Journal of Hepatology
Volume 36, Issue 1 , Pages 130-137, January 2002

Transplantation for alcoholic liver disease

  • James Neuberger

      Affiliations

    • Liver Unit, Queen Elizabeth Hospital, Birmingham, B15 2TH, UK
    • Corresponding Author InformationCorresponding author. Tel.: +44-121-627-2414; fax: +44-121-627-2449
    • ,
  • Karl-Heinz Schulz

      Affiliations

    • Departments of Hepatobiliary Surgery and Medical Psychology, University Hospital Hamburg Eppendorf, Martinistrasse 52, Pavillon 69, 20251 Hamburg, Germany
    • ,
  • Christopher Day

      Affiliations

    • Centre for Liver Research, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
    • ,
  • Wolfgang Fleig

      Affiliations

    • First department of Medicine, Martin-Luther University, Halle Wittenberg, 06097 Halle (Saale), Germany
    • ,
  • Gabriela A Berlakovich

      Affiliations

    • Department of Transplant Surgery, University of Vienna, Waehringer Guertal 18-20, A-1090 Vienna, Austria
    • ,
  • Marina Berenguer

      Affiliations

    • Hospital La Fe, Servicio de Medicina Digestiva, Hospital Universitario La Fe, Avda Campanar 21, Valencia 46009, Spain
    • ,
  • Georges-Phillippe Pageaux

      Affiliations

    • Federation medico-chirugicale d'hepato, gastroenterologie, 80, rue Augustin Fliche, CHU, Saint Eloi, 34295 Montpellier, France
    • ,
  • Michael Lucey

      Affiliations

    • Section of Gastroenterology and Hepatology, Department of Medicine, H6/516 Clinical Sciences Center, University of Wisconsin School of Medicine, 600 Highland Avenue, Madison, WI 53792, USA
    • ,
  • Yves Horsmans

      Affiliations

    • Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium
    • ,
  • Andrew Burroughs

      Affiliations

    • The Liver and Liver Transplant Unit, Royal Free Hospital, Pond Street, London NW3, UK
    • ,
  • Krister Hockerstedt

      Affiliations

    • Transplantation and Liver Surgery Unit, Helsinki University Hospital, Kasarminkatu 11, FIN-00130 Helsinki, Finland

Accepted 8 November 2000.

Article Outline

 

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1. Introduction 

Alcoholic liver disease (ALD) is now the commonest indication for liver transplantation and has accounted for 5716 transplants in Europe between January 1988 and June 2000 [1]; however, it remains controversial. The proportion of patients grafted for ALD in Europe is overall 17%; however, both the proportion of patients grafted for alcohol-related liver disease and the absolute number of patients grafted has risen; there is great variation between countries (from 0% (in Poland) to 30% (in Spain)) (Fig. 1). Survival after transplantation for ALD is possible (5 and 10-year survival rates are 67 and 55% (graft survival) and 71 and 59% (patient survival)) [1] which is similar to those for other indications although this does not necessarily imply that the outcome is as good in the two groups since there may be considerable differences in case-mix. There is no doubt that a small proportion of patients return to a damaging pattern of drinking but the number of grafts lost through a return to drinking is, at least according to published reports, small [2].

  • View full-size image.
  • Fig. 1. 

    (A) Number of liver transplants done in Europe according to the ELTR [1] and the proportion done for ALD. Total number of transplants: ALD 5723 (17%), others 27057. (B) The evolution of transplantation for patients with ALD. The number of patients transplanted in Europe for cirrhosis by year and the proportion of patients grafted for ALD (lower shaded area); data from ELTR [1].

The European Association for the Study of the Liver (EASL) and European Liver Transplant Registry (ELTR) organised a workshop to draw up guide-lines to clarify the role of liver transplantation in the management of patients with ALD. In this report from the workshop, we describe the patterns of alcohol use, those factors which may affect susceptibility as well as the indications for liver transplantation in patients with ALD and discuss the need and extent of abstinence required before transplantation. In order to manage patients optimally and to make most effective use of the scarce availability of donor livers, it is important that transplant clinicians understand and agree the patterns, causes and extra-hepatic consequences of alcohol excess and the possible role of therapies.

