked to a complication of alcoholic cirrhosis. Alcoholic cirrhosis is the main cause of LT in France and the second in Europe and the United States. Of the 850 liver transplants performed in France in 2003, 270 at most were for alcoholic cirrhosis. According to the European liver transplant registry, survival is 83%, 72%, and 59% at 1, 5, and 10 yr, respectively.

The controversy surrounding alcoholic cirrhosis as an indication of LT has already stirred debate regarding the duration of abstinence before the graft and the risk of recurrence, resulting in several recommendations for LT indications.

• NIH conference (1983): LT was recognized as a treatment for advanced alcoholic disease, but is restricted to a small number of patients known to be abstinent and presenting clinical indicators of poor prognosis;

• consensus conference (France-1993): alcoholic cirrhosis was debated as an indication for LT. Before 1993, it represented a small number of LT candidates due to long-held unfavorable opinions of physicians and LT teams;

• conference of the American Association for the Study of liver Disease (1997): it defined the minimum criteria for registering patients on the LT waiting list;

• severe cirrhosis defined by a minimum Child-Turcotte-Pugh B score;

• complications of cirrhosis: HCC (regardless of Child-Turcotte-Pugh score), gastrointestinal bleeding, and debilitating encephalopathy;

• recommendations of the British Society of Gastroenterology (1999): LT may be performed for severe alcoholic cirrhosis (grade A recommendation). Psychosocial evaluation to occur simultaneously (grade B recommendation);

• recommendations of the American Association for the Study of Liver Disease (1997): they emphasized the importance (which was a novelty) of follow-up in selected patients by a medical specialist experienced in the management of addictive behaviors (grades A, C, D: beneficial effects on survival, improvement in the quality of life).

This eloquently shows that guidelines evolve according to prevailing opinions. To the extent that there is a multidisciplinary approach to the patient, alcoholic cirrhosis is as good an indication for LT as is viral hepatitis.

I. At What Point in the Disease Should Transplantation Be Considered?

Alcoholic disease is chronic and leads to serious hepatic complications, which can jeopardize the vital prognosis. It can be resistant to treatment and may be complicated by periods of relapse. Treatment of the disease should therefore be considered with these factors in mind.

Except for HCC (see Question 3), the indication of alcoholic cirrhosis for LT is limited to complicated and severe cirrhosis (Child-Turcotte-Pugh C).

LT is not recommended in the case of Child-Turcotte-Pugh stage B (B); in fact: 1) in the Béclère Hospital model, LT did not improve the survival of stage B patients, neither in comparison to a theoretical cohort of nontransplant cirrhotic patients, nor to a sample of 169 matched controls, and 2) in a multicentric randomized control trial in 120 Child-Turcotte-Pugh B patients conducted by the Besançon team, the group of patients who received an LT as a first line treatment had excessive mortality, due principally to an increased incidence of de novo cancer (mainly linked to alcohol and tobacco).

It is possible to place patients with alcoholic cirrhosis on the waiting list under 2 conditions:

• that there is a pretransplantation assessment with particular attention paid to the presence of: 1) lesions related to alcohol consumption or smoking; 2) extrahepatic lesions, such as cancers and precancerous conditions including ears/nose/throat, bronchial, esophageal; and 3) respiratory and cardiovascular pathology;

• that alcoholic care management is started as early as possible by a team specialized in addictive behaviors. This can help in achieving abstinence from alcohol which may be a source of functional hepatic improvement, with recovery sufficient enough that transplantation is no longer required.

Abstinence is essential and the pretransplantation period should be used for strengthening the motivation to end alcohol use. This discontinuation commits the patient to a therapeutic program which may prevent posttransplantation relapse. A duration of 6 months of abstinence before LT (grade B) should no longer be the definite rule and should not be considered the determining factor for graft access.

II. Is Abstinence Necessary in the Case of Acute Serious Complications?

In a series of 269 patients with severe alcoholic hepatitis treated with corticosteroids, the application of a simple biological score, i.e., the absence of improvement of bilirubinemia at day 7 allowed 80% of deaths to be predicted with a mortality of about 60%, 40%, and 25% at 1, 2, and 6 months in nonresponders. A therapeutic trial of early LT in patients nonresponsive to corticosteroid therapy is therefore recommended by the jury despite the brevity of the required abstinence from alcohol.

III. What Is the Risk of Recurrence of Alcohol Consumption, What Is Its Impact, and How Can It Be Prevented?

The term recurrence seems incorrect; it would be better to consider it as a relapse in alcohol dependence in order to differentiate it from isolated alcohol consumption.

Its prevention should be a multidisciplinary concern following transplantation. Though essential, it seems that this is an area that has been neglected far too long.

