REVIEWS Liver transplantation for alcoholic liver disease Michael R. Lucey Abstract | Alcoholic liver disease (ALD) is the major cause of life-threatening liver disease in Western countries. Abstinence from alcohol is the foundation of all treatment programmes for patients with ALD. Liver transplantation is a valuable option for patients with life-threatening ALD. Although the role of liver transplantation in the treatment of alcoholic hepatitis that is unresponsive to medical therapy is controversial, the latest prospective studies support this approach. No single measure gives a reliable estimate of the risk of drinking relapses before or after liver transplantation, but careful evaluation by an addiction specialist with a particular interest in transplant medicine is the best available approach. Survival, both on the waiting list and after the operation, is better in patients with ALD than in patients with HCV infection. Alcohol relapse may lead to liver damage and increased mortality, albeit usually after many years of renewed drinking. After liver transplantation, patients with ALD have increased rates of mortality and morbidity that are attributable to cardiovascular disease and new-onset cancers of the aerodigestive tract. The latter are probably linked to the high prevalence of smoking in this population. Cessation of smoking is thus an important goal in the care of patients with ALD after they have undergone liver transplantation. Lucey, M. R. Nat. Rev. Gastroenterol. Hepatol. 11, 300–307 (2014); published online 7 January 2014; doi:10.1038/nrgastro.2013.247

Department of Medicine, Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, 1685 Highland Avenue, Suite 4000, Madison, WI 53705‑2281, USA. [email protected]

Introduction

ALD as a public health crisis

Liver transplantation is the ultimate treatment for  patients dying of liver failure. Liver disease arising in patients with a history of alcohol use disorder (previously called alcoholism) is a major cause of morbidity and mortality in many parts of the world. Alcoholic liver disease (ALD) has become one of the most common indications for liver transplantation. Yet the provision of liver transplantation to patients with a history of drinking to excess remains controversial, both within the medical profession and among the general public. This Review outlines the nomenclature of addiction to alcohol and the process of assessing patients who drink to excess for liver transplantation. The outcome of liver transplantation in patients with a history of excessive drinking is also discussed. The controversies about predicting future drinking behaviour and offering liver transplantation to patients with severe alcoholic hepatitis are explored. The nomenclature of alcohol-related injury to health is changing. The most recent iteration of the Diagnostic and Statistics Manual (DSM‑V), published in 2013, has adopted the term ‘alcohol use disorders’ to cover a spectrum of states of injurious drinking and has dismissed the distinction between alcohol abuse and alcohol dependency. Within the field of addiction medicine, it is useful to define slips, relapse and craving (Box 1). This Review does not use other frequently used terms such as recidivism, harmful drinking and alcoholism.1

The WHO estimates that alcohol accounts for 2.5 million deaths annually around the world. 2 Alcohol is the world’s third largest risk factor for disease burden, with the greatest effect in the Western Pacific, the Americas and Europe.2 Alcohol-related mortality and morbidity encompasses injuries at work and on the road, domestic violence, alcohol-related end-organ damage (including that to the liver and pancreas) and several cancers. Data from the WHO show that the injurious effects of alcohol disproportionately affect the young, resulting in 320,000 deaths among young people aged 15–29 years, which amounts to 9% of all deaths in that age group.2 In the USA, an estimated 136 million adults drink alcohol, with 17 million meeting the criteria for alcohol abuse or dependence (alcohol use disorder).2 Excessive alcohol consumption is the third leading cause of preventable death in the USA, accounting for 80,000 deaths per year from 2001 to 2005.3 ALD is a broad term that encompasses a spectrum of histopathology, including alcoholic steatosis (also known as fatty liver), alcoholic hepatitis and alcoholic cirrhosis. As this Review focuses on the role of liver trans­plantation as a treatment for patients with lifethreatening ALD, the article concentrates on alcoholic hepatitis and alcoholic cirrhosis. Alcohol is a major cause of life-threatening liver disease in North America, Europe and Australia. The mortality trends attributable to ALD differ across continents and countries. Europe is the region with the greatest alcohol consumption per capita in the world, but the amount and pattern of consumption is heterogeneous.

Competing interests The author declares no competing interests.

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REVIEWS ALD and nonalcoholic liver disease

Key points ■■ Liver transplantation is the standard of care for patients with life-threatening alcoholic liver disease (ALD), but is controversial in patients with alcoholic hepatitis that is unresponsive to medical therapy ■■ Evaluation by an addiction specialist with an interest in transplant medicine is the best approach to assess prognosis for abstinence ■■ Patients with ALD undergoing liver transplantation have a similar survival benefit to recipients of a liver transplant who do not have ALD ■■ Alcohol relapse may lead to liver damage and increased mortality, albeit usually after many years of renewed drinking ■■ Patients with ALD have increased rates of mortality and morbidity attributable to cardiovascular disease and new-onset cancers of the aerodigestive tract after liver transplantation ■■ Cessation of smoking is an important goal in the care of patients with ALD after liver transplantation, as the increased mortality and morbidity is probably linked with smoking

Box 1 | Nomenclature of alcohol addiction1,13 ■■ A slip is a temporary return to drinking, which is recognized by the patient as potentially harmful, and leads to renewed efforts towards abstinence. ■■ A relapse suggests a more sustained resumption of drinking than a slip. These events are sometimes characterized as ‘harmful’, ‘abusive’ or ‘addictive drinking’. A simple definition is consuming four or more drinks in a day, or at least one drink ≥4 days in succession. ■■ Craving is a strong subjective drive to use the substance. Craving is common to most (if not all) individuals with substance dependence. ■■ Alcohol use disorder is the term that replaces the categories of alcohol abuse and dependency in DSM‑V. It comprises 11 criteria, in four areas (biological, medical harm, behavioural and social harm). The presence of two or three criteria indicates a moderate disorder, whereas four or more is severe. ■■ AUDIT (the Alcohol Use Disorders Identification Test) is the best simple instrument to systematize the recognition and diagnosis of chronic excessive alcohol use. It consists of 10 questions each with five possible answers. ■■ The CAGE questionnaire comprises four yes or no questions and is a quick aid to identify patients at risk.