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2. Alcohol use, alcohol abuse and alcohol dependence 

While there is some evidence that modest alcohol consumption may be beneficial for survival, excessive alcohol consumption is associated with not only significant morbidity and mortality but also with physical, psychological and social disability [3]. Classification of the pattern of alcohol abuse is important for appropriate assessment and management of the potential liver transplant candidate.

Alcohol consumption can be classified into none, light, moderate and heavy. Heavy consumers can be considered as either abusers or dependent [4]. Abuse runs a different course to dependence and there is no evidence that abuse leads to dependence [5], [6]. There is a close relationship between alcohol dependence and psychiatric problems, although it is not clear whether this represents a causal relationship, a common basis or an independent effect. Antisocial personality disorder, depression, anxiety and psychotic syndromes are common. Several typologies for alcohol dependent/abusing patients have been developed, but empirical support for these classifications remains contradictory.

It is important to define relapse or recidivism: some Units will define relapse as any alcohol consumed, others define relapse as consuming over a set amount (such as 21 units/week for males and 14 units/week for females). In the non-transplant setting, addiction specialists define a relapse as more than 4 units/day or any alcohol consumed daily on 4 or more consecutive days. A return to alcohol consumption at a lower rate is defined as a ‘slip’.

There are two major diagnostic systems used to define alcohol dependence, ICD-10 and DSM-IV. While there is reasonably good agreement between the two systems for the classification of alcohol dependence, there is poor agreement with respect to abuse or harmful use [7], [8], [9]. Attempts to define the severity of alcohol dependence have been largely unsuccessful and the severity criteria present in DSM-IIIR have been removed from DSM-IV.

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3. Natural history of alcohol excess 

It is assumed by many that the natural history of people with alcohol dependence is one of progressive alcohol consumption: however, this view is not supported by the data available:

I. Treatment for alcoholism can be effective: a meta-analysis of 44 methodologically sound studies on the treatment of alcoholism showed a success rate of 34–48% [10], [11], [12], [13], [14].

II. Relapse is common: relapse usually occurs within the first 6 months with only about half of the patients achieving 1 year of continuous abstinence [15].

III. Natural recovery may occur: this may arise with or without support. In most cases where natural recovery occurs, there is a return to low risk drinking in up to 75% [16]. Indeed, recovery may occur without formal help and is the most frequent way out of alcohol dependency for 60–80% patients [17], [18], [19]. Contrary to what might be predicted, those who were likely to remit were more seriously dependent, experienced less social pressure to stop but did have a more stable employment situation [20].

Thus, in many cases there is a wide discrepancy between clinicians' beliefs and reality (Table 1) and clarification of misconceptions will help inform the debate as to the appropriateness and the indications for orthotopic liver transplantation in patients with ALD.

Table 1. Some common misconceptions about alcohol dependency
BeliefReality
Alcoholism is a problem of current timesAlcoholism has been present throughout history
Alcoholics are social drop-outsOnly 5% alcoholics conform to this phenotype
Alcoholism is self-inflictedStrong evidence for genetic and environmental influences
Alcoholics have specific personality traitsAlcoholics have a varied profile
Alcoholics will be detected and treated by the medical systemPatients with alcohol dependence are usually undetected and not treated
There is a low probability of recoveryThere is a natural recovery of more than 60%
Relapse rates increase with timeRelapse is most common in the first year
To recover, absolute abstinence is neededThere is evidence that dependency may be overcome without total abstinence

There are several approaches to help the patient become and stay abstinent and selection of the most appropriate approach is important in determining the outcome. Several factors have been identified which help predict abstinence (Table 2).

Table 2. Predictors of relapse
AffectiveNegative mood states

Behavioural

Poor coping skills
Poor social skills

Cognitive

Negative attitude for recovery
Poor self perception
Poor perception of illness
Low level of cognitive functioning

Interpersonal

Lack of social support
Social pressures
Lack of involvement in leisure activities
Lack of productive work

Physiological

Craving for alcohol
Chronic illness and/or pain

Psychiatric

Co-morbidity

Spiritual

Excessive guilt
Lack of purpose

Treatment

Negative attitude of care-givers
Inadequate after-care
Lack of integrated services for support

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4. Risk factors for the development of ALD 

While it is clear that there is a close correlation between both the amount of alcohol consumed and the duration of alcohol consumption and the probability of developing severe liver damage within a population, between individuals, there is a great variation. Both the risk of developing alcohol dependence and progressive liver damage are multi-factorial.