There are some risk factors, which can be predictive of relapse, such as age at the start of alcohol consumption, family history, and difficult socioeconomic conditions (grade B).

In any event, an episode of alcohol intoxication does not necessarily translate into relapse. The intervention of a psychiatrist, psychologist, and addictive specialist, if possible, is necessary for the diagnosis and to avoid relapse. The jury recommends that this type of intervention be routinely implemented and that studies be done on its efficacy.

Additionally, the alcoholic patient with massive alcohol relapse may not be compliant with immunosuppressive treatment, leading to the subsequent risk of graft rejection.

The comorbid association between hepatitis C and alcohol (affecting 30-40% of alcoholic patients) does not constitute a contraindication for LT. It includes problems in management which are relative to both diseases. The natural history of this comorbidity is usually the result of intravenous drug use, which is the source of hepatitis C virus contamination, followed by alcohol dependence. Alcohol is a known factor of cirrhogenic evolution in hepatitis C.

Likewise, the association of alcohol and tobacco requires careful attention in that patients who abstain from alcohol may increase their tobacco consumption. It is therefore recommended that a nicotine substitute be considered.

In conclusion, alcoholic cirrhosis remains a good indication for LT, with success and failure rates comparable to LTs for nonalcoholic cirrhosis.

A 6-month period of abstinence before transplantation, required by certain teams, may be justified when carried out as part of a larger strategy for management of alcohol dependence. It should take into account time for motivation, achievement of abstinence, and for the prevention of relapse, and should never be carried out under the pretext of coercion. It is necessary that as much importance is accorded in the posttransplantation period to the treatment of the causative disorder of alcoholic cirrhosis as in cirrhosis of other origins.

LT for alcoholic cirrhosis should be a central event in the management of the alcoholic patient, imposing certain responsibilities on the medical team in his follow-up care. The participation of a team specialized in alcoholic-related problems in this period should be recommended and their involvement should be based on a contract of care. Without being a written document, this contract may be seen as a therapeutic alliance in which empathy plays a key role.

Societal attitudes towards the patient must change. The alcoholic patient should be considered as suffering from a double pathology, both hepatic and alcoholic.

QUESTION 3. WHICH CANCERS OF THE LIVER CAN BE TREATED WITH LT?

The annual incidence of HCC in cirrhosis is about 5%. A recent French study showed that the number of new cases of HCC has gone from 1,500 to 5,000 cases per yr in 20 yr. Statistical modeling suggests that this incidence is going to increase further in the coming years due to the epidemic of viral hepatitis C.

Due to the existence of underlying cirrhosis in the majority of cases, surgical resection can only be performed on a minority of patients. The initial use of LT in the treatment of liver cancers became immediately promising, since it allowed simultaneous treatment of both the cancer and cirrhosis, which should be considered a preneoplastic lesion. LT was first performed for inextricable tumors by partial hepatectomy. The results were highly discouraging. While HCC as an indication for LT seemed doomed, a retrospective analysis showed that these tumors are very heterogeneous and that prognosis depends on the size, the number of tumors and vascular invasion. This was confirmed by a prospective study carried out by a team in Milan, which showed that survival after transplantation for early HCC was similar to that for benign liver disease. LT is contraindicated in case of metastasis, and vascular invasion, therefore this option may only be offered to a small number of patients.

Today in Europe, HCC represents 15% of LT indications. The evaluation of LT indications is not based on any randomized prospective study comparing this treatment to another; only cohort studies are currently available.

I. What Are the Indications for Liver Biopsy?

Biopsy of hepatic tumors is not contraindicated in LT candidates; this is provided that there is protection from tumoral seeding along the abdominal wall and careful selection of indications (single tumor without metastasis) (expert opinion). Liver biopsy can therefore be useful in the pretransplantation assessment but interpretation difficulties may be encountered related to sampling error and interobserver variability. The goal of the biopsy is to specify the nature of small isolated nodules and to avoid false positives. In fact, 14% of American patients recently transplanted for small-sized tumors did not have cancer on the hepatectomy piece.

In patients with larger tumors, biopsy helps to detect histological criteria of poor prognosis which would contraindicate LT. Considering the inhomogeneous character of the tumor nodules, biopsy has decision-making value only if it finds poor prognostic histological factors. The analysis of tumors after total hepatectomy allows negative factors to be defined, such as poor histological differentiation and/or the presence of microvascular invasion. The frequency of these negative histological factors seems to be correlated to tumor size. While the prognostic value of these factors at the time of the pretransplantation assessment has not been demonstrated, some teams advocate patient exclusion from the transplant list in the presence of a poorly differentiated tumor due to the high risk of recurrence. The jury can not settle this question and so suggests that specific studies be carried out.