For example, whereas the total consumption of alcohol and the death rate as a result of cirrhosis have declined in southern Europe, both have increased in England, Scotland, Ireland and Finland.4 In the USA, recorded deaths from ALD have declined from 6.9 per 100,000 deaths in 1980 to 4.4 per 100,000 deaths in 2003. 5 Despite this decline, ALD remains an important cause of m­ortality in the USA. In the USA and Europe, ALD is one the most common diagnoses among patients receiving a liver transplant.6,7 Either alone or in combination with HCV infection, ALD accounted for 20% of all the primary liver transplants in the USA over 1988–2009, accounting for >19,000 recipients.6 This figure is in contrast to the prediction made at the landmark NIH consensus conference in 1984 that not many patients with ALD would be selected for liver transplantation.8

Alcohol may also exacerbate several other aetiologies of liver disease, such as NAFLD, HCV infection, HBV infection and haemochromatosis. 9–12 Therefore, it is important to assess alcohol use in all patients being considered for liver transplantation. The Alcohol Use Disorders Identification Test (AUDIT), developed by the WHO, consists of 10 questions, each with five possible answers, and is the best simple instrument to system­ atize the recognition and diagnosis of chronic excessive alcohol use.13 The CAGE questionnaire is made up of four yes or no questions and is a quick aid to identify patients who consume excessive amounts of alcohol (Box 2). Patients identified by the CAGE questionnaire should be evaluated further, starting with AUDIT. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) provides a simple AUDIT form and helpful support for medical professionals.14

Role of abstinence in ALD Abstinence from all alcohol is the key to the recovery of all patients with ALD. Withdrawal of alcohol enables complete recovery from alcoholic steatosis, and is essential for the treatment of alcoholic hepatitis and compensated and decompensated alcoholic cirrhosis.15,16 Whether a threshold exists below which alcohol intake can be maintained safely is unclear. However, people with chronic alcohol use disorder who have developed major end-organ damage are rarely able to sustain a low intake of alcohol, probably as a result of addiction to alcohol.17 For these reasons, medical providers should give clear and unequivocal advice to stop all alcohol to any patient with clinical evidence of alcohol-mediated liver injury, either occurring in isolation or in association with other liver diagnoses.18–20 Acute deterioration in patients with ALD, presenting as alcoholic hepatitis or acute-on-chronic decompen­ sation manifesting as sepsis, bleeding from varices, jaundice and/or ascites, is often the consequence of recent alcohol use. Among other benefits, an extended interval of abstinence provides the opportunity to recover from the deleterious effects of recent exposure to alcohol. Indeed, patients with ALD whose clinical condition is serious without being life-threatening derive a better outcome from medical management than from placement on the transplant waiting list.21,22 Unfortunately, rigid application of an abstinence interval (usually 6 months) will also force some patients who would have a low risk of alcohol relapse to wait for a liver transplant­ ation, and for some patients this delay could be hazard­ ous. 23 A retrospective review of the UNOS (United Network for Organ Sharing) database, admittedly a highly selected cohort, showed that the survival benefit from time of placement on the transplant waiting list for patients with ALD began at a fairly low MELD (Model for End-Stage Liver Disease) score of 12–15. 24 The question arises as to when in a patient’s clinical course it becomes more likely that the patient will die rather than recover if they do not have a liver transplantation. For patients with acute-on-chronic decompensation,

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REVIEWS Box 2 | The CAGE questionnaire C Have you ever felt you should cut down on your drinking? A Have people annoyed you by criticizing your drinking? G Have you ever felt bad or guilty about your drinking? E Eye opener: Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover? The CAGE questionnaire can identify alcohol problems over a lifetime. Two positive responses are considered a positive test and indicate that further assessment is warranted.

failure to recover after 3 months abstinence is a sign of a poor prognosis.25 In patients with severe alcoholic hepatitis, failure to improve after 7 days of high-dose corticosteroids has been proposed as an indicator of treatment failure.26

Referral for liver transplantation Access to liver transplantation requires referral to a liver transplant centre, evaluation (at the centre) and present­ ation to the transplant selection committee, placement on the waiting list, and finally receipt of an offer of a viable donor organ. The American Association for the Study of Liver Diseases (AASLD) guideline states that “patients with cirrhosis should be referred for transplantation when they develop evidence of hepatic dysfunction (CTP [Child–Turcotte–Pugh] >7 and MELD >10) or when they experience their first major complication (such as ascites, variceal bleeding or hepatic encephalopathy)”.27 Referral to a transplant centre in the USA is influenced by diverse factors, including geographical location, insurance status and access to community gastroenterology services.28 Data are inconclusive as to whether patients with chronic alcohol use disorder and life-threatening liver disease are negatively discriminated against compared with people who have other liver diagnoses. Opinion surveys in the UK and France suggest that primary-care doctors give a lower priority to patients with chronic alcohol abuse than other candidates when assessing suitability for liver transplantation.29,30 However, whether this reticence translates to failure to refer suitable patients for consideration for transplant­ation is unclear. This lack of clarity arises because we are uncertain of the true number of patients with ALD who are suitable for liver transplantation, as concurrent use of alcohol confounds the determination of suitability by referring phys­icians. Among 199 patients at a large Veteran’s Affairs Hospital who met AASLD guidelines for referral for liver transplantation, the procedure was mentioned in only 59 (20%) of 300 meetings with a health-care provider.31 Older age, ALD and African American ethnicity were independently associated with not mentioning liver transplantation. Further review of the medical records revealed an inferred contra­indication, such as current alcohol use or disseminated cancer, in 94% of patients. The clinical events that lead to decompensation of alcoholic cirrhosis, such as sepsis or haemorrhage, are often difficult to distinguish from systemic circulatory failure in cirrhosis, and may themselves overlap with 302  |  MAY 2014  |  VOLUME 11

