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Ethical considerations regarding early liver transplantation in patients with severe alcoholic hepatitis not responding to medical therapy
Frontiers in Liver Transplantation
Ethical considerations regarding early liver transplantation in patients with severe alcoholic hepatitis not responding to medical therapy Vincent Donckier1,⇑, Valerio Lucidi1, Thierry Gustot2, Christophe Moreno2 1
Department of Abdominal Surgery, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; 2Department of Gastroenterology, Liver Transplant Unit, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Summary
Ó 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
A recent study proposed that liver transplantation may represent life-saving treatment in patients with severe alcoholic hepatitis not responding to medical therapy. In this pilot experience, stringent patient selection resulted in major improvement of shortterm survival with low rates of post-transplant alcohol relapse. In the context of organ shortage, which imposes a need for strict selection of transplant candidates, these results raise major ethical questions. Reluctance to perform liver transplantation in alcoholics is based on the fact that alcoholism is frequently considered to be self-inflicted and on fears of harmful post-transplant alcoholism recurrence. A minimal interval of sobriety lasting at least 6 months is a widely adopted criterion for the selection of patients with alcoholic liver disease for liver transplantation. In severe alcoholic hepatitis, the disastrous short-term prognosis in patients not responding to medical therapy does not allow one to reasonably impose an arbitrary period of 6-months of abstinence. This means that these patients must be either systematically excluded from transplantation or selected according to other criteria. Without significant pre-transplant abstinence, it might be argued that these patients do not merit a graft as they have not demonstrated their ability to gain control over their disease through durable modification of their behaviour. Consequently, this procedure could have a negative impact in the public, affecting organ donation and confidence in the fairness of transplant programs. In contrast, ethical principles recommend active treatment of patients, without discrimination, according to the best scientific knowledge. At this stage, we propose that there are no major ethical barriers for further evaluation of this new therapeutic option. The next steps should include transparent communication with the public and further studies to reproduce these results and identify the selection criteria that provide the best long-term outcomes.
Keywords: Alcohol; Hepatitis; Severe; Early; Transplantation; Ethic. Received 11 June 2013; received in revised form 15 November 2013; accepted 19 November 2013 ⇑ Corresponding author. Address: Department of Abdominal Surgery, Hôpital Erasme, Université Libre de Bruxelles, 808 Route de Lennik, 1070 Brussels, Belgium. Tel.: +32 2 555 43 32; fax: +32 2 555 49 05. E-mail address: [email protected] (V. Donckier).
Introduction The lack of available organs for transplantation imposes a need to define priorities for graft allocation and creates a situation in which the objectives of equity, justice, utility, and benefit are frequently in conflict and impossible to fully reconcile. As transplantation is, in many cases, a life-saving procedure, the selection of transplant recipients is a crucial question, integrating major ethical aspects. Such dilemmas, where optimal individual treatment cannot be provided to each patient, are not unique in modern medical practice. These choices are made in similar cases where financial limitations exist in many parts of the world, such as in cases where patients lack medical insurance or do not have the ability to pay for the costs of medical care. It is therefore a primary necessity for the transplant community to establish a fair system for organ allocation and to define the selection criteria for admission to transplantation waiting lists. This will require regular re-evaluation of the criteria used for selection and prioritization of organ recipients, and verification of the adequacy of the system based on patient outcomes. There is also a need for clear definition of the desirable end-points, which may vary from the evaluation of primary disease recurrence, to graft and patient survival, or to social re-integration. In addition, these reflections must be shared with the public who are central actors in the success of transplantation programs as organ donors and providers of the health care system. It is in this context that a pilot study recently evaluated the role of early liver transplantation (LT) in treatment of patients with severe alcoholic hepatitis (SAH) not responding to medical therapy [1]. In this indication, LT was performed rapidly after the diagnosis of alcohol-induced life-threatening liver failure, without respect to the broadly-accepted rule that 6 months of alcohol sobriety must be achieved before a patient is accepted onto a waiting list for LT. As might be expected, this new therapeutic proposal created vigorous discussions within the institutions involved in the study and in the transplantation community. The central point of controversy is the question of the fairness of the allocation of scarce transplantation resources to patients who have not demonstrated a period
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JOURNAL OF HEPATOLOGY of abstinence from alcohol. Reluctance to adopt these programs is, in part, related to concerns about the risk of harmful alcohol relapse after LT, potentially leading to the waste of a precious organ. Further, some people believe that these patients do not deserve a transplant, as their condition is often considered to be self-inflicted and patients at this advanced stage have not convincingly shown repentance for their behaviour by demonstrating an ability to gain control over their disease. These debates, concerning patients with SAH, and the broader group of patients with alcoholic liver disease (ALD), trigger fundamental ethical questions about the selection of patients for transplantation. These include a necessity to respect the right of each individual to be treated without discrimination, the interpretation of notions such as the merit to be treated, the responsibilities of the medical community to the public, the relationship between public opinion and medical decisions, and finally, the potential conflicts between moral and ethical positions in the context of medicine.