II. The Milan Criteria

HCC composed of an isolated tumor of less than 5 cm or of 2 to 3 nodules less than 3 cm are the best validated indications for LT (Milan criteria) (grade B). Transplant cures 2/3 of these patients with a survival without recurrence comparable to that of patients transplanted for cirrhosis without tumor. While LT is the most efficacious treatment in the long-term, HCC less than 2 cm (T1 of the tumor-node-metastasis classification) should no longer be considered an automatic indication of LT except in the case of Child-Turcotte-Pugh C cirrhosis (expert opinion). This is due to the existence of alternative therapies, the risk of false positives, and the scarcity of grafts which is bound to worsen in the foreseeable future.

The criteria which should be considered are:

• age, size less than 5 cm;

• number (less than 3);

• tumor type (histological differentiation, may be difficult to obtain);

• venous invasion, sometimes difficult to predict or diagnose.

III. Indications Under Consideration

III.1. Small HCC: Should the Indications for LT Be Limited?

In the case of isolated tumors less than 2-3 cm, therapeutic alternatives may be considered and should be compared to LT in terms of efficacy and cost.

III.2. HCC Beyond the Milan criteria: Can Indications for LT Be Expanded?

A total of 28% of HCC transplants in France exceeded the size of the Milan criteria. Tumors as defined by the University College of San Francisco criteria (1 nodule <6.5 cm diameter, or several nodules with a total diameter no more than 8 cm, the largest being <4.5 cm) had a 50% survival. The jury recommends an evaluation to confirm this 5-yr survival and to specify the prognostic factors, particularly those which are histological and biological. It is essential, taking into account the scarcity of grafts, that such LTs be performed only within therapeutic trials.

IV. The Waiting List

About 10% of patients after 6 months and 35% after 1 yr are removed from the list due to tumor progression, death. or transplant contraindications. This raises the question of treatment during the waiting period, particularly chemoembolization and/or radiofrequency. Till now, there has been no evidence of its value (grade C). A living donor may be considered if the expected wait time seems excessive (particularly in cases of rare blood groups).

V. Other Cancers

The role of LT in the medical management of malignant tumors other than HCC is uncertain due to the multiple etiologies, the heterogeneity of the medical care approach, and the methodological insufficiency of data in the literature.

Rare patients who are afflicted with hepatoblastoma, epithelioid hemangioendothelioma, or carcinoid tumor metastasis are authorized to receive transplants since the usual 5-yr survival is 50% (grade C).

The conditions for transplant in metastatic colorectal cancers, pancreatic endocrine tumors, and peripheral cholangiocarcinoma contraindicate these indications. They are either resectable and do not require transplant, or they are inextirpable by partial hepatectomy, hence advanced, and the transplant would have poor results.

Hilar cholangiocarcinoma appears to be part of the latter mentioned group: the high rate of recurrence and the frequency of septic complications, combined with the scarcity of grafts has contraindicated this indication for the majority of teams. Recent experience from the Mayo Clinic raises the issue once more, however it concerned an extremely selected group (2% of patients), required burdensome adjuvant treatment and consisted of only 28 cases.

QUESTION 4. WHAT IS THE ROLE OF THE LIVING DONOR IN LT?

I. Preface

Living donor-related organ transplantations are one of the rare therapeutics, which depend on the integrity of a person other than the patient himself as a technical condition to the procedure, and which may possibly jeopardize his health, his living conditions, and even his life. For this reason, living donor liver transplant (LDLT) requires original and thorough examination. This consensus conference offers the opportunity to continue to clarify the proceedings of the 1993 conference.

Considering the current state of knowledge, it is legitimate to begin by asking whether the LDLT represents:

• a technique which may be used to compensate for the lack of cadaveric graft resources in a time of great need, but which poses considerable medical, psychological, social, as well as relational difficulties between the donor and recipient;

• or a technique that is evolving toward full legal status, justifying the pursuit of improved results and social guarantees, while remaining cautious about its long-term future, which is conditioned by social acceptance at large;

• or the initial state of a technique that will become fully mature from a medical, social, and especially cultural perspective. Indeed, in our countries, cadaveric organ transplantation has itself become part of the moral culture, both symbolically and philosophically.

In the first case, LDLT should be immediately discarded as an option, together with the principle of maximal therapeutic efficacy. This is due to its incompatibility with the Hippocratic maxim “do no harm.” In the second case, LDLT should be accompanied by the implementation of a specific multidisciplinary observation of its medical, psychological, social, and philosophical aspects in order that a decision may be made on the future of the technique. It would then be helpful to have guarantees of the donor's decision, and of the follow-up of the donor and of his needs, both material and moral.

