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Liver Transplantation for Alcoholic Liver Disease

Addolorato, Giovanni MD; Bataller, Ramón MD, PhD; Burra, Patrizia MD, PhD; DiMartini, Andrea MD; Graziadei, Ivo MD; Lucey, Michael R. MD; Mathurin, Philippe MD, PhD; O'Grady, John MD; Pageaux, Georges MD, PhD; Berenguer, Marina MD

doi: 10.1097/TP.0000000000001156
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Alcohol-related liver disease is the second most frequent indication for liver transplantation (LT), yet as many as 90% to 95% of patients with alcohol-related end-stage liver disease are never formally evaluated for LT. Furthermore, despite its significance as a cause of chronic liver disease and indication for LT, it has received little attention in recent years for several reasons, including the good posttransplant short-term results, and the lack of specific “drugs” used for this disease. A writing group, endorsed by the International Liver Transplant Society, was convened to write guidelines on Liver Transplantation for Alcoholic Liver Disease to summarize current knowledge and provide answers to controversial and delicate ethical as well as clinical problems. We report here a short version of the guidelines (long version available at www.ilts.org) with the final recommendations graded for level of evidence. The writing group membership is expected to remain active for 5 years, reviewing the guideline annually, and updating the online version when appropriate.

The ILTS guidelines for liver transplantation for alcoholic liver disease are set forth in this publication. Considerations include the candidate population and the challenges regarding both the assessment of sobriety before and the maintenance of quality of life after transplantation. The authors identify special considerations, including immunosuppression in this setting and the special considerations regarding patients with acute alcoholic hepatitis.

1 Alcohol Use Disorders Unit, Department of Internal Medicine, Gastroenterology and Hepatology, Catholic University of Rome, Rome, Italy.

2 Liver Center, Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina, Chapel Hill, NC.

3 Multivisceral Transplant Unit, Gastroenterology Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy.

4 Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, PA.

5 Department of Internal Medicine II, Medical University of Innsbruck & Academic Teaching Hospital Hall, Innsbruck, Austria.

6 Department of Internal Medicine, Academic Teaching Hospital Hall, Austria.

7 Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, WI.

8 Service des Maladies de l'Appareil Digestif, Hôpital Huriez, Lille, France.

9 Liver Unit, King's College Hospital, London, United Kingdom.

10 Département d'Hépatogastroenterologie et Transplantation, CHU Saint Eloi, Université de Montpellier, Montpellier, France.

11 Liver Transplantation and Hepatology Unit, La Fe University Hospital, Ciberehd and Valencia University, Valencia, Spain.

12 Ciberehd, University of Valencia, Valencia, Spain.

Received 12 November 2015. Revision received 22 December 2015.

Accepted 9 January 2016.

G.A. served as a consultant for Ortho-McNeil Janssen Scientific Affairs, LLC, and D&A Pharma, and has received lecture fees from D&A Pharma. R.B. served as a consultant for Sandhill Scientific, Oncozyme Pharma Inc and Vital Therapies. P.M. served as a consultant for Verlyx Pharma Inc. G.P. served as consultant for Astellas and Novartis.

Ciberehd is funded by the Instituto de Salud Carlos III.

Correspondence: Marina Berenguer, MD, International Liver Transplant Society, 1120 Route 73, Suite 200, Mt. Laurel, NJ 08064. (marina.berenguer@uv.es).

Alcohol-related liver disease (ALD) is one of the most common indications for liver transplantation (LT) in Europe and in North America, accounting for 20% to 30% of all transplants, and this proportion may be on the increase.1,2 Even though a return to some degree of alcohol consumption after transplantation is seen in up to 50% recipients, survival after transplantation is good. Indeed, most large registries have shown that the outcome for patients transplanted for ALD, characterized as either survival benefit from time of placement on the waiting list or posttransplant patient survival, is at least as good as that for most other diagnoses, and better than that for Hepatitis C virus1-3 with 1-, 3-, 5-, and 10-year survival rates of 87% to 84%, 78%, 71% to 73%, and 58% reported in the European Liver Transplant Registry and the Scientific Registry of Transplant Recipients.1,2 Interestingly, whereas LT for ALD has excellent results in Europe and North America, the causes of death in this posttransplant population are different to those observed in patients transplanted for other etiologies of liver disease. De novo tumors, cardiovascular events, and social causes are the main causes of death in patients transplanted for ALD.1-8 In contrast, only a minority die of alcohol abuse, suggesting that alcohol relapse is not a major problem in these patients. Despite these excellent outcomes, health care professionals remain reluctant to refer these patients for formal assessment, formal transplant assessment which eventually is only performed in a minority of patients with ALD.3,4 Clearly, a more profound understanding is needed regarding the larger population that is being screened out. Summary of subtopics and experts involved, grading system for recommendations and final recommendations are summarized in tables 1 to 3.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

