Transplantation for alcoholic liver disease: Report of a consensus meeting

Abstract

A one-day consensus meeting was convened at the Clinical Research Facility in Birmingham on 19 November 2004. The group sought to include representatives from the eight UK and Eire liver transplant units and in the event received 28 delegates from seven units. The purpose of the group was to look at issues regarding the transplantation of patients with alcoholic liver disease (ALD) primarily from a psychosocial and addiction perspective rather than from a physical one. The group hoped to define some of the issues and dilemmas that surround the decision to transplant the ALD patient in an era of donor shortage, paying particular attention to the issue of return to alcohol use post-transplant. Transplantation for liver disease has been an accepted treatment option for many years. Where the cause of the liver disease is alcohol induced (ALD) there has increasingly been a tendency to consider transplantation despite the cause of the disease often being viewed in the wider domain as “self-induced”. Indeed, according to the British Liver Trust records, between 1996 and 2000 inclusively, 13.8% of all transplants (468/3400) were for ALD. In an era of donor shortage, however, there is always a concern that organ utility is as successful as possible.1 This can surely not be the case where patients with ALD demonstrate a risk (perceived or real) of returning to alcohol use post-transplant. The difficulty has always been trying to identify those at risk of relapsing to alcohol use post-transplant as well as defining exactly what constitutes a relapse. Does it mean the return of the behaviour (alcohol consumption) that led to the onset of ALD in the first place or does it mean the return of medical pathology, indicating damage to the graft? In the addiction field, return to alcohol after a period of abstinence can be defined as either a lapse (slip) or a relapse, depending on whether the use was a one-off episode or a more prolonged period of alcohol use. In studies looking at recidivism post liver transplant, there is no such clarity and thus a transplant patient consuming a single glass of champagne at their daughter's wedding 10-years post transplant is often classified along with the patient who returns to dependent alcohol use immediately post-transplant. It would be unlikely that the former patient would in any way insult their graft through a single unit of alcohol, whereas the latter patient is at grave risk of either direct damage to the graft or indirect damage through, for example, the resumption of alcohol problems leading to complacency and non-compliance with the transplant follow-up programme. The transplant unit has a responsibility not only to explore the issues of transplantation for ALD but also to understand their own motives and examine their own view point in the role of transplanting for ALD. The transplant team has to not only consider the needs of the patient but also the needs of each patient on the transplant waiting list at any one time, as offering a graft to one patient as it becomes available might mean another patient dying before a further suitable graft becomes available. The team also has a duty to understand its own prejudices, positive or negative, toward transplanting “the alcoholic”. Finally, the team might also perceive a need to consider the public examination of their use of organ donation. If the public perception is such that they believe that use of the donated graft is ill-advised or wasteful, will they be less likely to donate and thus impact negatively upon the overall size of the national transplant programme? It is important, however, to inform the public rather than just respond to their reaction. Indeed studies have been conducted that show that the public may be likely to make decisions about how to utilise organs based on empathic responses rather than objective ones would be likely, in turn, to make less effective use of available organs.2 In general, indications and contra-indications for liver transplantation in those with ALD are similar to those being assessed for transplantation for other indications; however, additional considerations apply to the work-up of such patients in addition to the assessment for the reasons for alcohol excess and estimations of the probability of the person returning to alcohol consumption.3 The effect of abstinence is often uncertain. Indeed, a proportion of patients with ALD may improve with abstinence to such an extent that transplantation is no longer indicated or can be deferred.4 While the full effects of abstinence may take up to 18 months to achieve the maximum effect, in practice, for those with advanced disease, it is often very difficult to predict the extent of hepatic recovery, and the patient may require close monitoring to ensure that the timing of transplantation is appropriate. Alcoholic damage is not confined to the liver and evidence of other organ damage must be considered. It is common practice to evaluate cardiac function (with imaging and stress tests),5 although the extent to which cardiac impairment may prejudice successful outcome remains uncertain. We also will consider brain scanning (usually with CT scanning) to look for evidence of structural brain damage, but again, there is relatively poor correlation between structure and function. A neuropathy (autonomic, sensory, or motor) may indicate a less good outcome but this has not been conclusively shown. Post-transplant, there is a higher incidence of malignancy, especially of the head and neck and oesophagus.6 It is prudent therefore to ensure that early cancers in these areas have been excluded as far as is possible. The extra cancer risk may be related to smoking rather than alcohol. Finally, alcoholic liver disease may be associated with other causes of liver damage, such as hepatitis B or C viral infection, obesity, and other drug toxicity.7 When considering the non-medical issues in transplantation for ALD, these can broadly be split into those related to assessment of the patient and those related to the treatment and follow-up of the patient post-transplantation. When assessing the patient, there needs to be a comprehensive assessment of their alcohol and illicit substance (mis)use history, as well as the physical, psychological, forensic, and social consequences of this.8 In performing this assessment, it is acknowledged that clinicians might want to focus on the absolutes, such as length of abstinence from alcohol. However in the absence of an absolutely reliable test for sporadic alcohol consumption, even this can be difficult