In the third case, it is important that deliberations be undertaken now, based on a large transdisciplinary approach, concerning cultural questions about the living donor. In particular, consideration on:

• the essence of the donation, in so far as it does not fundamentally involve return compensation (which of course should not exclude all other forms of care of the donor which will be addressed later);

• the essence of the decision (that of both the donor/receiver), in so far as, though it is said to be “informed,” the decision may be affected by factors which go beyond the scope of information given (e.g., emotional), evading the rationality and “freedom” of choice required.

• the essence of the social or community ties, as to this being a gesture which belongs, in our culture, to the most intimate sphere (since it is nothing less than a question of love or compassion).

An alternative interpretation would be a very different cultural model in which an individual would have the same value to the group as to himself and in which the “gift of self” would have a meaning similar to that of a religious and/or patriotic sacrifice. The remarkable differences seen in attitudes toward LDLT by societies with a higher degree of social integration (such as Turkey, Egypt, or Algeria, and more generally the holist model societies, in the anthropological sense of the term, that is to say forming a “whole”) incites thought in this direction; however, this may raise other problems—some considerable—as to the implications of similar models, like the subordination of certain social groups (women, etc). When the question of living donation is raised in relation to a person deprived of decisional and psychological autonomy, it is all the more necessary to give thought to the cultural model and the nature of the community ties.

Keeping in mind the limitations of the above-mentioned considerations, the responses of the jury stem from current understanding and laws.

II. Legal Framework

The Bioethics Law of 1994 defined the circle of donors as the father, mother, brother, sister, child, and spouse, the latter in an urgent situation. The Bioethics Law of August 2, 2004 expanded the circle of donors: “…the donor should be the father or mother. Through derogation, the following persons are also authorized to consent to organ harvesting in the direct therapeutic interest of the receiver: his spouse, his brothers or sisters, sons or daughters, grandparents, uncles or aunts, first cousins and other cousins as well as the spouse of his father or mother. The donor can also be any person showing proof of a common life of at least two years with the receiver.”

The donor must be an adult.

“The donor, informed prior by the expert committee mentioned in article L 1231-3 (of the Public Health Code) of the risks incurred and of the potential consequences of organ removal, must express his consent before the president of the county court or the magistrate which he appoints, which ensures beforehand that the consent is free and informed and that the donation conforms to the conditions expressed in the first and second paragraphs. In case of vital emergency, the consent is obtained, through all means, by the public prosecutor. The consent is revocable at any time without conditions.”

“The authorisation (concerning donors other than the mother or father) is issued subsequent to the expression of consent by the expert committee” (Article L1231-1 of the French Public Health Code).

The term living donor must be understood as familial living donor, since current law does not authorize organ removal beyond the family structure.

The response to the question should take into account 3 elements:

• i
  the rationale (justification) for the choice of LDLT is embedded in 2 dimensions:

  • a cultural dimension, in countries where cadaveric liver transplant is inconceivable. It may be necessary someday to determine if and under what circumstances this applies in France, based on changing cultural demographics of the population; an economic dimension related to;

  • the scarcity of grafts, though insisting on the existing need to search for new sources of grafts (with consideration of subject age, donors with cardiac arrest, etc.);

  • the need to find a graft quickly for emergency situations or to shorten the waiting time in less urgent cases so as to reduce the risk of death, which is estimated as 7 % of patients on the waiting list. This procedure must not try to expand the indications beyond those that have already been defined for LT with a cadaveric donor (CDLT).

• ii
  the current state of LT with living donors in France and Europe. LDLT has developed mostly over the last 10 yr, mainly due to the overall scarcity of grafts and especially to the more rapid availability of living donor grafts. The initial experiences concerned children, followed by adults, especially beginning in 1994. Currently in Europe, the annual number of LDLTs is about 340, with an adult-child ratio of 2:1. In France, the total LDLTs performed from 1992 to October 2004 was 302, with a yearly average of 40-50 over the last 5 yr. Overall in Europe, the percentage compared to the total number of CDLTs does not exceed 2.9% (5% in France in 2003) and only 12/24 centers are involved in France.

The techniques have evolved, but the experiences of the centers are heterogeneous. As a result, according to the retrospective data, it is not possible to make a fine and comparative analysis of LDLT compared to other procedures, particularly according to the indications. However, this treatment, which must remain as a recourse, has acquired legitimacy through the results of graft survival, which are somewhat better in children than in adults, though are comparable overall to those of CDLT (grade B). A comparative prospective study is not feasible in practice, but the maintenance of a thorough transplantation registry is absolutely essential.