Patients with severe alcoholic hepatitis not responding to medical therapy as potential candidates for liver transplantation SAH is a well-defined entity, corresponding to clear clinical, biological, and histological criteria [2]. Alcoholic hepatitis (AH) is a clinical syndrome associated with recent onset of jaundice and/or ascites in a patient with ongoing alcohol abuse, and characterized, at the histological level, by the presence of steatosis, hepatocyte balonization, and inflammatory infiltrate [3]. Severity of AH can be objectively graded, on the basis of laboratory data, using the Maddrey function [4]. SAH is defined by a Maddrey discriminant function P32 and is associated with a high risk of early mortality [4]. Among patients with SAH, medical therapies, particularly corticosteroids, have proven effective in reducing mortality [5–7]. However, the prognosis remains very poor for patients not responding to medical therapy with 6-month mortality rates of 75% [8]. The majority of these deaths occur in the first 3 months [8]. A major step forward for the management of SAH has been the development of the Lille Model, which allows rapid evaluation of the response to treatment on the basis of bilirubin level evolution at day 7 [8]. It is in the subgroup of patients, identified by the Lille Model as presenting with SAH not responding to medical therapy, that LT was first advocated [9] and then evaluated [1]. Not surprisingly, in these patients, LT provided a highly significant short-term survival advantage as compared with a matched group of non-transplanted patients [1]. In transplanted patients, the 6-month survival rate was 77% as compared with 23% in control patients and 90% of deaths in this last group occurred within 2 months after the identification of the non-response to medical therapy. This benefit was maintained at 2 years in transplanted patients, with overall survival reaching 71%. Certainly, longer follow-up is required to recommend LT as an option in these patients but these results serve as a proof of concept for further evaluations. Importantly from an ethical point of view, this also means that LT was performed in approximately 25% of the SAH cohort who would have recovered despite failing medical therapy, raising the issue of providing a liver graft to someone who was destined to recover and underlining the need for other predictive markers of early mortality in this setting.
The 6-month rule and other potential selection criteria for liver transplantation in patients with severe alcoholic hepatitis not responding to medical therapy In current practice, compliance in patients with ALD who are candidates for LT is predominantly evaluated by their presumed capacity to remain abstinent after transplant. In the selection process, a patient’s adhesion to this principle can be considered to be part of a contract with his treatment team. The rule that 6 months of alcohol abstinence is required before acceptance to the LT list is broadly applied worldwide and has two main objectives: First, to challenge a patient’s motivation and to identify those that will remain abstinent after LT, and second, to evaluate the possibility for stabilization or improvement of liver function, which may eventually obviate the need for further LT. The validity of the 6-month rule has been recently debated in the literature [10]. Several weaknesses of this criterion have been shown, including its arbitrary duration, limited specificity [11], limited predictive value [11–13], and the fact that it does not consider the presence of other predictive factors associated with alcohol relapse, such as drug dependence, tobacco use, or depression [12]. Still, on a consensual basis, 6 months of abstinence remains accepted as obligatory for listing ALD patients for LT. In addition, some may argue that the ability to respect the 6month abstinence period is a necessary step toward reassuring the community that the patient merits a transplant [14]. While this concept is debatable, it widely exists in the medical community and in the public, influencing, at least subliminally, the entire discussion about the fairness of LT in patients with ALD. For patients with SAH not responding to medical therapy, however, the question relies more on the applicability of the 6-month rule than on its validity. In these patients, both objectives of an observational period before transplant decision are essentially elusive when one takes into account the nearly 70% mortality rate at 3 months and the very small chance for spontaneous clinical improvement. Realistic options are, therefore, either to systematically deny these patients for transplantation or to evaluate other potential selection criteria that can be obtained in a time period compatible with rapid therapeutic decision. In the first prospective study in patients with SAH not responding to medical therapy, strict selection criteria were applied, including first liver decompensation, strong familial support, absence of psychiatric disorders, and expressed adherence to lifelong complete alcohol abstinence programs [1]. The selection was based on meetings of multidisciplinary groups that included physicians, specialists in addiction, patients, and family members. In these patients, after a follow-up ranging from 2 to 3 years, alcohol relapse after LT was 11%. Importantly, none of these recurrences occurred in the first 6 months, corresponding to the period classically used to select LT candidates [1]. These selection criteria were extremely restrictive, taking into account the fact that this was a pilot study and, at this point, additional work is needed to assess their reproducibility. Restricting inclusion to patients in their first episode of decompensation is based on the concept that patients who had previous episodes of liver failure deliberately chose to ignore a warning. This is ethically questionable as it introduces a judgmental aspect to the therapeutic decision, leading to distinct treatments for patients with the same disease based on their different behaviours. In addition, group decision making itself carries its own limitations, as it may be influenced by individual authorities, potentially leading to some form of subjectivity [15].