recent alcohol use. The complexity of decompensated ALD calls for a coordinated approach to management of patients with this disease, the resources for which may not be available in community settings.28,32,33 A further impediment to referral to a tertiary-care centre may be uncertainty on the part of community physicians about the duration of abstinence required before referral to a transplant centre. Nevertheless, small retrospective studies of referral patterns in the UK and the USA suggest that potentially suitable patients with ALD are not being referred for consideration for liver transplantation.31,34,35

Evaluation for liver transplantation Patients with end-stage ALD require a thorough evaluation of their medical and psychosocial suitability for transplantation as they are at risk of a broad range of end-organ injuries that might reduce their chances of surviving the transplant operation, or achieving sustained survival. All patients should be assessed for common comorbid liver conditions, including hepatocellular carcinoma or chronic viral hepatitis. Coaddiction to nicotine is very common in patients with chronic alcohol use and all the diseases associated with smoking can occur in patients with ALD who are undergoing evaluation for transplantation.36 Careful assessment of cardiopulmonary health is a mandatory part of the evaluation of patients with ALD before they can receive a liver transplant.36 In addition, chronic excess use of alcohol either alone or in combination with other injurious agents might damage the neurological and haematological systems.19,37 Many seriously ill patients with ALD are malnourished as a result of a combination of factors, including poor nutrition, poor dentition, chronic pancreatic insufficiency and accompanying psychosocial disorders.19,36 The burden of psychiatric disorders in patients with ALD is high and includes bipolar disorders, current or past abuse of drugs and chronic pain syndromes.20,36

Assessment of abstinence Assessing abstinence in patients with ALD has two parts: determining the drinking status at the current time, and making a prognosis about the likelihood that the candidate will remain abstinent both before and after transplantation. Both of these elements are best managed when the transplant team includes an expert in addiction medicine.38 Assessing the drinking status of the recipient, either before or after transplantation, can be challenging. For example, self-report and family corroboration are prone to under-reporting.39,40 The patient is likely to minimize drinking out of a sense of guilt, fear of upsetting their family and because a return to drinking might jeopardize access to a primary allograft or to a second transplant, were such an operation to be necessary. 10,40 However, it is possible to foster candour on the part of the patient by distinguishing slips from relapses (Box 1), by incorporating an addiction specialist into the transplant team, and by supporting treatment for addiction, without necessarily jeopardizing access to transplant­ ation, whenever a patients slips or relapses.20,40,41 Several candidate biomarkers of alcohol use (such as ethyl



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REVIEWS glucuronide, ethyl sulphate, phosphatidyl ethanol and carbohydrate-deficient transferrin) have been reviewed, and although some of these tests have been reported in clinical studies, none has yet become established in the clinical setting of transplant medicine.42,43 Alcohol use disorder is a dynamic condition, and slips and relapses are probable among patients presenting for liver transplantation or in the follow-up period after surgery.41,44 Even experiencing one of the life-threatenin­g events that often occur in patients with alcoholic cirrhosis, such as variceal haemorrhage, is insufficient to prevent a future return to drinking in many cases.45 Once a drinking episode has become known, opinion is divided as to how liver transplantation professionals should respond. The UK Liver Transplants Units’ Working Party took the view that “return to drinking after full professional assessment and advice (which includes permanent removal from the transplant list if found drinking whilst listed)” precluded placement on the transplant waiting list.46 A contrary view is that such rigid rules fail to understand the distinction between a slip and relapse (Box 1) and “force(s) alcoholic liver patients who have resumed alcohol use while waiting for or after transplantation to choose between hiding their drinking to remain suitable candidates for transplant­ation or risk death by asking for treatment of alcoholism.”40 Consequently, a flexible approach to clinical decisionmaking has been advocated for health-care providers working with patients who have a history of chronic alcohol use and have resumed drinking, and specific guidelines for patient management have been provided.40

Predicting future drinking Whilst both prospective and retrospective studies show that 6 months of abstinence alone is a weak indicator of future drinking in patients who have undergone a liver transplantation, these studies are confounded by failure to distinguish slips from relapses, by inherent flaws in the methods used to recognize drinking and many other biases.47,48 Although the duration of abstinence is loosely tied to future drinking behaviour, rigid adherence to this rule will place a potentially hazardous delay on patients with a low risk of relapse after transplantation.23 At the same time, many patients with a history of chronic alcohol use relapse despite 6 months of abstinence.49 Indeed, abstinence might not be secure until after 5 years.22 That said, the use of a 6‑month abstinence requirement before a transplantation is carried out is widespread in North America,50 and was included in the last USA consensus document for treatment of ALD (published in 1997);51 6 months of abstinence is also often a requirement imposed by paying agencies. By contrast, consensus conferences in France and the UK whose findings were published in 2006 did not advocate a fixed interval of abstinence.46,52 Approximately 20 years ago, Beresford proposed assessing the risks of relapse after liver transplantation by undertaking a careful assessment of the candidate’s psycho­logical health.38 Since then, the role of the addiction specialist has become commonplace in transplant teams.35