LDLT clearly has an advantage due to the more rapid availability of the graft in urgent situations. Excluding urgent cases, it considerably decreases the waiting time, avoiding a fraction of the 7% of deaths on the list. It also allows for better evaluation of the donor, better preparation of the receiver, and all the advantages of a scheduled intervention, including the reduction in cold ischemia time.

However, LDLT presents very specific problems, which should reserve its use to experienced centers (the available data shows a correlation between the experience of a team and the transplant results).

The volume of the liver that is removed should be taken into consideration; first, to avoid complications of liver failure in the donor; and second, to avoid graft dysfunction in the recipient. For instance, if the graft of the left lobe or left liver seems sufficient in children, graft survival is significantly lower than that of the total liver and right liver in adults (grade B). Even if the morbidity/mortality is higher, the right liver graft is therefore preferred in the adult.

In the publications available to the jury, the vital risk for the donor is about 0.27% in Europe (0.46% in right LT), and the negative impact on this type of graft can be measured by the very publicized death of a donor in the United States in 2002.

The postoperative morbidity (hemorrhage, biliary leak, pleurisy, pneumonia, infection, pulmonary embolism, etc.) for the donor is on average 27%. It is negatively correlated with the experience of the teams and their volume of activity. The long-term morbidity is not known.

It is necessary to note that perioperative complications are more frequent for the receiver as well than with a total liver, even if the mortality does not seem to differ. The jury does not have sufficient information to form an opinion on the difference of results according to etiology, even if certain publications suggest that viral recurrence is more severe in hepatitis C and that there is better graft survival in fulminant hepatitis.

Finally, it has been confirmed that morbidity is statistically correlated to the extent of the hepatectomy. Observed complications after right hepatectomy total 25%, compared to 10% after left hepatectomy or left lobectomy.

III. Contraindications

The contraindications of LDLT for the donor, beyond those noted in the legal framework and those concerning the receiver, are related, more than age, to:

• the volume of the graft, which should not be less than 0.8% of the receiver's weight, nor more than 70% of the volume of the total liver;

• the quality of the hepatic parenchyma (no fibrosis, nor steatosis higher than 30%);

• the anatomic variations of the liver;

• transmissible viral infections;

• general comorbidity, coagulation anomalies, obesity, etc.;

• severe or disabling psychiatric disorders.

Also, certain anatomic anomalies of the receiver, particularly vascular ones (for example portal thrombosis, etc.), are also contraindications.

IV. The Consent

The donor consent, after passing through the expert committee as described in the Law of 2 August 2004, must be found by the medical team to be authentic, informed and without constraints, in addition to being spontaneous from the beginning and then well thought out.

V. Preoperative Assessment of the Donor

The donor is the central player in the LDLT. The widening of the circle of donors increases the number of potential donors, thereby qualifying more people for the donor candidature process, with its implications both medical and psychological.

The psychological aspect therefore constitutes one of the essential keys to the success of the operation for the donor. Therefore, the following need to be verified:

• the donor candidate's ability to understand the risks and benefits for himself: mortality and morbidity are linked to the intervention itself as well as to its long-term effects; the donor candidate's ability to understand the risk of mortality and morbidity for the recipient; the clarity of the consent or of its expressed refusal, as well as, the recognition that at any time throughout the process the initial decision may be revoked, whether in consent for the donation or its refusal; the apprehension held by the donor candidate regarding potential risks, and the anticipation of the psychological consequences related on one hand to the donation of self and on the other, to the changes in the relationship with the receiver, as well as his significant others.

The donor's generosity may confer to himself a temporary sense of valor due to his consent. The return to daily life may then meet with psychological difficulties which warrant a postdonation follow-up. Likewise, the psychological consequences of any contraindications that may have been revealed during the medical assessment should be anticipated by the multidisciplinary team.

The psychological and medical assessment should therefore be adapted according to the “super-urgent” circumstances, but also to the psychological profiles of donor candidates.

The consent, both before the public prosecutor and the expert committee, should proceed from the provision of information and the verification of its comprehension and assimilation. The expert committee issues an authorization, which is a prerequisite to performance of the intervention.

The true validity of the informed, voluntary, and authentic consent is difficult to estimate for several reasons. Firstly, the long-term consequences for the donor are unknown; decisions are often made in the context of urgency or extreme urgency; and the internal pressures (psychological) and external ones (sociofamilial) are difficult to control.