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Frontiers in Liver Transplantation Although this first prospective study has not validated selection criteria in these patients, it has opened the door to the possibility that LT may be considered an option in highly selected patients, for whom no real therapeutic alternative exists. These data should be now confirmed by other groups and additional work is necessary to refine these selection criteria. This is the aim of an ongoing multicentre prospective study [16]. In parallel to this, an accurate definition of selection criteria requires a precise and consensual identification of the end-points to be reached after transplantation. In ALD, including in SAH, a provocative question concerns the real necessity for exclusion of patients predicted to be at risk of any alcohol relapse from LT programs. In a strict utilitarian view, it may be argued that the primary objective of organ transplantation is to achieve satisfactory long-term graft and patient survival, irrespective of any other considerations. Such a utilitarian end-point may appear limiting but has the clear advantage of being easily, objectively, and transparently evaluable. In this regard, a particular question in ALD is the relation between post-transplant alcohol consumption, and graft and patient outcomes. A correlation between alcohol recidivism and impaired long-term survival has been observed, but mostly due to increased incidence of malignancy and cardiovascular events rather than to toxic effects of alcohol on the liver graft [17]. In this setting, the discriminatory value of the 6-month rule is limited, as duration of pre-transplant abstinence does not correlate with post-transplant survival [18]. Several studies have demonstrated no direct deleterious effects of alcohol drinking on posttransplant outcomes, including therapeutic compliance, graft function, and graft survival [17,19], while others have reported negative impacts of heavy drinking on outcomes [20]. These conflicting data underline the need for better distinction of the different types of alcohol drinking after transplantation, ranging from occasional to moderate or severe, when alcohol habits could correspond to use, abuse, or dependence. This also explains the wide variation among post-LT alcohol relapse rates reported in the literature, ranging from 20 to 50%, and the rates of heavy drinking, which range from 10 to 20% [17,21–25]. In fact, similar rates of any alcohol use have been reported in patients transplanted for ALD and for non-ALD, but the risk of heavy drinking appears much higher in ALD patients [12]. Therefore, in order to proceed with a utilitarian objective, the key would be to identify the predictive factors for harmful recurrent drinking after transplantation. Among patients with ALD, these factors have not been established and one might wonder if the pilot experience in SAH could not be extended to evaluate the added predictive value of criteria such as psycho-social environment, supportive willingness of the family, and systematic multidisciplinary reviewing, as compared with the strict application of a mandatory duration for abstinence before listing. Another level of confusion is related to the heterogeneity of the means for monitoring alcohol use in patients on waiting lists [26,27]. This issue has been partially addressed in retrospective studies evaluating the impact of the presence of histological features of AH on liver explant [28–30]. As histological features of alcoholic hepatitis may persist for a prolonged period after alcohol withdrawal [31], histological observations cannot be systematically interpreted to be the result of the presence or absence of abstinence before LT and are not directly pertinent in the context of SAH. Still, some authors consider the presence of these histological changes to be a marker for clandestine drinking in patients listed for LT [32] and, it could be reasonably assumed that at least a pro-
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portion of these patients had recently drunk alcohol while on the waiting list. Importantly, these studies showed that graft and patient survival were not affected by the presence of histological changes of AH on the explant as compared with control patients transplanted for alcoholic cirrhosis [28,29]. With regard to postLT alcohol use, there was a tendency to higher relapse in patients with histological AH, for which a majority reported heavy drinking [28]. Taken together, if every effort is made to minimize the risk for alcohol relapse after LT, this does not mean that any form of post-transplant alcohol use corresponds per se to a failure of the selection process and of the treatment as its impact closely depends on the type of consumption. The importance given to the risk for post-LT alcohol recurrence in general and its role as a major barrier for development of LT programs in patients with SAH in particular, may also rely on emotional factors. In this setting, an obvious comparison can be made with patients with hepatitis C (HCV)-related liver disease, a non-controversial indication for LT. In HCV patients, viral recurrence is almost universal and 5year cirrhosis recurrence reaches 20 to 30% [33], leading to 5- and 10-year survivals of 67% and 54%, respectively. This is significantly inferior to the 73% and 58% obtained in patients transplanted for ALD [34,35]. Yet, in contrast with post-LT disease recurrence in HCV or in hepatocellular carcinoma, alcohol use after having received a graft for SAH is often interpreted as a breach of contract, vexatious, and hurtful for transplant professionals, and, more importantly, disrespectful for the organ donors.
Potential negative impacts on organ donation Negative public perception of the use of LT in patients with SAH has the potential to negatively impact organ donation. Reluctance to share collective resources for treatment of alcoholic people has been illustrated in surveys showing that potential donor families might refuse organ donation if it is possible that the recipient could be an alcoholic patient [36]. In addition, the attribution of grafts to SAH patients could create a strong impression of injustice because, in MELD-based allocation systems, these patients are transplanted with a high degree of priority, before other candidates, including ALD patients selected according to the 6month criteria. In this situation, however, the risk for a loss of confidence from the public to the transplant practitioners should be weighed against ethical requirements. It was recently stated in the Declaration of Istanbul that: ‘‘Organs for transplantation should be equitably allocated within countries or jurisdictions to suitable recipients without regard to gender, ethnicity, religion, or social or financial status’’ [37]. This general recommendation was not addressed to the problem of alcoholism, but extended to the present discussion, this could be interpreted to mean that potential transplant candidates should not be discriminated against on the basis of their previous individual and social behaviours unless those behaviours have a clear predicted impact on graft outcomes. Undoubtedly, in the public and in the medical community, alcoholic people suffer from very poor image [36,38,39]. Whether this should influence organ allocation is debatable but it should be acknowledged that this would represent a form of discrimination based on moral rather than medical criteria. It is possible that reactive opinions from the public could be balanced by transparent communication about SAH that highlights two aspects of the disease: First, that a disastrous prognosis
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JOURNAL OF HEPATOLOGY can be accurately and objectively predicted in a small subset of patients, and second, that these patients should not be categorized as non-compliant and actively drinking, but rather as patients in whom compliance must be evaluated by other means than a prolonged period of abstinence. An unequivocal distinction should be made, therefore, between evaluation of compliance in SAH patients and failure of pre-transplant abstinence in patients with alcoholic cirrhosis who were previously informed of this requirement for listing. Moreover, the public’s lack of esteem for alcoholic people does not mean that these patients are systematically excluded from general empathy. This has been illustrated recently by the massive outpouring of emotion in the UK when a young patient with SAH was denied LT on the basis of the 6-month rule and finally died [40]. Opinions in this debate were contradictory, but interestingly, some of the arguments that were used in the press to plea for transplantation, such as ignorance of previous liver disease and good familial support, were identical to selection criteria used in the multicentre study [1]. Along the same lines, it should be noted that among different European countries the rates of organ donation are not correlated with the stringency of the selection. In the UK, where criteria for LT are restrictive and alcoholic hepatitis is specified as a contraindication, the donation rate remains low as compared with other countries in which such contraindication is not mentioned.
patient’s complicity in his disease, the indication for LT strictly relies on prognostic scores identifying the patients that will die without transplantation. Remarkably, in patients with SAH, the Lille Model is similarly able to determine the outcome and particularly the risk of rapid death. Still, the distinction of meritorious and non-meritorious patients is widely shared by society and the medical world. Studies that surveyed physicians and the public, found that patients with ALD were placed at a very low level of priority for transplantation, independently of their disease and prognosis, just above the people in prison for violence [36,38]. Interestingly, this opinion was almost equally prevalent among the public, general practitioners, and gastroenterologists. Such a position implies that, comparable to deprivation of the civil rights of criminals, alcoholics are considered to be responsible for delinquent acts and should be deprived of the right to be treated. This represents a central aspect of the present discussion: To refuse treatment to a patient on judgmental or moral bases would correspond in fact to denying the fundamental human right of every individual to be treated without discrimination (The Universal Declaration of Human Rights, article 25) [42]. It would confer to the transplant professional a judgmental position, in profound contradiction with the objective of a fair system for organ allocation. This contradictory practice could discredit the entire transplant organization.