to monitor and prove without doubt.9 It is also important to note that abstinence is usually in the context of deteriorating health, often precipitating lengthy hospital stays; thus pre-transplant abstinence cannot be seen as an absolute predictor of abstinence post-transplant.5 Given that some patients may need to be listed for transplantation before they are able to prove their abstinence, serious consideration needs to be given to this issue. On completion of the assessment it may be possible to rate the patient as low, medium, or high risk (after Gish et al., 2001)8 for relapse, but should we consider transplanting high risk patients given the shortage of donors?10 When considering these issues, clinicians have to think about the purpose of assessment, whether the information gained is to inform treatment for the patient's alcohol problem or whether the information is used as part of a screening mechanism. Either way, the assessors, be they specialist nurse or psychiatrist, have to acknowledge the conflicting issues of gaining information that may inform the team but potentially reduce the patient's chance of being listed. Looking at the issues in treatment post-transplantation the survival of both the graft and patient is paramount. Abstinence is the aim, as supported by substance misuse models of practice for alcohol-dependent patients. However, not all patients transplanted for ALD are dependent on alcohol,9 and some do return to drinking at low levels that do not appear to harm them.11 If this happens, should we persist with the abstinence message or satisfy ourselves that a harm minimisation message is acceptable? When thinking about this, we need to acknowledge that patients talk to each other and may decide to drink based on their perceptions of other patients' behaviours and health. In providing treatment and follow-up for this patient group, the emphasis needs to be on the long term, given that lapse/relapse can often happen some years post-transplant.12 If we accept this, then we need to think about who provides this follow-up, for how long. and in what context, given that substance misuse provision, and models of practice, vary across the country. This may limit local support to short-term follow-up rather than long-term relapse prevention, which runs contrary to evidence that suggests that in some cases relapse may occur some years post-transplant.12 There are other issues that need to be addressed that follow on from this discussion. If clarity and consistency of approach is addressed with ALD, then what of smoking, obesity, non-compliance (as in teenagers with auto-immune hepatitis), and transplantation for patients on Methadone.13 Likewise when the patient presents with a mixed aetiology, e.g., alcohol with haemachromatosis, HCV, alpha-1 anti-trypsin deficiency, or hepatocellular carcinoma the picture is often more complex. Perhaps when considering these issues around liver transplantation for ALD there are more questions than answers? Although this may be the case, informed discussion based on the evidence currently available needs to occur to ensure best possible use of donated organs and increased trust in the transplantation process on the part of the general public. The prognosis for cases transplanted for ALD is roughly the same as that for non-ALD cases, but in an era of organ shortage, the procedure remains controversial. A key issue is the likelihood of relapse and its influence on outcome. Abstinence from alcohol is considered important for compliance with medication and follow-up protocols, avoiding the development of new or pre-existing extra-hepatic alcohol-induced organ damage, or the development of alcohol-induced liver damage in the allograft.12 There are still many unanswered questions about the clinical course of alcohol problems. The few long-term follow-up studies of untreated populations have suggested that possible outcomes of a diagnosis of alcohol dependence include stable abstinence, a return to controlled asymptomatic use, continued misuse, or premature death.14-16 A few individuals maintain a relatively stable pattern of intermittent alcohol misuse without dependence from a young age, but in general, this group have fewer substance-related problems, do not develop physiological dependence, and manifest fewer risk factors. However, in general alcohol dependence (as opposed to misuse) is a relapsing and remitting disorder. Several studies indicate that only about 2% of all individuals with a diagnosis of alcohol dependence achieve stable abstinence each year, with or without treatment.16 Mann et al. (2005) recently found that although 27% had died, 40% of patients were abstinent 16 years after a 6-month treatment programme, and 55% of these had been continuously abstinent since the index treatment episode.17 If this is the case, how long should abstinence from alcohol use persist before subsequent relapse is deemed unlikely? After 2 years of abstinence, 40% of alcoholics will eventually relapse, but after 5 years of abstinence relapse is relatively unlikely.18 Vaillant concludes that, analogous to cancer patients, a follow-up of 5 years rather than 1 or 2 years is necessary to determine stable recovery.15 This should be contrasted with the 6-month abstinence rule suggested by some transplant guidelines.19 An improved knowledge of the predictors of relapse would help the assessment and possibly also refine attempts at treatment. However, studies in the liver transplant population have led to contradictory results, with no reliable predictive factors identified.20 These studies are beset by a number of methodological problems, not least that a variety of definitions of relapse are used, making the results hard to compare.21, 22 Furthermore, most studies are retrospective case note reviews with inconsistent methods of assessing the level and severity of alcohol problems before transplantation. Follow-up periods have usually been too short to provide meaningful information about relapse, and investigators have seldom been independent of the transplant team. Compulsory supervision or experiencing a consistent aversive experience related to drinking, Finding a substitute dependency to compete with alcohol use, Obtaining new social supports, and Inspirational group membership (e.g. Alcoholics Anonymous). Membership of Alcoholics Anonymous provides each of the four components, but they are also present in the experience of liver transplantation. The transplant and the subsequent need for daily immunosuppressive drugs for the rest of the subject's life provide a constant reminder of the dangers of relapse to alcohol misuse. Frequent