VI. Recommendations

According to the jury, LDLT is an exceptional recourse solution. The implementation of a follow-up registry of donors is imperative. The main arguments for this intervention are:

• in children, biliary atresia (65%) and metabolic diseases (13%),

• in adults, the scarcity of grafts and the increase in the median waiting time for a graft, making LDLT a better option than CDLT for cancer or cirrhosis and less often indicated for acute liver failure or retransplantation.

VI.1. Nonurgent Situations

LDLT should not be considered without investigating all other solutions beforehand (split, domino liver, etc.), and being sure that the possibilities have been exhausted for an etiologic treatment which could be at least partially effective (such as alcohol abstinence).

The acknowledged indications for CDLT must be followed. There is no particular indication than perhaps allowing more rapid accessibility in the case of primary liver cancer.

Before completing the legal consent procedure, the following steps should be considered, in order:

• preliminary information is provided for the recipient regarding LDLT in the case when CDLT is not possible;

• agreement of the recipient is obtained before searching for a living donor;

• open discussion with the potential donor(s) and the recipient is instituted, giving general information and responding to questions;

• initial preoperative assessment of the donor is begun, with the intention of detecting contraindications: infectious process transmission, coagulation anomaly, anatomic variations, medical comorbidity, and psychiatric disorder. The potential donor should be allowed to interrupt or terminate the procedure at any time;

• informed, voluntary, and authentic consent of the donor is obtained. The medical team must especially ensure the absence of strong familial constraints that could alter the authenticity of the consent;

• following postdonation events and needs thereof, the jury insists on the necessity of long-term follow-up of the donor, in terms of medical, psychological and social care;

• an analysis of social and financial consequences (loans, insurance, etc.) of the donation is necessary; the potential compensation should be an issue of national concern;

• LDLTs should be restricted to experienced centers, considering the link between improved results and acquired experience.

VI.2. Cases of “Super-Urgency”

The members of the jury do not have a definitive position but emphasize:

• the absolute necessity that the donor have a medical and psychiatric assessment, the most thorough possible, taking into account the time allowed by the “super-urgency” state;

• the future family difficulties considering the broadening of the definition of living donor: excessive solicitations, perhaps even unjustified, of family members other than first degree relatives.

The complete success of the intervention integrates adequate overall care before and during the procedure and in the long term for all involved: donor, receiver, and significant others.

VII. What Are the Surgical Means Available, Other Than the Living Donor, for Palliating the Lack of Hepatic Grafts?

Three techniques have been developed, other than LDLT, in order to increase the number of available grafts in a situation of cadaveric graft scarcity: the bipartition of the liver (split), sequential transplantation (domino liver), and liver procurement from a cardiac arrest donor. The reutilization of a recently implanted graft in a patient suffering perioperative cerebral death to the advantage of another recipient is a rare possibility and a decision can only be made on an emergency basis by the transplant team.

These three procedures require, especially for the bipartition technique, very skilled surgical teams, which have perfectly mastered these techniques. They also require sophisticated organization of the operative procedure and the collaboration of several teams.

VII.1. Bipartition (Split)

The crucial point is the selection of the available organ according to accepted criteria by the principal teams experienced in this technique. Total confidence between the organ procurement and receiving teams is essential. The survival results in the most experienced centers, after a less favorable initial period, are comparable between patients receiving a right hemiliver and those receiving a whole liver (grade B). The results in recipients of a left hemiliver transplant are only positive in children. They are not as good in adults (nonfunctioning graft, biliary, and vascular problems) (data of the literature). The ideal therefore is to divide the liver between an adult and a child (literature and experts). If two adults are to receive the liver, the one receiving the left graft (which is exposed to an increased risk of complications and reduced hepatic volume) should be carefully selected, particularly according to weight. According to the experts, the use of bipartition could increase the number of grafts by 10%.

VII.2. Sequential or Domino Transplantation

This mainly applies to familial amyloid polyneuropathy in which hepatic transplantation has become the treatment of choice. The utilization of the explanted liver in the patient is possible for the graft since it is anatomically normal and does not provoke amyloid deposits in the recipient with a mean follow-up of 21 months (data from the literature); indeed, the disease appears after more than 10 yr. The series are limited (1.7% of grafts in France), and the results in the medium- and long-term are not sufficiently known.

In the case of primary hyperoxaluria, the transplanted liver may induce renal injury after 4 to 48 months (literature) and the use of these livers cannot be accepted except under extremely exceptional circumstances, such as super-urgency.

VII.3. Marginal Livers

The utilization of marginal livers cannot be accepted routinely but may be used by recipients with life-threatening live disease at short term. The literature shows (in more than 100 patients) that HCV-positive grafts give results, which are comparable to those of HCV-negative grafts in HCV-positive receivers.