The notion of merit to be treated
Conclusions: The necessity of acting vs. the principle of precaution
The notion of merit for access to medical treatment represents a fundamental issue here. As the entire care system, particularly transplant programs, is primarily built on community support, the concept that patients with disrespectful social comportments may be less deserving of treatment than others could understandably emerge. In much of our society, morality remains profoundly inspired by Judeo-Christian principles. Individual and societal comportments are frequently judged through distinctions of good and bad, and faults are considered to be justification for some form of chastisement. Alcoholism is largely perceived to be a self-chosen condition with negative consequences for the entire society and is therefore considered a faulty behaviour. Therefore, some consider that patients who develop liver failure ‘‘through no fault of their own’’ should have a higher priority for transplant than those whose disease results from misconduct [32]. Accordingly, if disease in this case appears to be a form of natural punishment, restricted access to medical treatment, such as transplantation, would constitute a second punishment, as it is now imposed in a concerted way by society on the basis of judgmental and moral criteria. In this view, transplantation is a privilege, but not a right, and pre-transplant abstinence represents some form of expiation, necessary to regain society’s confidence and access to treatment. The concept that alcoholism is a selfinflicted disease is highly debatable. Alcoholism results from a combination of many factors and the consequences of alcohol intoxication depend on individual variation including genetic predisposition [41]. Therefore, a susceptible individual cannot be considered to be entirely responsible for alcoholism that leads to liver failure. Several other liver diseases that eventually lead to LT can also be considered self-inflicted, including viral hepatitis in intravenous drug users, obesity, or paracetamol intoxication. As an example, in patients with acute liver failure related to paracetamol overdose, independently of interpretation about a
For medical, ethical, and emotional reasons, LT in patients with SAH is a challenging and sensitive procedure, which will require careful evaluation and transparent communication in the coming years. According to the results that have been reported thus far, LT represents a potential new therapeutic option in SAH that cannot be ignored [3]. Still, this procedure raises several delicate questions for which it may be useful to go back to fundamental ethical principles. Major principles in the Hippocratic Oath are Primum non nocere (first do not harm), the notion of beneficence, meaning to act in the best interest of the patient, and the notion of justice, meaning a fair distribution of health resources. Medical ethics also recommend that therapeutic acts have to be performed according to best scientific knowledge of the moment. In current medical knowledge, we may assume that, in the majority of patients with SAH not responding to medical therapy, abstention, which may correspond to systematic denial of LT or the imposition of a period of 6 months of abstinence before decision, would carry a very high risk of harming the patient. In that sense, on ethical grounds, the necessity of acting, that is, to evaluate the possibility of an early transplantation, may override the principle of precaution. In terms of utility also, this is supported by the first results obtained in strictly selected patients, suggesting that LT in these cases represents a valuable use of a scarce resource. The issue of justice or equity, implying a comparable opportunity for everyone to receive treatment, remains much more complex in this setting. In the current situation of organ shortage, the identification of a new indication for transplantation inevitably penalizes the other patients on the waiting list. It is at this point that judgmental or moral criteria may interfere with strict medical decisions. To counterbalance this, objective and reliable selection criteria have to be defined
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Frontiers in Liver Transplantation and globally accepted, both by transplant professionals and the public. Extremely selective criteria of the type used in the first study evaluating LT in SAH patients allowed satisfactory results in terms of survival and alcohol relapse. At the same time, it is possible that these stringent criteria may also introduce a source of discrimination, such as partially relying on nonmedical parameters such as a patient’s socio-economic level [10] that influences the familial environment and support. At this stage, despite many unresolved issues, this first experience has opened a door. These initial favorable results should now be confirmed in longer follow-up studies and by other groups. Major ethical requirements that dictate that we must not discriminate against patients in their access to medical treatment must take precedence over moral considerations and we should continue to move toward defining the precise role of this procedure in the future.
