Abstract Alcohol relapse after liver transplantation (LT) for alcoholic liver disease (ALD) is a common event that has been extensively studied. In contrast, alcohol consumption has usually been neglected in patients transplanted for other liver diseases. First off, patients can be mislabeled as ‘non-ALD’ when they suffer from another chronic liver disease. Then, alcohol consumption is not systematically tracked after LT in recipients having a primary indication other than ALD, although there are increasing data incriminating alcohol as responsible for graft damage and impaired survival. This review discusses the potential consequences of alcohol after liver transplantation, focusing on patients transplanted for non-alcoholic liver disease, as well as the legitimate role of an addiction specialist, before and after LT. Short Summary Alcohol relapse after liver transplantation (LT) for alcoholic liver disease (ALD) is a common event that has been extensively studied. In contrast, alcohol consumption has usually been neglected in patients transplanted for other liver diseases. There are increasing data showing that alcohol consumption and its consequences should be tracked in every transplant candidate and recipient. INTRODUCTION Alcohol relapse after liver transplantation (LT) for alcoholic liver disease (ALD) impacts the graft and patient survival. This issue has been increasingly recognized by the transplant community (Cuadrado et al., 2005; Pfitzmann et al., 2007; DiMartini et al., 2010; Rice et al., 2013). Nevertheless, little attention has been given to the consequences of alcohol consumption after LT for non-alcoholic liver disease. First of all, there is a lack of recognition of addictive behavior prior and after transplantation in patients followed for liver diseases other than ALD such as chronic viral hepatitis. Then, only a few studies have focused on the burden of alcohol consumption after LT outside the frame of patients suffering from ALD prior to transplantation. WHAT IS THE DEFINITION OF NON-ALCOHOLIC LIVER DISEASE? Alcoholic liver disease encompasses a wide array of histological abnormalities due to alcohol consumption, ranging from simple steatosis, alcoholic hepatitis or steatohepatitis, progressive fibrosis, and ultimately cirrhosis and/or hepatocellular carcinoma (HCC) (O’Shea et al., 2010). However, the definition of non-alcoholic liver disease, particularly in the field of liver transplantation, is imprecise. Indeed, it is not uncommon to diagnose a decompensated cirrhosis complicated by hepatocellular carcinoma in a patient having a history of harmful drinking and another liver disease (such as chronic viral hepatitis). If this patient were to need liver transplantation, what should be listed as the indication for LT? Similarly, a transplant candidate with a cholestatic liver disease having a minor, controlled and occasional alcohol consumption can be considered, depending on the studies and the transplant teams, as an abstainer or a drinker. The designation of a primary and secondary indications can be helpful, but often is an impossible task, once the harm has been done, to rank the causality of each factor in the development of the liver disease. Thus, non-ALD can be defined, in the setting of LT, as acute or chronic liver failure without any past or present history of alcohol utilization sufficient to cause liver injury. This definition implies that every transplant candidate should be evaluated by an addiction specialist, in order to detect lifetime alcohol consumption leading to liver injury. IS ALCOHOL CONSUMPTION ROUTINELY SCREENED BEFORE AND AFTER TRANSPLANTATION IN NON-ALD PATIENTS? Guidelines from the professional societies (namely AASLD (Murray et al., 2005) and EASL) indicate that substance abuse should be screened in every transplant candidate, although they remain vague regarding to the preferred modalities of the evaluation. For example, the EASL 2016 guidelines on liver transplantation say that ‘it is important to assess social network, psychiatric illness and addiction in order to evaluate adherence of the recipient’ (European Association for the Study of the Liver, 2016). In a study published in 2008 (Day et al., 2008), the authors evaluated lifetime alcohol consumption of 208 consecutive patients referred for LT to the Birmingham (United Kingdom) transplant program. The assessment was conducted by a researcher completely independent of the transplant team in order to foster candor. Interestingly, they found out that the referring physician had not raised the possibility of alcohol consumption as a causative factor in 10 (12.5%) of the 80 patients meeting DSM-IV criteria for alcohol abuse or dependence (Day et al., 2008). Since 2000, we adopted a protocol in our center the ensures that every transplant candidate, regardless of the primary indication, undergoes an interview by an independent substance abuse specialist (Faure et al., 2012). Because of this screening protocol, we have ascertained that up to 72% of the liver transplant candidates between 2008 and 2014 have experienced excessive alcohol use at some time in their life. Only 40% of them were labeled as ‘alcoholic liver disease’ as the primary indication (data unpublished). Following LT, a multitude of methods have been tested to identify relapsing patients. The most relevant seems to be a multi-method approach, including clinical, histological, biochemical data as well as urinary and blood alcohol levels (DiMartini, 2013). There is also great interest in biomarkers to detect recent drinking (Allen et al., 2013; Cabezas et al., 2016). WHAT ARE THE RATES OF ALCOHOL CONSUMPTION AFTER LT? Since there is no consensus about the definition of alcohol relapse after LT for ALD, figures vary considerably. When any amount of alcohol consumption is taken into account, relapse rates can climb