TABLE 3

TABLE 3

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Comorbidities in ALD With an Impact on Pre- and Post-LT Outcomes

Multisystemic effects of long-term ethanol abuse are frequently present at time of LT in patients with a history of ALD.5,6 These comorbidities include malnutrition, vitamin deficiencies, bone density loss, nonimmune hemolytic anemia, peripheral and central neural system abnormalities, nephropathy and muscle wasting (sarcopenia) among others. Therefore, the integral care of the transplanted patient with ALD ideally requires a multidisciplinary approach. Importantly, deconditioning and sarcopenia have been associated with significantly worse outcomes after LT, even to the point where they may become potential contraindications, especially when associated with other comorbidities.9 Assessment of nutritional status is recommended during the evaluation of ALD patients. The help of a specialized nutritionist is advisable. Vitamins (folate, D, E, B12, B1, B3, B6) and mineral deficiencies (Fe, Mg, P) are frequently seen and should be corrected. In selected cases, enteral nutrition is indicated.

Special attention should be paid to neurological complications of alcohol use disorder (AUD).5,6 In some patients with ALD undergoing pre-LT evaluation, alcohol-related dementia cannot be differentiated from hepatic encephalopathy. This distinction is important, because alcohol related dementia is often irreversible, unlike hepatic encephalopathy, which is largely reversible after LT.

In addition to significant cognitive impairment, patients may suffer from neurological syndromes, such as spastic paraparesis, seizures, and myoclonic convulsions, and language and visuospatial dysfunction. A careful evaluation by a neurologist is highly recommended. Significant neurologic defects may influence a patient's candidacy for LT, particularly because these complications affect adherence to the complicated medication and physical rehabilitation regimen required post-LT. After LT, seizures and neurologic complications caused by immunosuppression, particularly calcineurin inhibitors (CNIs), are more common in patients with ALD. Most neurological complications due to alcohol abuse in patients with ALD are irreversible. Thiamine administration can prevent Wernicke-Korsakoff syndrome, and vitamin B supplementation (eg, cobalamine) can slow down the progression of peripheral neuropathy. In patients with symptomatic neuropathy, gabapentin can be useful to decrease the symptoms (ie, pain, numbness).

Identification of diminished bone density is imperative in the pre-LT period, because during the post-LT period, osteopenia and osteoporosis often worsen, especially due to the use of steroids. Bisphosphonates, taken together with supplements of calcium and vitamin D, are safe and effective for increasing bone mass in patients with severe osteoporosis after LT.10

Several studies have suggested that the risk of de novo malignancy is increased 1.5- to 2-fold in LT recipients for ALD compared with patients transplanted for other indications and that these cancers are associated with a worse prognosis.8,11-13 Patients with ALD are at particularly increased risk of upper gastrointestinal, oropharyngeal-laryngeal and lung cancers. This elevated risk suggests that besides chronic immunosuppression, the oncogenic factors in these patients are likely to include alcohol metabolites, carcinogens from cigarette smoking or obesity, as well as intrinsic carcinogenic properties of CNIs. Recent studies have shown that applying a strict surveillance protocol to all LT recipients is associated with improved detection rates of cancer and patient survival.14,15 More data are needed though to define the optimal surveillance protocol after LT with individualized emphasis laid on patients' particular risk profiles.13-15 Interestingly, the increased incidence of cardiovascular deaths and of new-onset cancers of the aerodigestive tract in patients receiving LT for ALD strongly hints to a causal linkage with cigarette smoking.15 Smoking is prevalent in ALD patients undergoing evaluation for LT, and most ALD recipients who were smokers before transplantation quickly reestablish smoking at addictive levels after LT.16 If the link between cigarette smoking and death from either cancer or cardiovascular disease is correct, it points the way to improving posttransplant health through promotion of smoking cessation in alcoholic liver transplant recipients.15

The incidence of cardiovascular events is higher in patients transplanted for ALD compared with patients transplanted for other causes of liver disease (8% vs 5.3%).17-19 Similarly, the incidence of chronic kidney disease, diabetes mellitus, hypertension, and other components of the metabolic syndrome may be higher after transplantation for ALD than other indications, yet large studies are warranted to confirm this association.17-19