Key Points •
Lack of available organs for transplantation imposes the need to define priorities for graft allocation. Selection criteria for transplantation have to reconcile the objectives of equity, justice, and utility and should be shared by the transplant community and the general population
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Severe alcoholic hepatitis refers to a life-threatening syndrome of liver failure and systemic inflammation arising in persons who have been consuming excess amounts of alcohol. In this condition, the absence of response to medical therapy is associated with extremely high early mortality
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A first prospective study demonstrated that rapid liver transplantation could represent a lifesaving intervention in these patients. In this pilot experience, stringent patient selection resulted in major improvement of short-term survival, and was associated with low rates of post-transplant alcoholism relapse
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In the current context of global organ shortage, this procedure has created controversy in the medical community and in the public. Reluctance to adopt this procedure is mainly related to the fact that these patients have not demonstrated their ability to gain control over their disease, fears of harmful alcoholic recidivism, and perceptions that these patients may be less deserving of a transplant than other patients
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In this situation, principles of medical ethics should take precedence over moral positions, and the need for active and non-discriminatory treatment of these patients with few therapeutic options should encourage further work in this field
Conflict of interest The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
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Ethical considerations regarding early liver transplantation in patients with severe alcoholic hepatitis not responding to medical therapy Vincent Donckier1,⇑, Valerio Lucidi1, Thierry Gustot2, Christophe Moreno2 1
Department of Abdominal Surgery, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; 2Department of Gastroenterology, Liver Transplant Unit, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Summary
Ó 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
A recent study proposed that liver transplantation may represent life-saving treatment in patients with severe alcoholic hepatitis not responding to medical therapy. In this pilot experience, stringent patient selection resulted in major improvement of shortterm survival with low rates of post-transplant alcohol relapse. In the context of organ shortage, which imposes a need for strict selection of transplant candidates, these results raise major ethical questions. Reluctance to perform liver transplantation in alcoholics is based on the fact that alcoholism is frequently considered to be self-inflicted and on fears of harmful post-transplant alcoholism recurrence. A minimal interval of sobriety lasting at least 6 months is a widely adopted criterion for the selection of patients with alcoholic liver disease for liver transplantation. In severe alcoholic hepatitis, the disastrous short-term prognosis in patients not responding to medical therapy does not allow one to reasonably impose an arbitrary period of 6-months of abstinence. This means that these patients must be either systematically excluded from transplantation or selected according to other criteria. Without significant pre-transplant abstinence, it might be argued that these patients do not merit a graft as they have not demonstrated their ability to gain control over their disease through durable modification of their behaviour. Consequently, this procedure could have a negative impact in the public, affecting organ donation and confidence in the fairness of transplant programs. In contrast, ethical principles recommend active treatment of patients, without discrimination, according to the best scientific knowledge. At this stage, we propose that there are no major ethical barriers for further evaluation of this new therapeutic option. The next steps should include transparent communication with the public and further studies to reproduce these results and identify the selection criteria that provide the best long-term outcomes.
Keywords: Alcohol; Hepatitis; Severe; Early; Transplantation; Ethic. Received 11 June 2013; received in revised form 15 November 2013; accepted 19 November 2013 ⇑ Corresponding author. Address: Department of Abdominal Surgery, Hôpital Erasme, Université Libre de Bruxelles, 808 Route de Lennik, 1070 Brussels, Belgium. Tel.: +32 2 555 43 32; fax: +32 2 555 49 05. E-mail address: [email protected] (V. Donckier).
Introduction The lack of available organs for transplantation imposes a need to define priorities for graft allocation and creates a situation in which the objectives of equity, justice, utility, and benefit are frequently in conflict and impossible to fully reconcile. As transplantation is, in many cases, a life-saving procedure, the selection of transplant recipients is a crucial question, integrating major ethical aspects. Such dilemmas, where optimal individual treatment cannot be provided to each patient, are not unique in modern medical practice. These choices are made in similar cases where financial limitations exist in many parts of the world, such as in cases where patients lack medical insurance or do not have the ability to pay for the costs of medical care. It is therefore a primary necessity for the transplant community to establish a fair system for organ allocation and to define the selection criteria for admission to transplantation waiting lists. This will require regular re-evaluation of the criteria used for selection and prioritization of organ recipients, and verification of the adequacy of the system based on patient outcomes. There is also a need for clear definition of the desirable end-points, which may vary from the evaluation of primary disease recurrence, to graft and patient survival, or to social re-integration. In addition, these reflections must be shared with the public who are central actors in the success of transplantation programs as organ donors and providers of the health care system. It is in this context that a pilot study recently evaluated the role of early liver transplantation (LT) in treatment of patients with severe alcoholic hepatitis (SAH) not responding to medical therapy [1]. In this indication, LT was performed rapidly after the diagnosis of alcohol-induced life-threatening liver failure, without respect to the broadly-accepted rule that 6 months of alcohol sobriety must be achieved before a patient is accepted onto a waiting list for LT. As might be expected, this new therapeutic proposal created vigorous discussions within the institutions involved in the study and in the transplantation community. The central point of controversy is the question of the fairness of the allocation of scarce transplantation resources to patients who have not demonstrated a period
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JOURNAL OF HEPATOLOGY of abstinence from alcohol. Reluctance to adopt these programs is, in part, related to concerns about the risk of harmful alcohol relapse after LT, potentially leading to the waste of a precious organ. Further, some people believe that these patients do not deserve a transplant, as their condition is often considered to be self-inflicted and patients at this advanced stage have not convincingly shown repentance for their behaviour by demonstrating an ability to gain control over their disease. These debates, concerning patients with SAH, and the broader group of patients with alcoholic liver disease (ALD), trigger fundamental ethical questions about the selection of patients for transplantation. These include a necessity to respect the right of each individual to be treated without discrimination, the interpretation of notions such as the merit to be treated, the responsibilities of the medical community to the public, the relationship between public opinion and medical decisions, and finally, the potential conflicts between moral and ethical positions in the context of medicine.