up to almost half of patients (DiMartini et al., 2010), while major and harmful drinking can be detected in 10–25% of liver recipients for ALD (Cuadrado et al., 2005; Faure et al., 2012; Dumortier et al., 2015). There are only scarce data available about alcohol consumption rates after LT in non-ALD patients. The first report arose from a LT follow-up clinic in a non-transplantation center in Canada, which followed 58 liver recipients, transplanted between 1987 and 1997, for a mean period of 41 months. Alcohol consumption was considered significant above 20–30 g per day and was detected in one out of 48 patients (2%) transplanted for non-alcoholic liver disease, whereas 50% of the 10 ALD patients relapsed (Abosh et al., 2000). In a single-center study comprising 441 patients transplanted between 1991 and 2007 (mean follow-up duration of 81 months) published in 2012, Faure et al. reported that 24.3% of patients transplanted with non-ALD as a primary indication (mostly HCC and viral hepatitis C) consumed alcohol, and the consumption pattern was excessive (i.e. >20 g or >30 g per day for women and men, respectively) for 3.1% of this population. Of interest, when history of excessive alcohol consumption before LT was found in these patients, the proportion exhibiting a relapse (ie drinking in a harmful or addictive manner) reached 9.3% of the cohort (Faure et al., 2012). Recently, a multicentric US-based study (Russ et al., 2016) showed similar results on alcohol consumption, with 9% of recipients for non-ALD displaying heavy-drinking patterns after LT. WHAT ARE THE CONSEQUENCES OF ALCOHOL USE AFTER LIVER TRANSPLANTATION? Histopathological studies have demonstrated that steatosis, steatohepatitis, and advanced fibrosis were associated with alcohol relapse (Burra et al., 2001; Rice et al., 2013). Similar to the situation described with the hepatitis C virus recurrence (Neumann et al., 2004), the liver graft is more prone to alcohol-mediated damage and fibrosis can progress rapidly. Thus, in a French multicentric report that analyzed the outcomes of 712 recipients for ALD, recurrent alcoholic cirrhosis occurred in 32% of the severe relapsers in a median time of 4 years (range 1.2–11.5) between alcoholic relapse and the diagnosis of cirrhosis (Dumortier et al., 2015). The damage to the graft appeared to be independent of the initial indication for LT, and by extension, the same is also likely to be true among patients transplanted for non-ALD indications. Besides histological changes, most studies have observed impaired graft and patient survival after alcoholic relapse in ALD recipients (Conjeevaram et al., 1999; Cuadrado et al., 2005; Rice et al., 2013; Dumortier et al., 2015). Only one study has considered survival in patients in whom the primary indication was non-ALD (Faure et al., 2012). These authors observed an impaired 10-year survival rate in recipients who had reported excessive alcoholic consumption after LT when compared with the abstainers or moderate alcohol users (49% vs. 75%). Some studies have suggested that the survival rates of patients transplanted for mixed alcoholic and HCV cirrhosis are worse when compared to ALD alone (Lucey et al., 2009; Burra et al., 2010) although there is no consensus about a negative interaction between alcohol relapse and HCV recurrence (Goldar-Najafi et al., 2002; Aguilera et al., 2009; Singal et al., 2013). Moreover, the arrival of highly effective direct antiviral agents targeted against HCV will probably overcome this issue. To our knowledge, there are no data concerning the effects of alcohol consumption after LT and HCC or auto-immune diseases recurrence. WHAT SHOULD WE ADVISE TO TRANSPLANTED PATIENTS? IS THERE A ‘SAFETY LIMIT’ OF ALCOHOL CONSUMPTION AFTER LT? LT has been described as a life-changing experience, especially for patients transplanted for end-stage liver disease, and many patients return to a normal life, thus regaining old habits such as alcohol consumption. When the primary indication of LT is ALD, the transplant community is widely aware of the usefulness of the prevention and early detection of alcohol relapse. Early education about abstinence following LT in the pre-transplant and early post-transplant periods is crucial. Every outpatient visit has to be the occasion to discuss about alcohol consumption. We are convinced that every liver transplant candidate and recipient ought to be tracked by a dedicated addiction specialist to enable early recognition of a lifetime addictive disorder in. This is the first step that will help avoid patients mistakenly receiving the label ‘non-ALD’. These clandestine ALD patients should then be considered at risk for alcoholic relapse (and its consequences). There are obviously no data regarding a ‘safety limit’ of alcohol consumption after LT. Since the consequences of heavy-drinking can be rapidly disastrous, we believe that all transplant patients with a history of previous lifetime alcohol problems, whether this is a primary or secondary diagnosis, should be counseled to abstain from alcohol consumption in the future. CONCLUSIONS This review draws attention to the widely neglected issue of alcohol consumption after LT for ‘non-ALD’ indications. Since the consequences of an under-diagnosis of this condition can be devastating, the transplant team should systematically screen for alcohol consumption in every transplant candidate and recipient. Moreover, information about potential harmful consumption should be addressed, preferably by an addiction specialist. CONFLICT OF INTEREST STATEMENT Georges-Philippe Pageaux: board membership Astellas and Novartis. REFERENCES Abosh D, Rosser B, Kaita K, et al. . 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Alcohol and Alcoholism – Oxford University Press
Published: Mar 1, 2018
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