The favourable factors for future sobriety that Beresford proposed were the patient’s acknowledgement of addiction, social support (particularly a spouse), paid employment and a home, and four indicators of social integration: activities to replace drinking in the patient’s daily life, the support of a ‘rehabilitation relationship’, a source of improved self-esteem or of hope for the future, and the identification by the patient of negative consequences of returning to drinking. Patients with less severe drinking patterns, previously called alcohol abuse, seem to be at a lower risk of relapse after liver transplantation than patients with severe drinking patterns, previously termed dependence.38 Finally, Beresford has counselled against the notion that one ideal prognostic indicator exists. In his view “the range among the various factors is too wide to justify using any one as a strict inclusion or exclusion criterion”.38 Consequently, the transplant team needs to integrate the report of the addiction specialist with all the other pieces of information that make up the transplant evaluation, and make a balanced decision of what is in the best interests of the patient. This approach is considerably different to that used by Mathurin and co-workers in their important pilot study of rescue liver transplantation in patients with alcoholic hepatitis who are unresponsive to medical management in which the addiction specialist had a veto on transplantation.53

Transplant for alcoholic hepatitis Mortality at 6 months might exceed 70% in patients with severe alcoholic hepatitis who have failed medical therapy with high-dose corticosteroids.54 However, both because of the opportunity to recover with abstinence and because of the requirements for patients with ALD to demonstrate extended abstinence before they undergo transplantation, patients with life-threatening alcoholic hepatitis have been explicitly excluded from liver transplantation.36,51 The EASL (European Association for the Study of the Liver) guidelines on ALD, published in 2012, did not take a position on transplantation for alcoholic hepatitis.19 Similarly, the French and British position papers did not place a specific requirement for abstinence as a prerequisite to transplantation, thereby opening up the possibility of transplantation in patients with alcoholic hepatitis.46,52 This evolution in attitudes to liver transplantation for patients with alcoholic hepatitis has come about because of limited retrospective data and one prospective pilot study.53,55–57 A retrospective review of the UNOS database from 2004 to 2010 found that 130 patients with a diagnosis of alcoholic hepatitis had been listed for transplantation, of whom 59 received a transplant.55 Despite confounding elements such as HCV infection in 14 patients (25%), and the fact that only 11 patients had histological evidence of alcoholic hepatitis on explant pathology, it should be noted that graft and patient survival were similar in the patients with alcoholic hepatitis and in a control cohort of recipients without a history of chronic excessive alcohol use. Two single centre retrospective reviews of explant histology have defined small cohorts of patients with

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REVIEWS

Log 3-week interval of drinks

5

Group Group Group Group Group

4

1 2 3 4 5

3

2

1

The transplant evaluation committee The decision to place a patient on the transplant waiting list is usually taken by a committee. In the USA, this committee consists of transplant surgeons, transplant hepato­ logists, an addiction specialist, medical social workers and other professionals involved in the evaluation of candidates and management of patients before and after transplantation. Some of the most difficult discussions concern patients with ALD, trying to find the correct balance between the medical condition of patients and what weight to give the psychosocial assessment.59

Clinical outcomes

0 0

500

1,000 1,500 2,000 2,500 Time from discharge after liver transplantation (days)

3,000

Figure 1 | Patterns of drinking behaviour in a prospective cohort of patients with alcoholic liver disease following liver transplantation in a single centre. Group 1 contains 113 patients (51.3%) who consumed no alcohol. Group 2 contains 55 patients (28.6%) who had rare slips. Group 3 contains 13 patients (6.4%) who had early harmful use, which then declined. Group 4 contains 15 patients (7.9%) who had late onset harmful use. Group 5 contains 12 patients (5.8%) who had early and continued severe harmful use. Permission obtained from Wiley © DiMartini, A. et al. Am. J. Transpl. 10, 2305–2312 (2010).

histological evidence of alcoholic hepatitis.54,55 Graft and patient survival did not differ to that of recipients without such features in their native livers.56,57 These studies are limited by being retrospective, and the low numbers of patients who received transplants for alcoholic hepatitis. A prospective pilot multicentre Franco–Belgian study of liver transplantation as a therapy for patients with severe alcoholic hepatitis that did not respond to 40 mg per day of prednisolone for 7 days reported contrasting results.53 Selection required agreement among all members of the multidisciplinary team. The median MELD score of the 26 participants undergoing transplantation was 34. Patients received a transplant on average 9 days after placement on the waiting list, and 13 days after stopping corticosteroids. The 6‑month survival of patients who received a transplant was 77.8%, compared with 23.8% in historical controls with similar severe alcoholic hepatitis, unresponsive to medical therapy. The patients with alcoholic hepatitis who received a transplant represented only 2.8% of transplants done in the seven centres during the time of the study. Only three participants returned to drinking at 720, 740 and 1,140 days after transplantation, respectively. We await more studies, such as those on-going or planned in France and Spain.58 A more practical selection tool would also be helpful, as use of the Lille score threshold of >0.45 means that 1 in 4 patients would have recovered with medical management alone.54 Finally, it is possible that local factors, such as the advent in the USA of a protocol for regional sharing of deceased donor livers unless for a recipient with a MELD score of ≥35 (‘the share 35 rule’) will encourage transplant centres to list patients with severe alcoholic hepatitis for transplantation. 304  |  MAY 2014  |  VOLUME 11