Patients with severe alcoholic hepatitis not responding to medical therapy as potential candidates for liver transplantation SAH is a well-defined entity, corresponding to clear clinical, biological, and histological criteria [2]. Alcoholic hepatitis (AH) is a clinical syndrome associated with recent onset of jaundice and/or ascites in a patient with ongoing alcohol abuse, and characterized, at the histological level, by the presence of steatosis, hepatocyte balonization, and inflammatory infiltrate [3]. Severity of AH can be objectively graded, on the basis of laboratory data, using the Maddrey function [4]. SAH is defined by a Maddrey discriminant function P32 and is associated with a high risk of early mortality [4]. Among patients with SAH, medical therapies, particularly corticosteroids, have proven effective in reducing mortality [5–7]. However, the prognosis remains very poor for patients not responding to medical therapy with 6-month mortality rates of 75% [8]. The majority of these deaths occur in the first 3 months [8]. A major step forward for the management of SAH has been the development of the Lille Model, which allows rapid evaluation of the response to treatment on the basis of bilirubin level evolution at day 7 [8]. It is in the subgroup of patients, identified by the Lille Model as presenting with SAH not responding to medical therapy, that LT was first advocated [9] and then evaluated [1]. Not surprisingly, in these patients, LT provided a highly significant short-term survival advantage as compared with a matched group of non-transplanted patients [1]. In transplanted patients, the 6-month survival rate was 77% as compared with 23% in control patients and 90% of deaths in this last group occurred within 2 months after the identification of the non-response to medical therapy. This benefit was maintained at 2 years in transplanted patients, with overall survival reaching 71%. Certainly, longer follow-up is required to recommend LT as an option in these patients but these results serve as a proof of concept for further evaluations. Importantly from an ethical point of view, this also means that LT was performed in approximately 25% of the SAH cohort who would have recovered despite failing medical therapy, raising the issue of providing a liver graft to someone who was destined to recover and underlining the need for other predictive markers of early mortality in this setting.
The 6-month rule and other potential selection criteria for liver transplantation in patients with severe alcoholic hepatitis not responding to medical therapy In current practice, compliance in patients with ALD who are candidates for LT is predominantly evaluated by their presumed capacity to remain abstinent after transplant. In the selection process, a patient’s adhesion to this principle can be considered to be part of a contract with his treatment team. The rule that 6 months of alcohol abstinence is required before acceptance to the LT list is broadly applied worldwide and has two main objectives: First, to challenge a patient’s motivation and to identify those that will remain abstinent after LT, and second, to evaluate the possibility for stabilization or improvement of liver function, which may eventually obviate the need for further LT. The validity of the 6-month rule has been recently debated in the literature [10]. Several weaknesses of this criterion have been shown, including its arbitrary duration, limited specificity [11], limited predictive value [11–13], and the fact that it does not consider the presence of other predictive factors associated with alcohol relapse, such as drug dependence, tobacco use, or depression [12]. Still, on a consensual basis, 6 months of abstinence remains accepted as obligatory for listing ALD patients for LT. In addition, some may argue that the ability to respect the 6month abstinence period is a necessary step toward reassuring the community that the patient merits a transplant [14]. While this concept is debatable, it widely exists in the medical community and in the public, influencing, at least subliminally, the entire discussion about the fairness of LT in patients with ALD. For patients with SAH not responding to medical therapy, however, the question relies more on the applicability of the 6-month rule than on its validity. In these patients, both objectives of an observational period before transplant decision are essentially elusive when one takes into account the nearly 70% mortality rate at 3 months and the very small chance for spontaneous clinical improvement. Realistic options are, therefore, either to systematically deny these patients for transplantation or to evaluate other potential selection criteria that can be obtained in a time period compatible with rapid therapeutic decision. In the first prospective study in patients with SAH not responding to medical therapy, strict selection criteria were applied, including first liver decompensation, strong familial support, absence of psychiatric disorders, and expressed adherence to lifelong complete alcohol abstinence programs [1]. The selection was based on meetings of multidisciplinary groups that included physicians, specialists in addiction, patients, and family members. In these patients, after a follow-up ranging from 2 to 3 years, alcohol relapse after LT was 11%. Importantly, none of these recurrences occurred in the first 6 months, corresponding to the period classically used to select LT candidates [1]. These selection criteria were extremely restrictive, taking into account the fact that this was a pilot study and, at this point, additional work is needed to assess their reproducibility. Restricting inclusion to patients in their first episode of decompensation is based on the concept that patients who had previous episodes of liver failure deliberately chose to ignore a warning. This is ethically questionable as it introduces a judgmental aspect to the therapeutic decision, leading to distinct treatments for patients with the same disease based on their different behaviours. In addition, group decision making itself carries its own limitations, as it may be influenced by individual authorities, potentially leading to some form of subjectivity [15].