VII.4. Cardiac Arrest Donor

Organ procurement from a cardiac arrest donor is not currently authorized in France. Published experience shows that the results are not as good as those for renal grafts due to the prolonged ischemic phase. Furthermore, problems with material organization are many and often limiting; the latter is because of constraining situations, when familial information has to be delivered in extreme urgency, which are imposed by necessary procedures for the donor body (refrigeration, extracorporal circulation). These are always complex and require the immediate availability of specialized teams and sophisticated equipment.

QUESTION 5. WHAT ARE THE EXPANSIONS TO LT INDICATIONS?

I. How Should Age Be Taken into Consideration in LT?

In 1983, an age over 50 yr excluded a potential recipient from transplantation.

In 1993, the notion that physiologic age is more important than chronological age opened up a new era in transplantation for subjects over age 60 yr. This evolution has been confirmed in 2005. In fact, it is expected that the ages of donors and recipients will continue to increase. One of 3 donors in 2003 and 4% of transplanted patients were over age 65 yr; 15% of transplant recipients were over age 60. The age of hepatitis C carrier patients who develop cirrhosis and require a transplant is constantly increasing. The proportion of transplanted patients in Europe over age 60 yr has gone from 9 to 16% within the last 10 yr. These were mainly transplants for cirrhosis (69%) and cancer (20%).

Comorbidities increase with age and can negatively affect survival results. The liver itself ages, even if its aging is less than that of other organs, and this might increase the risk of liver graft dysfunction. Vascular aging can make vascular anastomoses more difficult, which can increase the ischemic risk.

I.1. The Impact of Age on the Donor

The limit of age 60 yr is frequently exceeded these days. It does not seem that donor age has an impact on graft survival outside HCV-induced cirrhoses, where older grafts appear to have higher rates of cirrhotic recurrence. In the case of HCV-induced cirrhosis, it is currently impossible to conclude whether or not LT is efficacious in older recipients when the donor himself is older.

I.2. The Impact of Age on the Recipient

The physiological age, as has been pointed out, is more important than the chronological age. In the absence of comorbidity (arteriosclerosis, diabetes, hypertension, etc.), it seems legitimate to accept the transplantation of a patient up to age 70 yr, except if he is already hospitalized in intensive care, which would increase the risk of excessive peri- and postoperative complications. In elderly patients, preoperative assessment should especially focus on vascular and neoplastic disease before the patient is put on the waiting list. The fact that immunosuppression after age 65 yr increases the risk of developing renal insufficiency, hypertension, severe osteoporosis, sepsis, and neurological lesions probably explains why LT survival 8 to 10 yr posttransplantation in patients over age 60 yr is significantly less than for those under 60 yr (approximately less than 10%). Short-term survival is not very different at 1 or 2 yr. Therefore, the indications should not differ from those generally accepted for younger patients.

Therefore, if recipients over age 65 yr can not be excluded from the outset, it is essential to take the presence of comorbidities into consideration.

II. Liver Retransplantation (Medical and Surgical Aspects)

The incidence of liver retransplantation is about 10% in the majority of series. Overall, the rate of survival in both children and adults is 20% less than that observed after primary transplantation (42% vs. 63% at 5 yr, 35% vs. 55% at 10 yr). It is somewhat better for retransplantations performed within 8 days.

In France, primary nonfunctioning of the graft or thrombosis of the hepatic artery results in early retransplantation before 8 days in super-urgency. Retransplantation for ischemic necrosis or rapid functional failure of the graft can be performed according to a regional emergency procedure after college of expert approval.

Late retransplantation, also called elective, is incompletely defined, falling neither under the heading of being urgent nor super-urgent. Published studies on these late transplantations lack homogeneity due to the variation of definitions. Therefore, a European evaluation regrouping the retransplantations according to time (before 8 days, after 3 or 6 months, and intermediaries) is necessary.

Chronic rejection as a cause of elective retransplantation has diminished in the last several years. The recurrence of the initial disease represents the principal indications for late retransplantation. Recurrence of HBV infection as a cause for retransplantation has tended to diminish (bibliography and expert opinion). The results of retransplantation for HBV recurrence have not been completely reported. HCV recurrence is already a significant cause for retransplantation that is rapidly becoming dominant. The recurrence of the disease on the second graft, particularly in the case of hepatitis C, is even more problematic in the medium-term than for the first transplant. The predictive factors of worsening evolution are the same as after a first transplantation, including the age of the donor. The main causes of postretransplantation death are mainly sepsis, followed by cardiovascular failure. Contraindications to retransplantation do not exist in the literature, nor are they reported by the experts. However, renal insufficiency, which is frequent, poses a difficult problem. It is important that a common position of the involved teams be defined while remaining flexible. The decision of retransplantation rests first of all on the detailed analysis of the patient's wishes, and should take into account physiologic age and subsequent treatment options of etiologic factor(s). The utilization of a living donor graft has been done but remains rare.