follow-up by a team of experts also provides additional community supervision. Dependence on the liver team's continued care and the group support among transplant survivors is analogous to dependence on the comfort provided by self-help groups. Being given a new life and an expensive operation may be analogous to a “born again” religious experience. Finally, the OLT survivor becomes intimately involved with a health care team unscarred by their past misuse of alcohol and filled with hope for the future.18 Therefore, although the research evidence base for this group is still developing, there is evidence that suggests that carefully selected alcohol-dependent patients with ALD can have a good outcome in terms of graft survival and relapse to alcohol use post-operation. Patients in the UK should have a right to be assessed for liver transplantation on the same basis irrespective of which unit they attend. This universality should be readily achieved when the disease is an uncontroversial indication, runs a predictable course, and is not associated with multi-system pathology. However it becomes more difficult when these conditions do not apply, added to which with ALD, hostile public attitudes complicate the picture.2 There is a consensus that it is unethical to regard ALD as an absolute contraindication, given the post-transplant outcome, to 5 years at least, is as good if not better than for most other aetiologies. Supporting this position, following a liver transplant, recurrent ALD is rare while few patients die of an alcohol-related cause.24 Lastly, ALD is essentially diagnosed by exclusion of other causes married to a credible history of alcohol misuse: it is not an infallible diagnosis, having a false positive rate in our unit of 5%, and as much as 13% in one American series.25 Given this, it might be argued that ALD patients should not be assessed differently from any other candidates, but irrespective of public policy considerations, it is surely as important to take into account the aetiology and management of the causal factor when it is alcohol abuse as for any other cause of liver disease. Regarding ALD as an absolute contraindication or disregarding the alcohol aetiology altogether would enable equity to be achieved more readily than the current approach of selection among ALD patients, involving an additional hurdle of an assessment of the drinking problem. As there is no standardised approach to either this process or its goal(s), equity is most improbable, i.e., a patient regarded as unsuitable for transplant because of their alcohol history in one UK unit might be listed by another. Because of organ shortages, selection for liver transplant is based on a utilitarian philosophy: no patient has a preordained right to a graft.26 In practice, this means identifying the hosts who will give grafts the longest and healthiest “lives”. Cohort outcome studies provide the evidence for determining this, with duration of survival being the primary endpoint. When selecting among ALD patients there is a second key end point, which is relapse drinking.24 However, because research has concentrated on “any drinking” as the outcome variable rather than harmful or dependent drinking, the endpoint is not utilitarian in terms of predicting survival. This focus has raised concerns that patients who are removed from liver transplant waiting lists because of an alcohol “slip” are being managed unethically,27 and transplantation is wrongly regarded as a failure if the patient drinks little and occasionally without any harm.28 To be just and equitable, predicting relapse as a selection criterion should be employed for a demonstrably utilitarian purpose, which implies identifying likely recurrent harmful or dependent drinking, or to advise the transplant team which ALD patients would be unlikely to cooperate with treatment in the event of relapse drinking. Any predictor should affect outcome, and discriminate consistently and well: if no predictors can satisfy these requirements, this strategy be abandoned. Further research should be refined to evaluate the usefulness of predictors that are intrinsically fair, objective, and reliably assessed in determining whatever key, utilitarian endpoint with regard to relapse alcohol use is agreed by the transplant community to be most appropriate. It is clear that liver transplantation has become a recognised and accepted form of treatment for those with end-stage ALD. The evidence base to date suggests that prognosis for survival at 5-years post-transplant is good and that alcohol-related graft damage post-transplant is relatively low. Despite this knowledge, the general public continue to hold reservations about the use of donated livers for those with “self-inflicted” injury such as “alcoholics“.2 Such debate will always be voiced in an era of donor shortage when those with ALD are particularly singled out. There has been less focus of attention toward those with recurrent hepatitis C (HCV) following transplantation, perhaps for intravenous drug use, despite the greater significance of graft loss at 5-years post-transplant.29 There is also less attention given to obese patients with non-alcoholic fatty liver disease, or teenagers re-grafted following non-compliance. The lack of quality prospective and longitudinal research data on ALD and recidivism post transplant has been highlighted above, and the study group is actively welcoming such research into the arena. However, even less work has been done to tackle the lack of consistent approach both intra- and inter-transplant unit. Such work would be a valid study in itself. Furthermore, little is known about the process of selection of candidates at local liver units for referral on to the transplant assessment teams, which must again question what factors control the selection of assessment candidates. In addition to the question as to “What is relapse?, how much does it occur, and how much does it matter?”, the study group would like to see all supra-regional transplant centres demonstrating transparent, measurable assessment processes that sustain an ethical service with equity of access based on factors correctly adjudged to select those candidates likely to do well. Where patients are transplanted outside of inter-unit guidelines, a rationale should be available. Finally, there may be a need for ALD patients to and support post-transplant in to sustain abstinence and risk factors have been correctly then treatment and support methods can be Liver and in in of Research Clinical in Liver Clinical in Liver Clinical in Liver Liver in Liver Liver Liver Liver in in Clinical in and Liver Liver