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Frontiers in Liver Transplantation Although this first prospective study has not validated selection criteria in these patients, it has opened the door to the possibility that LT may be considered an option in highly selected patients, for whom no real therapeutic alternative exists. These data should be now confirmed by other groups and additional work is necessary to refine these selection criteria. This is the aim of an ongoing multicentre prospective study [16]. In parallel to this, an accurate definition of selection criteria requires a precise and consensual identification of the end-points to be reached after transplantation. In ALD, including in SAH, a provocative question concerns the real necessity for exclusion of patients predicted to be at risk of any alcohol relapse from LT programs. In a strict utilitarian view, it may be argued that the primary objective of organ transplantation is to achieve satisfactory long-term graft and patient survival, irrespective of any other considerations. Such a utilitarian end-point may appear limiting but has the clear advantage of being easily, objectively, and transparently evaluable. In this regard, a particular question in ALD is the relation between post-transplant alcohol consumption, and graft and patient outcomes. A correlation between alcohol recidivism and impaired long-term survival has been observed, but mostly due to increased incidence of malignancy and cardiovascular events rather than to toxic effects of alcohol on the liver graft [17]. In this setting, the discriminatory value of the 6-month rule is limited, as duration of pre-transplant abstinence does not correlate with post-transplant survival [18]. Several studies have demonstrated no direct deleterious effects of alcohol drinking on posttransplant outcomes, including therapeutic compliance, graft function, and graft survival [17,19], while others have reported negative impacts of heavy drinking on outcomes [20]. These conflicting data underline the need for better distinction of the different types of alcohol drinking after transplantation, ranging from occasional to moderate or severe, when alcohol habits could correspond to use, abuse, or dependence. This also explains the wide variation among post-LT alcohol relapse rates reported in the literature, ranging from 20 to 50%, and the rates of heavy drinking, which range from 10 to 20% [17,21–25]. In fact, similar rates of any alcohol use have been reported in patients transplanted for ALD and for non-ALD, but the risk of heavy drinking appears much higher in ALD patients [12]. Therefore, in order to proceed with a utilitarian objective, the key would be to identify the predictive factors for harmful recurrent drinking after transplantation. Among patients with ALD, these factors have not been established and one might wonder if the pilot experience in SAH could not be extended to evaluate the added predictive value of criteria such as psycho-social environment, supportive willingness of the family, and systematic multidisciplinary reviewing, as compared with the strict application of a mandatory duration for abstinence before listing. Another level of confusion is related to the heterogeneity of the means for monitoring alcohol use in patients on waiting lists [26,27]. This issue has been partially addressed in retrospective studies evaluating the impact of the presence of histological features of AH on liver explant [28–30]. As histological features of alcoholic hepatitis may persist for a prolonged period after alcohol withdrawal [31], histological observations cannot be systematically interpreted to be the result of the presence or absence of abstinence before LT and are not directly pertinent in the context of SAH. Still, some authors consider the presence of these histological changes to be a marker for clandestine drinking in patients listed for LT [32] and, it could be reasonably assumed that at least a pro-
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portion of these patients had recently drunk alcohol while on the waiting list. Importantly, these studies showed that graft and patient survival were not affected by the presence of histological changes of AH on the explant as compared with control patients transplanted for alcoholic cirrhosis [28,29]. With regard to postLT alcohol use, there was a tendency to higher relapse in patients with histological AH, for which a majority reported heavy drinking [28]. Taken together, if every effort is made to minimize the risk for alcohol relapse after LT, this does not mean that any form of post-transplant alcohol use corresponds per se to a failure of the selection process and of the treatment as its impact closely depends on the type of consumption. The importance given to the risk for post-LT alcohol recurrence in general and its role as a major barrier for development of LT programs in patients with SAH in particular, may also rely on emotional factors. In this setting, an obvious comparison can be made with patients with hepatitis C (HCV)-related liver disease, a non-controversial indication for LT. In HCV patients, viral recurrence is almost universal and 5year cirrhosis recurrence reaches 20 to 30% [33], leading to 5- and 10-year survivals of 67% and 54%, respectively. This is significantly inferior to the 73% and 58% obtained in patients transplanted for ALD [34,35]. Yet, in contrast with post-LT disease recurrence in HCV or in hepatocellular carcinoma, alcohol use after having received a graft for SAH is often interpreted as a breach of contract, vexatious, and hurtful for transplant professionals, and, more importantly, disrespectful for the organ donors.
Potential negative impacts on organ donation Negative public perception of the use of LT in patients with SAH has the potential to negatively impact organ donation. Reluctance to share collective resources for treatment of alcoholic people has been illustrated in surveys showing that potential donor families might refuse organ donation if it is possible that the recipient could be an alcoholic patient [36]. In addition, the attribution of grafts to SAH patients could create a strong impression of injustice because, in MELD-based allocation systems, these patients are transplanted with a high degree of priority, before other candidates, including ALD patients selected according to the 6month criteria. In this situation, however, the risk for a loss of confidence from the public to the transplant practitioners should be weighed against ethical requirements. It was recently stated in the Declaration of Istanbul that: ‘‘Organs for transplantation should be equitably allocated within countries or jurisdictions to suitable recipients without regard to gender, ethnicity, religion, or social or financial status’’ [37]. This general recommendation was not addressed to the problem of alcoholism, but extended to the present discussion, this could be interpreted to mean that potential transplant candidates should not be discriminated against on the basis of their previous individual and social behaviours unless those behaviours have a clear predicted impact on graft outcomes. Undoubtedly, in the public and in the medical community, alcoholic people suffer from very poor image [36,38,39]. Whether this should influence organ allocation is debatable but it should be acknowledged that this would represent a form of discrimination based on moral rather than medical criteria. It is possible that reactive opinions from the public could be balanced by transparent communication about SAH that highlights two aspects of the disease: First, that a disastrous prognosis
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JOURNAL OF HEPATOLOGY can be accurately and objectively predicted in a small subset of patients, and second, that these patients should not be categorized as non-compliant and actively drinking, but rather as patients in whom compliance must be evaluated by other means than a prolonged period of abstinence. An unequivocal distinction should be made, therefore, between evaluation of compliance in SAH patients and failure of pre-transplant abstinence in patients with alcoholic cirrhosis who were previously informed of this requirement for listing. Moreover, the public’s lack of esteem for alcoholic people does not mean that these patients are systematically excluded from general empathy. This has been illustrated recently by the massive outpouring of emotion in the UK when a young patient with SAH was denied LT on the basis of the 6-month rule and finally died [40]. Opinions in this debate were contradictory, but interestingly, some of the arguments that were used in the press to plea for transplantation, such as ignorance of previous liver disease and good familial support, were identical to selection criteria used in the multicentre study [1]. Along the same lines, it should be noted that among different European countries the rates of organ donation are not correlated with the stringency of the selection. In the UK, where criteria for LT are restrictive and alcoholic hepatitis is specified as a contraindication, the donation rate remains low as compared with other countries in which such contraindication is not mentioned.
patient’s complicity in his disease, the indication for LT strictly relies on prognostic scores identifying the patients that will die without transplantation. Remarkably, in patients with SAH, the Lille Model is similarly able to determine the outcome and particularly the risk of rapid death. Still, the distinction of meritorious and non-meritorious patients is widely shared by society and the medical world. Studies that surveyed physicians and the public, found that patients with ALD were placed at a very low level of priority for transplantation, independently of their disease and prognosis, just above the people in prison for violence [36,38]. Interestingly, this opinion was almost equally prevalent among the public, general practitioners, and gastroenterologists. Such a position implies that, comparable to deprivation of the civil rights of criminals, alcoholics are considered to be responsible for delinquent acts and should be deprived of the right to be treated. This represents a central aspect of the present discussion: To refuse treatment to a patient on judgmental or moral bases would correspond in fact to denying the fundamental human right of every individual to be treated without discrimination (The Universal Declaration of Human Rights, article 25) [42]. It would confer to the transplant professional a judgmental position, in profound contradiction with the objective of a fair system for organ allocation. This contradictory practice could discredit the entire transplant organization.