4.1. Pattern of drinking 

The pattern of drinking influences the probability of developing liver disease. The development of liver disease is more common when drinking outside meal times (RR 3.4), multiple drinks (RR 23) [21] and daily compared to week-end drinking (RR 2.5) [22].

4.2. Gender 

Females are more susceptible than males, reasons for which are not clear but may be related to the effects of oestrogen on intestinal permeability to endotoxin.

4.3. Diet 

Obesity itself is a major factor for ALD; there is an increased risk in obese drinkers (BMI>25 for females and >27 for males) (RR2.15 for cirrhosis) [23]. The reasons for this are unclear but most likely reflect the close association between obesity and steatosis [24]. Data largely derived from animal studies suggest that diets that are low in carbohydrate, high in polyunsaturated fat and iron and/or deficient in antioxidant vitamins and trace elements may all lead to an increased susceptibility to ALD.

4.4. Genetic 

Studies of alcoholism and ALD in twins have shown a clear genetic component to susceptibility with a concordance rate increased two- to three-fold higher in monozygotic compared to dizygotic twin pairs [25]. Relevant genes have not yet been identified.

Thus, both environmental and genetic factors are implicated in susceptibility to ALD: some can be altered by the individual, other factors may be altered by transplantation and others will remain host dependent. Knowledge of these various factors may help the patient manage their risk factors better after transplantation.

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5. Indications for transplantation for patients with alcohol related chronic liver disease 

The indications for transplantation for the patient with cirrhosis of any aetiology have been identified by several groups (see Minimal Listing Criteria [26], BSG Guidelines [27]). Development of the clinical or serological features of end-stage disease are now relatively well defined and include such general features as Child grade B or C, intractable encephalopathy or variceal bleeding; while most centres give for indications a poor quality of life (because of liver disease) or anticipated length of life less than 1 year, it is clear from modelling evaluations both in France and in the UK that for most patients with ALD, the anticipated survival without transplantation is between 50 and 80% at 1 year [28], [29]; indeed it is not until 3 or more years after transplantation that there is a clear survival benefit, and as might be anticipated, survival benefit is greatest in those who are the sickest. Thus, either the models are inaccurate or further work is needed to define when transplantation is required in this group of patients.

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6. Alcoholic hepatitis 

A particular problem exists for patients with alcoholic hepatitis: these patients are often very sick with renal failure and malnutrition; the probability of survival without transplantation is very low. The Maddrey Discriminant function [30] will help identifying those with a poor prognosis: those values that predict a poor survival without transplantation (serum bilirubin and clotting time) are also associated with a poor outcome after transplantation. There is only limited experience of transplantation in such patients: although there have been isolated cases where there has been excellent survival [31] and some [32], [33] have reported good outcomes, although others [34] have suggested that there may be a rapid return to a damaging pattern of alcohol consumption. Until more patients have been studied, we feel that this is not a routine indication for transplantation outside a controlled study.

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7. Alcohol excess and other liver diseases 

Patients with ALDs often have co-existing liver disease: this increased association may reflect a common behavioural pattern (such as other substance abuse leading to chronic viral infection), or this may reflect the increased susceptibility to alcohol in patients with chronic liver disease (such as chronic hepatitis B or C viral infection or genetic haemachromatosis, or, more rarely, porphyria cutanea tarda). Where other causes for liver disease are present, appropriate additional investigations may be warranted.

7.1. Hepatitis C viral (HCV) infection and alcohol 

The liver disease most commonly associated with ALD is chronic HCV infection. Those with HCV who drink more than 50g alcohol/day develop cirrhosis more rapidly than those with a lower alcohol consumption [35]. Clinically, those with both HCV and ALD tend to resemble those with ALD alone rather than HCV alone (Table 3) with respect to age, gender and severity of disease, although liver cell cancer is more common in those with HCV alone or HCV and ALD compared to those with ALD alone. In general, however, liver allograft recipients with a combined cause for end-stage liver disease tend to be considered as HCV rather than ALD. Post-transplant, the survival of patients grafted for ALD appears, at least in the short-term (<4 years), similar to those grafted for ALD and HCV [36]. However, those with combined ALD and HCV have considerably more graft fibrosis (Fig. 2) [54], [55] and therefore the long-term graft survival is likely to be less in these patients; indeed, some centres are already observing this.