The U.S. teams base their arguments on the indicators of severity for retransplantation decisions (Model for End-State Liver Disease score), but this score is not very predictive of posttransplantation mortality. Other scores are being developed but have not been validated. Currently, as grafts are allocated to a transplant team, it is the team that makes the final decision for distribution between retransplantation and primary transplantation. The jury encourages, at the request of several experts, the definition of “transplantability scores,” including the risks of mortality on the waiting list and the risk of post-graft mortality.

III. Indications for Multiorgan Grafts

These represent 5% of CDLTs, mainly liver-kidney grafts, and are given a status of regional priority for the allocation of multiple grafts. If the indication of liver-kidney graft is indisputable in a condition such as Type I primary hyperoxaluria (in which double transplant should be discussed before the appearance of renal insufficiency) or in hepatorenal polycystic disease, it is much more questionable in cirrhosis. For instance, the indication in the case of alcoholic cirrhosis, associated with chronic preterminal nephropathy, is not clearly defined, while the interpretation of biological data in a malnourished patient can be all the more difficult. In viral cirrhosis, the overall survival is not different when compared to isolated CDLT. The hepato-renal syndrome is not an indication since renal injury is reversible after LT alone. The observed protective effect of the LT on the rejection risk of renal graft remains unexplained.

Whether patients needing double grafts should be granted priority, has been debated by the jury. Automatic prioritization of these patients has been criticized in favor of a case-by-case assessment. As for liver-heart or liver-intestine grafts, the lack of necessary donations to be able to correctly evaluate their indications requires an international collaboration and their exhaustive submission to a registry.

CONCLUSION

The scarcity of organ donations and the growth of increase must not push research efforts exclusively toward finding surgical techniques and always-more-complex substitute solutions.

Thanks to, or due to, medical-surgical innovations, which are increasingly bold, humanity today has become a permanent interactive network of resources; this should meld with the cultural mentality and therefore encourage the foresight of donor registration from people who may reach a state of cerebral death. Being a question not only of generosity and compassion, it is also a true pledge of human solidarity.

The scarcity, more appropriately called rarity, of transplantable organs, is not a situation to which we should resign ourselves. Some French and European examples show the efficacy of regional or national initiatives for maximizing donations.

It is only within this context that the expansion of new indications can be discussed. The recourse of the living donor, of the cardiac arrest donor, of split LT will certainly be able to improve the situation, but will never replace the pool of available grafts that have not been exploited. A major effort must be deployed in this field without hesitating to confront the contemporary cultural obstacles. The first of these is the paradox of an individualistic society that simultaneously demands the use of medical resources while being opposed to organ donation.

This consensus conference released several recommendations, which grew out of these reflections.

• 1
  The efficacy of transplantation for HBV-induced cirrhosis is excellent, thanks to antiviral therapies. The control of the recurrence of the viral infection is generally ensured after the graft.
• 2
  The frequent relapse after transplantation for HCV-induced cirrhosis, linked to the weakness of antiviral therapies, impedes the long-term results and justifies that major efforts be made in optimizing treatment and screening before broadening the current legitimate indications.
• 3
  The question of alcoholic disease should be integrated with other hepatic pathologies without moral value judgement. Pregraft and especially postgraft alcoholic care is an element of importance that cannot be emphasized enough.
• 4
  The extension of indications for tumors beyond the usual Milan criteria must be justified by multicentric protocols.
• 5
  The possibility of therapeutic recourses other than the first transplantation should be considered for small tumors according to collectively accepted criteria at the exception of Child-Turcotte-Pugh C cirrhotic patients in whom LT is the sole option.
• 6
  The LDLT does not need to have further indications than those given for cadaveric donors. They remain a recourse solution, which should be reserved for experienced centers.
• 7
  Comorbidity is a factor of exclusion for transplantation that is more decisive than age itself.
• 8
  Sharing results, proposals, thoughts, and experiences is of foremost importance in LT, as this is key to achieving efficacy and positive results. Networking between centers is a major requirement.
• 9
  The utilization of means for providing better information and education to the public and physicians for the improvement of organ donation efforts.

The French version of this text is available upon written demand from: Agence nationale d'accréditation et d'évaluation en santé Service communication, 2, avenue de Stade de France — 93218 Saint-Denis La Plaine cedex, or may be viewed on the ANAES internet site: http:www.has-sante.fr, under the heading “Publications.”