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Immunosuppression in ALD

Some studies suggest that patients transplanted for ALD have a reduced incidence of acute and chronic rejections compared with patients with nonalcoholic liver disease.20 In addition, among patients transplanted for ALD, the main causes of death are malignancies, infections, and cardiovascular events, extrahepatic complications largely due to environmental factors—tobacco, obesity, diabetes mellitus, and alcohol relapse—as well as chronic immunosuppression. As a result, there is a current trend to tailor immunosuppression in patients with ALD by minimizing the exposure to CNIs while promoting the use of mammalian target of rapamycin inhibitors. The rationale for this change in practice is that CNIs promote adverse cardiovascular events whereas mammalian target of rapamycin inhibitors may decrease tumor growth and angiogenesis. Although some recent retrospective studies support this strategy in patients with ALD,21 well-designed studies are needed to assess the optimal immunosuppressive regimes in LT recipients who have had ALD.

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Alcohol Use and Outcomes After LT

Alcohol consumption after LT covers a spectrum from occasional consumption (“slips”) to regular and harmful drinking (“relapses”). The rate of alcohol consumption after LT is highly variable with a percentage ranging from 10% to 95%, probably due to the different way to define and classify alcohol consumption.22 Furthermore, the incidence of alcohol use after LT is difficult to assess with accuracy, especially when self-reporting is used as the means of identification. In 16 case series involving a total of 1989 patients, the median rate of “any use” was 22.9% (range, 16-52%). The equivalent figure for heavy or harmful drinking in the 5 studies that specifically addressed this was 11.9% (range, 6.5-21%). A meta-analysis of 50 LT studies calculated standardized rates of 2.5 of “any,” and 5.6 cases of “heavy,” alcohol consumption per 100 patients per year posttransplant.22 The cumulative incidence rate of any alcohol use and/or relapse increases with duration posttransplant.23-25 This appears to be particularly the case for nonharmful consumption.

Although many risk factors for alcohol use after LT have been described, the duration of sobriety before LT has been the most consistent finding in the series reviewed. The meta-analysis of 50 series identified 3 significant risk factors for relapse, abstinence from alcohol for less than 6 months before liver transplantation, poorer social support, and a family history of alcoholism. However, the correlation coefficients were weak for all 3 factors with “r” values ranging from 0.17 to 0.21. Psychological or psychiatric comorbidities, particularly depression and personality disorders, were associated with an increased risk of relapse.22,23,26 Interestingly, there is evidence that the risk of relapse increases with the number of individual risk factors present.22 The consequences of alcohol use post-LT may not be apparent for some years. However, by 10 years, a clear survival detriment is evident in consumers of alcohol, with 2 studies reporting survival rates of 21.9% and 45.1% in alcohol consumer patients, as compared with 73.8% and 85.5% in nonalcohol consumers, respectively.26,27 However, whilst death as a consequence of recurrence of ALD was reported, it was not the main cause of inferior survival rates which remained cardiovascular disease and malignancy.

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Pre-LT Sobriety and Monitoring

As the posttransplant health and wellbeing of individuals transplanted for ALD in part depends on their continued abstinence, the ability to use pre-LT factors to prognosticate about post-LT alcohol use is of significant clinical importance.2,5 However, the current emphasis on a specific period of pre-LT abstinence, specifically 6 months, to determine future abstinence does not accommodate current understanding of AUDs nor address the therapeutic needs (eg, development of insight into the addiction, manage internalized shame associated with addiction, and develop relapse prevention skills such as identifying triggers and managing cravings) required to achieve successful abstinence for individuals with such AUDs. All patients undergoing evaluation for LT should be screened for AUD (especially those with hepatitis C) because any individual can have an AUD that was not the primary reason for LT referral and was not previously identified.28 Because the role of the pre-LT evaluation is to identify those best suited for transplant, the initial recommendation may be that the individual requires addiction treatment before a final determination is made.

Short periods of abstinence consistently predict future alcohol use rather than abstinence stability. Although pre-LT abstinence of 6 months or less is significantly associated with post-LT alcohol use,28 studies in both ALD LT populations and the general population of AUD individuals show that risk for relapse progressively decreases the longer the individual is sober, rather than being defined by a specific threshold of time.29 Thus, time-based sobriety rules, specifically those based on brief periods, are not consistent with the known course of AUDs or predictions of future abstinence.28,29 Additionally, although longer periods of abstinence indicate more stability, sustained abstinence is measured in years with 5 years indicating future alcohol use is unlikely.5 Therefore, although every month sober confers less risk to drinking, an individual with 6 months of abstinence will only have an incremental reduction in risk compared with those with 4 or 5 months of abstinence. Other risk factors, such as a family history of an AUD, lack of insight or desire to abstain, and weak social support, are also associated with increased risk to drinking after LT.22 Thus, the consideration of risk must encompass a variety of positive and negative factors best interpreted by a clinical professional versed in addictions and transplantation.