Table 3. Pre-transplant clinical variables in patients with ALD, chronic HCV associated liver disease and botha
ALD aloneALD+HCVHCV alone
N13138238
Age (years)50 (30–64)150 (31–64)257 (25–67)3
Male (%)85.5492555.56
Child class C (%)34.57408289
HCC (%)111026112812

a Data from Hospital La Fe, Valencia, Spain. 1991–2000 (unpublished). Ages are shown as median (range). HCC, hepatocellular carcinoma. P values: 1 vs. 2: P NS; 2 vs. 3: P<0.0001; 1 vs. 3: P<0.0001; 4 vs. 5: P NS; 5 vs. 6: P<0.0001; 4 vs. 6: P<0.0001; 7 vs. 8: P NS; 8 vs. 9: P=0.08; 7 vs. 9: P NS; 10 vs. 11: P=0.01; 11 vs. 12: P NS; 10 vs. 12: P<0.0001.

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  • Fig. 2. 

    Prevalence of severe hepatic fibrosis in patients at 1 and 5 years after liver transplantation for HCV infection, ALD or both (data (unpublished) from Hospital La Fe, Valencia, Spain.

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8. Abstinence and liver transplantation 

The greatest concerns about transplanting patients with ALD are related to abstinence before and after transplantation: in particular, there are concerns that the patient will return to the previous pattern of alcohol abuse which could result in graft loss or patient death because of, for example, non-compliance with immunosuppressive therapy, a direct hepatotoxic effect of alcohol on the graft or extra-hepatic alcohol-induced organ damage. There are, however, few reports in the literature of graft loss for these reasons. The two concerns are primarily whether there is a need for the patient to be abstinent pre-transplantation and if so, for how long, and whether the patient should be abstinent after transplantation.

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9. Need for abstinence pre-transplantation? 

Most centres in Europe and in North America have adopted a rule requiring 6 months abstinence before patients are accepted for listing, although relatively few centres follow their own guidance in all instances [2], [44], [51], [52]. The rationale for this approach is that a period of abstinence pre-transplant will

1.Ensure the patient will, with abstinence, recover adequate liver function: studies have indicated that a significant proportion of patients referred for liver transplantation may, with abstinence, regain sufficient liver function and a quality of life that makes transplantation unnecessary [29]. It is not possible, at present, to identify reliably those patients who will not need transplantation. Premature listing and transplantation, may, therefore lead to unnecessary transplantation.

2.Identify those patients who are likely to relapse and so avoid inappropriate transplantation: when a patient presents with decompensated alcohol liver disease, it may not be possible to determine whether the patient is at risk of relapse after transplantation, because of, for example, encephalopathy: while ‘death-bed repentance’ may reflect the true ambitions of the patient, intentions may not be translated into reality after transplantation. Some studies have suggested that relapse is commoner in those who have not had a 6-month period of abstinence.

3.Allow time for adequate rehabilitation and treatment for alcohol dependence: as indicated above, relapse is most common within the first year of stopping alcohol consumption.

However, more recently, the need for a set period of abstinence has been questioned on the basis of a number of observations:

I. There is no clear rationale for this rule and published data are conflicting. The 6-month period is not based on prospectively gathered data but rather on custom and practice.

II. Patients who would be abstinent post-transplant may die before the fixed period of abstinence is finished.

III. The length of wait for a liver often exceeds 6 months and therefore the patient can ‘work out the period of abstinence’ during this time. The time on the waiting list is one when the patient can be followed, and when indicated, offered support and treatment.

IV. Pre-transplant abstinence does not reliably predict post-transplant abstinence or compliance [43], [44], [45], [61], [62], [63], [64].