In a consecutive series of 9,880 European patients with ALD who received a liver transplant between 1988 and 2005, patient survival at 1, 3, 5 and 10 years from first transplantation was 84%, 78%, 73% and 58%, respect­ ively.7 An analysis of the UNOS database (n = 38,899) with a median follow-up after transplantation of 1.8 years compared transplant recipients with ALD to those with HCV infection.24 The presence of ALD did not influence mortality after transplantation, whereas survival after transplantation was notably lower in patients infected with HCV than in patients without HCV infection.24 In addition, most studies suggest that the combination of ALD and HCV is associated with worse survival after liver transplantation than either disease alone. 7,24,60 Neuberger’s group compared patient survival after liver transplantation among recipients who had survived the first 6 months, to that in the healthy general population.61 Patients who received a liver transplant for ALD had a life expectancy of 15 years, albeit with 14.2 years of life lost. For comparison, the best outcomes were observed in patients who received a transplant as a result of primary biliary cirrhosis: life expectancy was 35.8 years, with 6.6 years gained. Whilst liver transplant recipients with ALD have similar survival to liver transplant recipients who do not have ALD, evidence is emerging that patients with ALD who have drinking relapses (as opposed to experiencing a ‘slip’) have reduced survival, more progressive liver injury and episodes of alcoholic hepatitis.62–65 Thus, the interdictions regarding alcohol use mentioned before liver transplantation need to be reinforced after liver transplantation. The cause of death after transplantation for recipients with ALD differs from that in recipients who do not have ALD, with more deaths due to cardiovascular disease or de novo malignancies in the ALD cohort.7,66–70 Most of these studies suggest that new-onset malignancies are concentrated in the aerodigestive tract. A putative causal link between cigarette smoking and the preponderance of death from cardiovascular causes or aerodigestive cancer has been inferred, on account of the high prevalence of cigarette addiction in the population of patients with ALD who undergo liver transplantation. Indeed, it has been shown that liver transplant recipients with ALD who were smokers before transplantation quickly re-establish smoking after the procedure.71 The initiation of smoking cessation and adoption of a smoke-free



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REVIEWS lifestyle are important elements for maintaining health in this population.

Drinking relapses after a transplant Reported rates of alcoholic relapse after transplantation vary widely, ranging from ~10% to 90%.72 Understanding the distinction between alcoholic ‘slips’ and ‘relapses’ is important in clinical practice, which unfortunately most studies assessing relapse have failed to do (Box 1). DiMartini and colleagues have described alcohol use after liver transplantation in a single-centre longitud­ inal prospective group of 208 recipients with ALD (Figure 1).42 Of the patients in the cohort, 80% either did not drink or only consumed small amounts occasionally. Conversely, three patterns of excessive drinking were found in the remaining 20%. The patterns varied according to the time to relapse, and whether the patients demonstrated sustained heavy use or subsequently modified their drinking. These data are similar to a retrospective report in which harmful drinking was found in 16% of a smaller British single-centre cohort.73 Recipients of a liver transplant who relapse to excessive drinking are at risk of developing all the medical complications of excessive alcohol use seen in the nontransplant setting, such as alcoholic hepatitis, pancreatitis, delirium tremens, pneumonia, cellulitis and malnutrition.60,62,74,75 Although the data are limited to single-centre studies, long-term (that is, ~10 years) patient survival is reduced in recipients of a liver transplant who relapse.63,64 Reduced survival is observed in excessive drinkers after transplanta­­ tion irrespective of the pretransplant primary liver diagnosis.12 Finally, patients who relapse are more likely to have lapses from taking immuno­suppressive medications.65 These data offer strong support for the view that all patients with ALD who receive a liver transplant should be encouraged to maintain abstinence from alcohol after liver transplantation, and to get treatment for alcohol addiction whenever they experience an alcohol relapse.

Treatment of addiction Few studies have assessed the treatment of alcohol use disorder either before or after liver transplantation, and these studies have faced several difficulties.41,76,77 First, the patients with a history of chronic excessive alcohol use who are selected for placement on the liver transplanta­ tion waiting list comprise different populations with a spectrum of risk of relapse. At one extreme are patients who have been abstinent for many years, who deny craving for alcohol and who express little interest in entering formal programs for addiction treatment (Box 1).76 At the other end of the spectrum are the patients who acknowledge craving for alcohol, and who are anxious for treatment. As patients with long intervals of abstinence are preferentially selected for liver transplantation, the population of patients with ALD undergoing liver transplantation is enriched with patients in the first group. Indeed, lack of interest in treatment limited recruitment to a trial of n ­ altrexone in liver transplant recipients with ALD.77 Concern about h­epatotoxicity was a further barrier to recruitment to this trial.77

Box 3 | ALD and transplantation: unanswered questions ■■ What is the prevalence of patients with ALD in the community who do not have access to a transplant centre? ■■ What proportion of the unrecognized patients with ALD in the community would meet transplant criteria? ■■ Can we improve predictive tools in severe alcoholic hepatitis; does the Lille score work outside France and Belgium? ■■ Are there better medical treatments for severe alcoholic hepatitis than corticosteroids? ■■ Do we understand the dynamics of group decision-making regarding liver transplantation for patients with ALD? ■■ What influence should risk of alcohol relapse have in selection for liver transplantation? ■■ How should alcoholic relapse before or after transplantation be treated? ■■ How can long-term survival after liver transplantation in patients with ALD be improved? Abbreviation: ALD, alcoholic liver disease.