Once listed, candidates with ALD or an AUD should be monitored for alcohol use. Ongoing monitoring is necessary because AUDs commonly have a relapsing course and even for waitlisted ALD candidates, alcohol use rates of 15% to 25% have been reported.2,5 Monitoring through clinical interviewing is a useful and necessary method but is likely insufficient. The use of multiple methods will provide the greatest yield. Whether a transplant program would consider a strategy where monitoring is done through a clinician who is not part of the transplant team and alcohol use could be addressed therapeutically without disclosure to the team unless it compromises the patient's health or wellbeing is debatable.

Biochemical tests for alcohol use can supplement self-report data but have limitations as to the specificity, sensitivity, and detection based on the quantity of use and the time since last use which affects their interpretation for abstinence. Blood, urine, or breathalyzer alcohol levels are the most clinically available, inexpensive, and widely used methods. Because of its fast elimination, tools measuring alcohol will only detect recent use. Urine has a longer window of detection than blood (up to days vs hours) and is the preferred sample type. Hair toxicology analyses provides a longer window of ascertainment (90 days) and can identify alcohol and other drug use but labor intensity, lack of availability, and costs may make this prohibitive. Based on the detection window for hair analyses, 2 negative tests would support 6 months of continuous abstinence. Carbohydrate deficient transferrin is an abnormal form of a liver protein that is created from sustained heavy alcohol use (6 standard drinks for 2 weeks or more) and can remain elevated for 2 weeks even after abstinence. However, carbohydrate-deficient transferrin can be elevated (falsely suggesting alcohol use) in abstinent patients with advanced liver disease. It may be useful after liver transplant. The frequency of sampling and whether actual alcohol use will be detected depends on the specific marker and the quantity and duration of alcohol use. Although frequent random testing might be optimal, it may not be clinically practical. Random testing though can increase the yield of detecting alcohol use.

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Pre-LT AUD Treatment

It is important to recognize that establishing and maintaining a period of abstinence does not constitute treatment for an AUD nor is AUD treatment a time-limited phenomenon. Alcohol use disorders commonly have a relapsing-remitting course. Establishing abstinence is only the starting point. The clinical focus should be on treatment interventions which develop insight into the drinking problem and alcohol relapse prevention skills to promote long-term abstinence. Patients with ALD or AUD should be evaluated by mental health clinicians, optimally with addiction experience, to establish the correct psychiatric diagnosis of an AUD and develop an adequate treatment plan if indicated.30 Recent evidence suggests that the management of AUD patients by a team working in an alcohol addiction unit within the liver transplant center reduces alcohol relapse and mortality after LT.2,5,30 To allow LT listing to proceed as quickly as possible in the face of medical urgency, a balance needs to be established between the competing treatment needs of the patient's comorbid AUD and end-stage ALT.2,5,31

The most effective treatment for AUD is the combination of psychosocial interventions and pharmacological therapy.28,32 Psychosocial interventions include: Motivational Enhancement Therapy, Cognitive-Behavioral Therapy, attendance at 12-step support groups such as Alcoholics Anonymous (AA) and brief behavioral compliance enhancement treatment.28 The AA groups are composed of individuals with the shared goal to stop drinking. Alcoholics Anonymous represents the best known coadjuvant strategy and is not provided by health care, because its philosophy is based on self-help intervention. The method used in groups of AA is the Twelve-Step Facilitation therapy, an intervention used to achieve and maintain alcohol abstinence by encouraging motivation to stop drinking. However, at present, there is no standardized supportive approach in the management of AUD patients before and after LT, and available data are few and inconclusive.28 Importantly, a recent study showed a reduction of posttransplantation alcohol relapse in patients receiving treatment both before and after transplantation with respect to patients who received no treatment or treatment only before transplantation.33

Specific drugs combined with counselling are able to reduce alcohol consumption and prevent recidivism in patients with AUD without ALD.28 Disulfiram's adverse effects may reinforce the individual's desire to stop drinking by providing a psychological disincentive. However, because these adverse effects could be potentially dangerous and because of possible hepatotoxicity, it should be avoided in patients with liver disease. Naltrexone, approved in 1994 for the treatment of AUD, is an opioid antagonist and it is effective at reducing alcohol craving and intake.34 However, a randomized clinical trial to evaluate the effect of Naltrexone after LT failed to recruit patients mostly due to concerns of potential hepatotoxicity of the drug. Acamprosate, a modulator of the glutamatergic receptor system, has confirmed its efficacy in the treatment of AUD in a meta-analysis. However, no trials with repeated administrations of acamprosate in alcohol-dependent patients with cirrhosis have been conducted. To date, baclofen represents the only anticraving medication formally tested in a randomized clinical trial in patients with AUD affected by liver cirrhosis.35 However, baclofen is not yet Food and Drug Administration approved in the United States for this indication. The study showed that the oral administration of baclofen was safe and significantly more effective than placebo in inducing and maintaining alcohol abstinence and in relapse prevention. Prospective studies will be needed to evaluate the potential use of baclofen before and after LT to prevent alcohol recidivism.