V. Most centres do not routinely follow the 6 months rule [2].

VI. Although many patients do return to some form of alcohol consumption after liver transplantation, there is little evidence that this has a major impact on either patient or graft survival [53], [58], [59], [60]; however, as discussed below, these observations do not mean that a return to drinking is free of adverse effects on the liver.

Thus, while most guide-lines suggest that there should be a fixed period of abstinence it is clear that the basis for this is not firm. A reasonable practice is to wait until the patient can be fully evaluated by a multi-disciplinary team to ensure that there is a minimal risk of relapse and that suitable support will be provided, and to ensure that, with abstinence, the patient will not improve to an extent that transplantation is no longer needed.

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10. Investigation of patients with ALD for liver transplantation 

Alcohol will not only affect the liver but also other organs including heart, central and peripheral nervous system, the bone marrow and pancreas. Whether additional investigations are required for potential liver allograft recipients remains uncertain. There are few prospective data on the prevalence of significant extra-hepatic alcohol-related organ damage in candidates for liver replacement and there is little agreement on either the definitions or the contra-indications for liver transplantation. Furthermore, it may be difficult to distinguish organ dysfunction as a consequence of cirrhosis from that due to alcohol.

10.1. Cardiac disease 

The current practice in European Transplant Centres suggest that most use echocardiography and electrocardiography on a routine basis and about half use exercise or dobutamine stress tests. Radionucleotide or invasive testing is not routinely undertaken. Although most centres regard cardiomyopathy as a relative contra-indication for transplantation, the limits of left ventricular ejection fraction below which transplantation is contra-indicated vary widely, from 20 to 50%. Ongoing studies by Fleig (unpublished) and by Kryzhanovski and Betler [37] suggest that routine testing to exclude cardiomyopathy does not appear to be justified in asymptomatic patients.

10.2. Neurological disease 

Alcohol may be associated with both central damage (such as Wernicke–Korsakoff syndrome, dementia, cerebral atrophy and haematomas) and peripheral damage (motor, sensory or autonomic neuropathy). Clearly, significant irreversible brain damage will contra-indicate liver transplantation although there is no clear guidance as to the extent of cerebral damage that will preclude a successful outcome. Peripheral neuropathy does not seem to be associated with an adverse outcome; autonomic neuropathy is not uncommon in patients with end-stage liver disease, irrespective of aetiology, and improves after transplantation. While there is little evidence that neuropathy is associated with an adverse outcome, because there are few prospective studies, it cannot be assumed that neuropathy has no effect on outcome.

10.3. Nutrition 

Malnutrition is associated both with end-stage liver disease and alcohol excess, and is associated with a poor outcome after transplantation. However, there is no evidence that those with alcohol-associated liver disease should be assessed and managed any differently from those with other causes for the end-stage liver disease.

10.4. Cancer 

Patients grafted for ALD appear to have a higher incidence of some malignancies following liver transplantation, especially of the upper airway and upper gastrointestinal track: these factors should be considered in the routine assessment of patients for ALD [56], [57].

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11. Ethical issues 

The shortage of donor organs, despite the greater use of living related donors, splitting livers and use of marginal donors, means that not all those patients who could benefit from liver replacement are able to receive a graft and thus some form of rationing is needed. The cornerstone of medical ethics lies in four principles: justice, non-maleficence, patient autonomy and beneficence. The outcome of patients grafted for ALD clearly demonstrates beneficence but there remains a concern about justice. Certainly where the views of the public have been canvassed, it has been found that the public, who in the broadest sense, provide both the donor livers and the resources for transplantation, do rate liver allograft recipients with ALD at low priority. It remains a matter of debate the extent to which health care professionals should heed rather than lead the views (or prejudices) of the public. Some have argued that patients with ALD should not have the same claim on the limited donor pool as others with chronic liver disease not because the patients are responsible for their alcohol dependence but because they have not sought help: it was found that only 22% people with alcohol dependence sought help in a 1-year period [38], and conversely, fewer than one in eight substance abusers received formal treatment for drug and alcohol problems [39], [40].