A two centre prospective randomized controlled trial has assessed a serial psychotherapeutic intervention (motivational enhancement therapy, 46 patients) compared with standard advice to stop drinking (45 patients) administered to participants before they underwent liver transplantation.38 Candour concerning alcohol use was encouraged by keeping drinking questionnaires in confidence, except in medical emergencies.40 Unfortunately, a high rate of relapse was found in both groups, amounting to 25% of the patients awaiting transplantation. Whilst subtle improvements were seen in secondary end points in the group that received motivational enhancement therapy, no clear benefit was observed for this treatment. By contrast, Björnsson et al. described a plan for structured management of alcohol use disorder before and after liver transplantation, comprising assessment by a psychiatrist skilled in addiction medicine, structured addiction treatment in those who had not previously received treatment, and adoption of a sobriety contract.78 A reduction in the prevalence of ‘any use’ was found among the study participants compared with historical controls, although d­rinking behaviour was not reported in terms of e­xcessive use.78 Patients who have received a liver transplant to treat ALD are often cigarette smokers, and resume addictive smoking early in the recovery period.70 The long-term consequences of nicotine addiction are evident in the increased mortality and morbidity from hepatic artery thrombosis, cardiovascular disease and new-onset cancers of the aerodigestive tract.20,66,67,79 All recipients of a liver transplant who have previously been diagnosed with ALD and are users of tobacco should be encouraged to stop smoking.20

Quality of life after transplantation Assessment of quality of life after liver transplantation indicates that whereas quality measures improve in these patients in most domains compared with their status before transplantation, recipients of a liver transplant continue to have many deficits compared with age-matched

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REVIEWS control populations.80,81 Many of these studies are flawed and longitudinal studies with adequate numbers, duration of follow-up and validation of the quality of life measures are lacking. Furthermore, concerns exist that the improvements found initially are not sustained, with patients reporting deteriorating physical symptoms, fatigue and well-being over time.82 The effect of a diagnosis of ALD, or return to use of alcohol or smoking on quality of life is not well understood, and improved studies are needed.

Conclusions Liver transplantation for life-threatening ALD has progressed to become standard of care. Whilst many 1.

Fuller, R. K. Definition and diagnosis of relapse to drinking. Liver Transpl. Surg. 3, 258–262 (1997). 2. WHO. Global status report on alcohol, 2011 [online], http://www.who.int/mediacentre/ factsheets/fs349/en/index.html (2011). 3. CDC. Alcohol and Public Health: Alcohol-Related Disease Impact (ARDI) [online], www.cdc.gov/ alcohol/ardi.htm (2013). 4. Sheron, N. Alcoholic liver disease in Europe. Presented at the EASL postgraduate course, Barcelona 2012. 5. Paula, H. et al. Alcoholic liver disease-related mortality in the United States: 1980–2003. Am. J. Gastroenterol. 105, 1782–1787 (2010). 6. UNOS. UNOS Donation & Transplantation Data [online], http://www.unos.org/donation/ index.php?topic=data (2013). 7. Burra, P. et al. Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry). Am. J. Transplant. 10, 138–148 (2010). 8. [No authors listed]. National Institutes of Health Consensus Development Conference on Liver Transplantation. Sponsored by the National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases and the National Institutes of Health Office of Medical Applications of Research. Hepatology 4 (Suppl. 1), 1S–110S (1984). 9. Hutchinson, S. J., Bird, S. M. & Goldberg, J. D. Influence of alcohol on the progression of hepatitis C virus infection: a meta analysis. Clin. Gastroenterol. Hepatol. 3, 1150–1159 (2005). 10. Lin, C. W. et al. Heavy alcohol consumption increases the incidence of hepatocellular caricinoma in hepatitis B virus-related cirrhosis. J. Hepatol. 58, 730–735 (2013). 11. Day, E. et al. Detecting lifetime alcohol problems in individuals referred for liver transplantation for nonalcoholic liver failure. Liver Transpl. 14, 1609–1613 (2008). 12. Faure, S. et al. Excessive alcohol consumption after liver transplantation impacts on long-term survival, whatever the primary indication. J. Hepatol. 57, 306–312 (2012). 13. Saunders, J. B., Aasland, O. G., Babor, T. F., de la Fuente, J. R. & Grant, M. Development of the Alcohol Use Disorders Screening Test. (AUDIT). WHO collaborative project on early detection of persons with harmful alcohol consumption. II. Addiction 88, 791–804 (1993). 14. National Institute on Alcohol and Alcoholism. AUDIT [online], http://pubs.niaaa.nih.gov/ publications/Audit.pdf (2013).

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unanswered questions remain about the epidemiology, assessment and treatment of severe ALD in relation to liver transplantation (Box 3), liver transplantation for ALD is one of the most striking successes of solid organ transplantation. Review criteria PubMed was searched using the terms “liver transplantation”, “alcoholic liver disease”, “alcoholic cirrhosis”, “alcoholic hepatitis”. Guidelines were also consulted. Original articles, reviews, editorial and their reference lists were considered. There were no language restrictions. The literature search was performed in April 2013.

15. Powell, W. J. Jr & Klatskin, G. Duration of survival in patients with Laennec’s cirrhosis. Influence of alcohol withdrawal, and possible effects of recent changes in general management of the disease. Am. J. Med. 44, 406–420 (1968). 16. Alexander, J. F., Lischner, M. W. & Galambos, J. T. Natural history of alcoholic hepatitis. II. The long-term prognosis. Am. J. Gastroenterol. 56, 515–525 (1971). 17. Vaillant, G. E. A 60-year follow-up of alcoholic men. Addiction 98, 1043–1051 (2003). 18. O’Shea, R. S., Dasarathy, S. & McCullough, A. J. Alcoholic liver disease. Hepatology 51, 307–328 (2010). 19. European Association for the Study of the Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J. Hepatol. 57, 399–420 (2012). 20. Lucey, M. R. et al. Long-term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl. 19, 3–26 (2013). 21. Poynard, T. et al. Evaluation of efficacy of liver transplantation in alcoholic cirrhosis using matched and simulated controls: 5‑year survival. Multi-centre group. J. Hepatol. 30, 1130–1137 (1999). 22. Vanlemmens, C. et al. Immediate listing for liver transplantation versus standard care for ChildPugh stage B alcoholic cirrhosis: a randomized trial. Ann. Intern. Med. 150, 153–161 (2009). 23. Yates, W. R. et al. A model to examine the validity of the 6‑month abstinence criterion for liver transplantation. Alcohol Clin. Exp. Res. 22, 513–517 (1998). 24. Lucey, M. R., Schaubel, D. E., Guidinger, M. K., Tome, S. & Merion, R. M. Effects of alcoholic liver disease and hepatitis C infection on waiting list and posttransplant mortality and transplant survival benefit. Hepatology 50, 400–406 (2009). 25. Veldt, B. J. et al. Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and optimal timing. J. Hepatol. 36, 93–98 (2002). 26. Louvet, A. et al. The Lille Model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology 45, 1348–1354 (2007). 27. Murray, K. F. & Carithers, R. L. Jr. AASLD practice guidelines: evaluation of the patient for liver transplantation. Hepatology 41, 1407–1432 (2005). 28. Barritt, A. S., Telloni, S. A., Potter, C. W., Gerber, D. A. & Hayashi, P. H. Local access to