The notion of merit to be treated
Conclusions: The necessity of acting vs. the principle of precaution
The notion of merit for access to medical treatment represents a fundamental issue here. As the entire care system, particularly transplant programs, is primarily built on community support, the concept that patients with disrespectful social comportments may be less deserving of treatment than others could understandably emerge. In much of our society, morality remains profoundly inspired by Judeo-Christian principles. Individual and societal comportments are frequently judged through distinctions of good and bad, and faults are considered to be justification for some form of chastisement. Alcoholism is largely perceived to be a self-chosen condition with negative consequences for the entire society and is therefore considered a faulty behaviour. Therefore, some consider that patients who develop liver failure ‘‘through no fault of their own’’ should have a higher priority for transplant than those whose disease results from misconduct [32]. Accordingly, if disease in this case appears to be a form of natural punishment, restricted access to medical treatment, such as transplantation, would constitute a second punishment, as it is now imposed in a concerted way by society on the basis of judgmental and moral criteria. In this view, transplantation is a privilege, but not a right, and pre-transplant abstinence represents some form of expiation, necessary to regain society’s confidence and access to treatment. The concept that alcoholism is a selfinflicted disease is highly debatable. Alcoholism results from a combination of many factors and the consequences of alcohol intoxication depend on individual variation including genetic predisposition [41]. Therefore, a susceptible individual cannot be considered to be entirely responsible for alcoholism that leads to liver failure. Several other liver diseases that eventually lead to LT can also be considered self-inflicted, including viral hepatitis in intravenous drug users, obesity, or paracetamol intoxication. As an example, in patients with acute liver failure related to paracetamol overdose, independently of interpretation about a
For medical, ethical, and emotional reasons, LT in patients with SAH is a challenging and sensitive procedure, which will require careful evaluation and transparent communication in the coming years. According to the results that have been reported thus far, LT represents a potential new therapeutic option in SAH that cannot be ignored [3]. Still, this procedure raises several delicate questions for which it may be useful to go back to fundamental ethical principles. Major principles in the Hippocratic Oath are Primum non nocere (first do not harm), the notion of beneficence, meaning to act in the best interest of the patient, and the notion of justice, meaning a fair distribution of health resources. Medical ethics also recommend that therapeutic acts have to be performed according to best scientific knowledge of the moment. In current medical knowledge, we may assume that, in the majority of patients with SAH not responding to medical therapy, abstention, which may correspond to systematic denial of LT or the imposition of a period of 6 months of abstinence before decision, would carry a very high risk of harming the patient. In that sense, on ethical grounds, the necessity of acting, that is, to evaluate the possibility of an early transplantation, may override the principle of precaution. In terms of utility also, this is supported by the first results obtained in strictly selected patients, suggesting that LT in these cases represents a valuable use of a scarce resource. The issue of justice or equity, implying a comparable opportunity for everyone to receive treatment, remains much more complex in this setting. In the current situation of organ shortage, the identification of a new indication for transplantation inevitably penalizes the other patients on the waiting list. It is at this point that judgmental or moral criteria may interfere with strict medical decisions. To counterbalance this, objective and reliable selection criteria have to be defined
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Frontiers in Liver Transplantation and globally accepted, both by transplant professionals and the public. Extremely selective criteria of the type used in the first study evaluating LT in SAH patients allowed satisfactory results in terms of survival and alcohol relapse. At the same time, it is possible that these stringent criteria may also introduce a source of discrimination, such as partially relying on nonmedical parameters such as a patient’s socio-economic level [10] that influences the familial environment and support. At this stage, despite many unresolved issues, this first experience has opened a door. These initial favorable results should now be confirmed in longer follow-up studies and by other groups. Major ethical requirements that dictate that we must not discriminate against patients in their access to medical treatment must take precedence over moral considerations and we should continue to move toward defining the precise role of this procedure in the future.
Key Points •
Lack of available organs for transplantation imposes the need to define priorities for graft allocation. Selection criteria for transplantation have to reconcile the objectives of equity, justice, and utility and should be shared by the transplant community and the general population
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Severe alcoholic hepatitis refers to a life-threatening syndrome of liver failure and systemic inflammation arising in persons who have been consuming excess amounts of alcohol. In this condition, the absence of response to medical therapy is associated with extremely high early mortality
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A first prospective study demonstrated that rapid liver transplantation could represent a lifesaving intervention in these patients. In this pilot experience, stringent patient selection resulted in major improvement of short-term survival, and was associated with low rates of post-transplant alcoholism relapse
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In the current context of global organ shortage, this procedure has created controversy in the medical community and in the public. Reluctance to adopt this procedure is mainly related to the fact that these patients have not demonstrated their ability to gain control over their disease, fears of harmful alcoholic recidivism, and perceptions that these patients may be less deserving of a transplant than other patients
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In this situation, principles of medical ethics should take precedence over moral positions, and the need for active and non-discriminatory treatment of these patients with few therapeutic options should encourage further work in this field
Conflict of interest The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
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