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12. Outcome after liver transplantation 

The overall medium term outcome of patients transplanted for ALD is similar to that of patients grafted for other conditions; however, these findings must be interpreted with caution. For example, it has not been shown that there is a similar case-mix between those recipients with and without ALD and therefore simple comparisons may be simplistic and inappropriate. Equally, these data could imply that the rate of graft loss from HCV infection (at present, not always preventable) may be similar to that from a return to alcohol abuse (which could be prevented by better identification of suitable candidates). The world-wide shortage of donors means that not every patient who could benefit from liver replacement can be offered a graft and therefore transplant clinicians have to use their judgement to select appropriate candidates.

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13. Quality of life 

The quality of life after liver transplantation for any indication shows improvement in all domains [41], [42] and similar findings have been reported for patients grafted for ALD [43], [44], [45]: similar finds are seen whether the patient is abstinent or not [46], [47]. One study has suggested that while there was no difference in quality of life in those grafted for ALD, whether or not they returned to alcohol consumption, those who did drink three or more units daily had more sleep problems and were more likely to use benzodiazepines [47].

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14. Support for the allograft recipient and monitoring of abstinence 

Most, if not all, centres provide multi-disciplinary support for all patients on the waiting list and after transplantation. Patients with ALD do require additional support but there are no controlled data as to the most effective form of support for these patients. The range of effective support strategies for patients with ALD remains poor, and even in this highly selected cohort of patients, relapse is common. Therapeutic interventions for alcoholism which are efficacious in standard addiction studies may not be effective in the liver transplant population [48], [49]. However, one group [43] did report a significant reduction in a return to alcohol after a psychologist became involved in the management of patients before and after transplantation [53]. Further studies are needed to determine better methods to assist those with ALD who awaiting or following transplantation maintain abstinence.

There have been a few studies evaluating methods of monitoring abstinence. Standard liver tests are unhelpful as they are non-specific: carbohydrate-deficient transferrin may be of help [50]. Measurement of breath, blood or urine alcohol has been used in some centres in Europe but their role is, at best, limited.

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15. Conclusions 

I. Alcohol-related chronic liver disease remains a good indication for transplantation as survival rates are good and comparable to other indications.

II. For most patients transplanted for ALD, the survival benefit, calculated from prognostic models in the short-term (<2 years) is small and so the indications for transplantation need refining.

III. Alcoholic hepatitis is not an indication for transplantation at this time.

IV. Transplantation is not indicated in those who are likely to return to a pattern of drinking that will damage the graft or result in non-compliance.

V. Patients should be assessed, and if transplanted, followed by a multi-disciplinary team, including a clinician experienced in addiction.

VI. Although there are some factors which may identify those at risk of non-compliance, none has adequate sensitivity and specificity, so more work is required to identify those factors present pre-transplant which will identify those who will not benefit from the procedure.

VII. Although a fixed period of abstinence is not indicated, those patients who have stable abstinence should, after satisfactory assessment, be put on the waiting list. For the patient without stable abstinence, the patient should undergo addiction treatment. If successful, the patient should be listed; if not, transplantation is not indicated. If the patient whilst awaiting transplantation has a significant relapse, then the patient should be removed from the list and assessed and offered treatment: if successful, the patient should be re-listed. If the patient has had a slip, then it may be appropriate for the patient to remain on the list.

VIII. Extra-hepatic alcohol-induced end-organ damage may preclude transplantation: however, at present the routine use of additional investigations in asymptomatic patients solely because the patient has alcohol liver disease is not justified; further work is required to identify the degree of cardio-respiratory or cerebral impairment that contra-indicates transplantation.

IX. Abstinence should be recommended for most allograft recipients, but in a small, selected group, it may be possible to return to a controlled level of drinking (less than 14 units of alcohol/week): this option remains controversial and additional studies are required to identify those patients who may be able to return to controlled drinking.

X. The quality of life after transplantation is good even in those who return to alcohol use.

XI. There needs to be a programme to educate the general public as to the benefits of liver transplantation, even for patients with alcohol-related liver disease and all involved in the field need to demonstrate that the donor livers are used fairly and effectively.

XII. Additional work is required to identify treatments for patients with alcohol-associated liver disease both before and after liver transplantation.

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PII: S0168-8278(01)00278-1

Journal of Hepatology
Volume 36, Issue 1 , Pages 130-137, January 2002

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