29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

subspecialty care influences the chance of receiving a liver transplant. Liver Transpl. 19, 377–382 (2013). Neuberger, J., Adams, D., MacMaster, P., Maidment, A. & Speed, M. Assessing priorities for allocation of donor liver grafts: survey of public and clinicians. BMJ 317, 172–175 (1998). Perut, V. et al. Might physicians be restricting access to liver transplantation for patients with alcoholic liver disease? J. Hepatol. 51, 707–714 (2009). Julapalli, V. R., Kramer, J. R. & El-Serag, H. B. Evaluation for liver transplantation: adherence to AASLD referral guidelines in a large Veterans Affairs center. Liver Transpl. 11, 1370–1378 (2005). Arabi, Y. M. et al. Antimicrobial therapeutic determinants of outcomes from septic shock among patients with cirrhosis. Hepatology 56, 2305–2015 (2012). Olson, J. C. et al. Intensive care of the patient with cirrhosis. Hepatology 54, 1864–1872 (2011). Davies, M. H., Langman, M. J., Elias, E. & Neuberger, J. M. Liver disease in a district hospital remote from a transplant centre: a study of admissions and deaths. Gut 33, 1397–1399 (1992). Kotlyar, D. S., Burke, A., Campbell, M. S. & Weinrieb, R. M. A critical review of candidacy for orthotopic liver transplantation in alcoholic liver disease. Am. J. Gastroenterol. 103, 734–743 (2008). Murray, K. F. & Carithers, R. L. Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology 41, 1407–1432 (2005). Latvala, J., Parkkila, S. & Niemelä, O. Excess alcohol consumption is common in patients with cytopenia: studies in blood and bone marrow cells. Alcohol Clin. Exp. Res. 28, 619–624 (2004). Beresford, T. P. in Liver Transplantation and the Alcoholic Patient (eds Lucey, M. R., Merion, R. M. & Beresford, T. P.) 29–49 (Cambridge University Press, 1994). Orrego, H., Blake, J. E., Blendis, L. M., Kapur, B. M. & Israel, Y. Reliability of assessment of alcohol intake based on personal interviews in a liver clinic. Lancet 2, 1354–1356 (1979). Weinrieb, R. M., Van Horn, D. H., McLellan, A. T. & Lucey, M. R. Interpreting the significance of drinking by alcohol-dependent liver transplant patients: fostering candor is the key to recovery. Liver Transpl. 6, 769–776 (2000). Weinrieb, R. M., Van Horn, D. H., Lynch, K. G. & Lucey, M. R. A randomized, controlled study

www.nature.com/nrgastro © 2014 Macmillan Publishers Limited. All rights reserved

REVIEWS

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

of treatment for alcohol dependence in patients awaiting liver transplantation. Liver Transpl. 17, 539–547 (2011). Allen, J. P., Wurst, F. M., Thon, Z. N. & Litten, R. Z. Assessing the drinking status of liver transplant patients with alcoholic liver disease. Liver Transpl. 19, 369–376 (2013). Erim, Y. et al. Urinary ethyl glucuronide testing detects alcohol consumption in alcoholic liver disease patients awaiting liver transplantation. Liver Transpl. 13, 757–761 (2007). DiMartini, A. et al. Trajectories of alcohol consumption following liver transplantation. Am. J. Transplant. 10, 2305–2312 (2010). Lucey, M. R. et al. Alcohol consumption by cirrhotic subjects: patterns of use and effects on liver function. Am. J. Gastroenterol. 103, 1698–1706 (2008). Bathgate, A. J. Recommendations for alcoholrelated liver disease. Lancet 367, 2045–2046 (2006). DiMartini, A. et al. Trajectories of alcohol consumption following liver transplantation. Am. J. Transplant. 10, 2305–2312 (2010). De Gottardi, A. et al. A simple score for predicting alcohol relapse after liver transplantation: results from 387 patients over 15 years. Arch. Intern. Med. 167, 1183–1188 (2007). Karim, Z. Predictors of relapse to significant alcohol drinking after liver transplantation. Can. J. Gastroenterol. 24, 245–250 (2010). Everhart, J. E. & Beresford, T. P. Liver transplantation for alcoholic liver disease: a survey of transplantation programs in the United States. Liver Transpl. Surg. 3, 220–226 (1997). Lucey, M. R. et al. Minimal criteria for placement of adults on the liver transplant waiting list: a report of a national conference organized by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases. Liver Transpl. Surg. 3, 628–637 (1997). [No authors listed]. Consensus conference: indications for liver transplantation, January 19 and 20, 2005, Lyon-Palais Des Congres: text of recommendations. Liver Transpl. 12, 998–1011 (2006). Mathurin, P. et al. Early liver transplantation for severe alcoholic hepatitis. N. Engl. J. Med. 365, 1790–1800 (2011). Lucey, M. R., Mathurin, P. & Morgan, T. R. Alcoholic hepatitis. N. Engl. J. Med. 360, 2758–2769 (2009). Singal, A. K. et al. Outcomes after liver transplantation for alcoholic hepatitis are similar to alcoholic cirrhosis: exploratory analysis from