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Quality of Life After LT in Patients Transplanted for

Liver transplantation is associated with an improvement in overall quality of life (QOL). This improvement is however lower than expected, and although it is significant early after LT, it seems to decrease after the first year posttransplant.36 In patients transplanted for ALD, no differences are reported in the ability to return to society with active and productive lives compared with non–alcohol-related liver transplant recipients.36,37 A single-center study of ALD LT recipients showed symptoms of depression in the first posttransplant year were the strongest predictor of poorer survival conferring 2 times higher risk for death even controlling for other medical comorbidities.38 In addition, patients with ALD seem to have a significantly lower rate of employment—a factor associated with QOL—than patients with other etiologies of liver disease.39 Sexual functioning after transplantation has become a very important parameter in evaluating QOL in organ transplant recipients.40 Overall, a significant improvement of sexual function after transplantation has been shown in most studies, the improvement being similar in alcohol-related versus non–alcohol-related LT recipients.

Alcohol use after LT may result in poorer outcomes but not necessarily with worse adherence assessed as compliance with medications, incidence of rejection, or adherence to check-ups.41

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Alcoholic Hepatitis and LT

Although, at present, LT is not usually considered a therapeutic option for patients with alcoholic hepatitis (AH), experts note that the potential role of LT in managing patients with severe AH remains an undecided issue.31 Severe AH is associated with significant inpatient mortality that can reach 50% to 75% in the most severe forms.31 The modified Maddrey Discriminant Function, the model for end-stage liver disease score, the Glasgow Alcoholic Hepatitis, and ABIC (Age, Bilirubin, INR, Creatinine) are scoring systems available to assess severity and prognosis of AH. The purpose of these scoring systems is 2-fold: first to enable the managing physician to estimate the likelihood of short-term survival, and second to determine whether patients with the severe forms of AH should be treated with corticosteroids or pentoxyfilline. The so-called Lille model enables clinicians to identify early those patients unlikely to respond to medical management. Using this approach, it is possible to identify a cohort of AH patients in whom strict application of the 6-month abstinence rule likely excludes from the possibility of transplantation, because 70% to 80% of them will die before the end of the required abstinent period. In such patients, alternative therapies are ineffective.

Clinicians fear that liberalizing the guidelines for selection of alcoholic patients for LT may decrease public willingness to donate, circumstance that has not been proven so far.42 It should be emphasized that such a concern was not raised in the setting of emergent LT proposed to patients with fulminant hepatic failure due to voluntary acetaminophen poisoning, or to active drug abusers with acute hepatitis B virus. It is important to make the public aware that most moral philosophers and medical ethicists feel that patients with so-called self-inflicted diseases should have the same access to medical resources as patients with less controversial indications for care.

Recently, a French-Belgium multicenter pilot study has shown that LT may be an option for carefully selected patients with AH.43 Seven LT centers performed early LT in patients with severe AH failing to respond to medical therapy undergoing their first episode of liver disease.43 Subjects were selected using the following criteria: a first episode of AH only, absolute consensus among paramedical and medical staff, no comorbidities, social integration and supportive family members. Failure of medical therapy was identified using Lille score of 0.45 or higher or worsening of liver function by day 7. Based on these criteria, only a small minority of potential candidates were selected for LT. This case-controlled study showed an unequivocal improvement of survival in patients who received early transplantation. These data have been confirmed in a similar, albeit single-center, prospective evaluation of rescue LT in severe AH carried out in New York.44 In summary, these pilot studies, along with retrospective analysis of LT in patients found to have AH,45,46 support future evaluation of LT in a carefully selected subgroup of patients with severe AH failing to respond to medical therapy, despite the fact that early LT in such patients contravenes the 6-month abstinence rule. Future studies should clarify the methods of selection for LT, maintenance of addiction health both before and after LT, in addition to patient and graft survivals.

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ACKNOWLEDGMENT

The authors would like to acknowledge John Klinck for his insight with the production of this manuscript.

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