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

the UNOS database. Hepatology 55, 1398–1405 (2012). Tome, S. et al. Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for end-stage alcoholic liver disease. J. Hepatol. 36, 793–798 (2002). Wells, J. T. et al. The impact of acute alcoholic hepatitis in the explanted recipient liver on outcome after liver transplantation. Liver Transpl. 13, 1728–1735 (2007). Herrero, J. I., Tomé, S. & González-Pinto, I. Liver transplantation in alcoholic hepatitis. Gastroenterol. Hepatol. 36, 297–298 (2013). Volk, M. L. et al. Decision making in liver transplant selection committees: a multicenter study. Ann. Intern. Med. 155, 503–508 (2011). Aguilera, V. et al. Cirrhosis of mixed etiology (hepatitis C virus and alcohol): Posttransplantation outcome-comparison with hepatitis C virus-related cirrhosis and alcoholicrelated cirrhosis. Liver Transpl. 15, 79–87 (2009). Barber, K., Blackwell, J., Collett, D. & Neuberger, J. Life expectancy of adult liver allograft recipients in the UK. Gut 56, 279–282 (2007). Conjeevaram, H. S. et al. Rapidly progressive liver injury and fatal alcoholic hepatitis occurring after liver transplantation in alcoholic patients. Transplantation 67, 1562–1568 (1999). Cuadrado, A., Fábrega, E., Casafont, F. & Pons‑Romero, F. Alcohol recidivism impairs long-term patient survival after orthotopic liver transplantation for alcoholic liver disease. Liver Transpl. 11, 420–426 (2005). Pfitzmann, R. et al. Long-term survival and predictors of relapse after orthotopic liver transplantation for alcoholic liver disease. Liver Transpl. 13, 197–205 (2007). Rice, J. P. et al. Abusive drinking post-liver transplant is associated with allograft loss and advanced allograft fibrosis. Liver Transpl. 10, 1132–1141 (2013). Watt, K. D., Pedersen, R. A., Kremers, W. K., Heimbach, J. K. & Charlton, M. R. Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study. Am. J. Transplant. 10, 1420–1427 (2010). Duvoux, C. et al. Increased incidence of oropharyngeal squamous cell carcinomas after liver transplantation for alcoholic cirrhosis. Transplantation 67, 418–421 (1999). Bellamy, C. O. et al. Liver transplantation for alcoholic cirrhosis: long term follow-up and impact of disease recurrence. Transplantation 72, 619–626 (2001). Saigal, S. et al. Evidence of differential risk for posttransplantation malignancy based on

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2014 Macmillan Publishers Limited. All rights reserved

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

pretransplantation cause in patients undergoing liver transplantation. Liver Transpl. 8, 482–487 (2002). Dumortier, J. et al. Negative impact of de novo malignancies rather than alcohol relapse on survival after liver transplantation for alcoholic cirrhosis: a retrospective analysis of 305 patients in a single center. Am. J. Gastroenterol. 102, 1032–1041 (2007). DiMartini, A. et al. Tobacco use following liver transplantation for alcoholic liver disease: an underestimated problem. Liver Transpl. 11, 679–683 (2005). Tome, S. & Lucey, M. R. Timing of liver transplantation in alcoholic cirrhosis. J. Hepatol. 39, 302–307 (2003). Tang, H., Boulton, R., Gunson, B., Hubscher, S. & Neuberger, J. Patterns of alcohol consumption after liver transplantation. Gut 43, 140–145 (1998). Lucey, M. R. et al. Alcohol use after liver transplantation in alcoholics: a clinical cohort follow-up study. Hepatology 25, 1223–1227 (1997). Pageaux, G. P. et al. Alcohol relapse after liver transplantation for alcoholic liver disease: does it matter? J. Hepatol. 38, 629–634 (2003). Weinrieb, R. M. et al. Drinking behavior and motivation for treatment among alcoholdependent liver transplant candidates. J. Addict. Dis. 20, 105–119 (2001). Weinrieb, R. et al. Alcoholism treatment after liver transplantation: lessons learned from a clinical trial that failed. Psychosomatics 42, 110–116 (2001). Björnsson, E. et al. Long-term follow-up of patients with alcoholic liver disease after liver transplantation in Sweden: impact of structured management on recidivism. Scand. J. Gastroenterol. 40, 206–216 (2005). Pungpapong, S. et al. Cigarette smoking is associated with an increased incidence of vascular complications after liver transplantation. Liver Transpl. 8, 582–587 (2002). Bravata, D. M., Olkin, I., Barnato, A. E., Keeffe, E. B. & Owens, D. K. Health-related quality of life after liver transplantation: a metaanalysis. Liver Transpl. Surg. 5, 318–331 (1999). Tome, S., Wells, J. T., Said, A. & Lucey, M. R. Quality of life after liver transplantation. A systematic review. J. Hepatol. 48, 567–577 (2008). Ruppert, K., Kuo, S., DiMartini, A. & Balan, V. In a 12-year study, sustainability of quality of life benefits after liver transplantation varies with pretransplantation diagnosis. Gastroenterology 139, 1619–1629 (2010).

VOLUME 11  |  MAY 2014  |  307

Liver transplantation for alcoholic liver disease.

Alcoholic liver disease (ALD) is the major cause of life-threatening liver disease in Western countries. Abstinence from alcohol is the foundation of ...
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