Abstract Aims Liver transplantation (LT) for alcoholic liver disease (ALD) remains controversial yet following transplantation outcomes for patients with this disease are generally similar to patients transplanted for other types of liver diseases. Methods In this review, we cover critical literature of ALD LT including established and recent findings of medical and psychosocial outcomes for ALD patients and compare their outcomes to other liver transplant recipients where evidence exists. Results Overall medical and psychosocial outcomes for ALD LT recipients compare favorably to patients transplanted for other types of liver diseases. While alcohol relapse occurs following transplant, the rates of return to heavy alcohol use, especially at amounts that are health harmful, are low at ~20%—substantially under rates of relapse for non-transplant patients with alcohol use disorders. However, ALD LT recipients are more likely to be smokers and experience causes of death different than other LT recipients with cardiovascular and malignancies being more common. Depression is one of the more common mental health disorders experienced by ALD LT recipients and is especially important to consider due to increasing evidence of its negative impact on post-transplant survival. In general, ALD LT recipients’ quality of life is as good as recipients transplanted for other types of liver disease. Post-LT re-employment and social reintegration are also comparable. Conclusions Early identification may improve outcomes with the first post-transplant year being an important time for close monitoring. Additionally, efforts to identify and treat tobacco use and depression may also improve overall outcomes in this specific population. Short Summary In this review, we cover medical and psychosocial outcomes for ALD patients and compare their outcomes to other liver transplant recipients. While alcohol relapse occurs following transplant, the rates of return to heavy alcohol use, especially at amounts that are health harmful, are low at ~20%. INTRODUCTION Liver transplantation (LT) for alcoholic liver disease (ALD) remains controversial despite several decades of clinical experience transplanting ALD patients with surgical outcomes generally comparable to other types of liver diseases. In this paper, we will review the literature on specific post-LT ALD outcomes, including a range of both medical and psychosocial outcomes. While medical events (e.g. patient and graft survival) are key results, and most the literature focuses on these findings, awareness of psychosocial outcomes is also critical to understanding the overall outcomes for ALD LT patients. It is essential to consider whether ALD LT recipients recover adequate physical functioning, have good mental health and quality of life, and are able to resume normal pre-LT activities and employment. Data on these types of outcomes are limited, especially in comparison to other LT recipients. We will report prospective findings to the extent they are available, although the bulk of the studies are either cross-sectional or retrospective. We will also report on meta-analytic reviews relevant to ALD recipient outcomes. Some studies we review characterized LT recipients as those with alcohol use disorders rather than ALD. These studies were more likely among those that considered behavioral health outcomes. Finally we include a brief overview of relapse to alcohol use after LT as an in-depth discussion of this topic can be found in other recent reviews (Iruzubieta et al., 2013; Lucey, 2014; Dom et al., 2015). MEDICAL AND SURGICAL OUTCOMES Post-LT survival Transplantation improves overall survival for patients with ALD as with other forms of liver disease (Poynard et al., 1999). LT for ALD has generally resulted in post-transplant survival comparable to rates for recipients with other etiologies of chronic liver disease (O’Grady, 2006; Lucey, 2011). Table 1 summarizes of some of these studies. For example, in one retrospective study of 1026 LT recipients, 398 of whom had ALD, recipients with ALD or autoimmune hepatitis were found to have the best short- and long-term post-transplant survival (Legaz et al., 2016). In another study of 3600 LT recipients in the United Kingdom National Transplant database, recipients with ALD had equivalent survival to recipients with hepatitis C virus (HCV) but shorter post-LT survival compared to recipients with other liver disease diagnoses (e.g. autoimmune and cryptogenic cirrhosis) (Barber et al., 2007). However, beyond age, sex and primary diagnosis survival was not adjusted for other medical confounders (Barber et al., 2007). A study using the European Liver Transplant Registry data on 24,711 LT recipients found ALD recipients have significantly longer survival compared with recipients who had cryptogenic or viral cirrhosis, after controlling for recipient and donor graft variables (Burra et al., 2010). United States data from the Scientific Registry of Transplant Recipients on 38,899 adults placed on the wait list found no difference in wait list or post-LT survival by ALD vs. non-ALD, although HCV with ALD conferred increased risk of post-transplant mortality (Lucey et al., 2009). However, it is unclear whether patients with both ALD and HCV are at higher risk than patients with HCV alone given that another study found that patients with HCV alone had an increased mortality risk compared to patients with ALD or ALD with HCV (Aguilera et al., 2009). One study of ALD recipients who received a living liver donation showed an excellent 10-year survival of 84% (Ahn et al., 2014). Table 1. Post-transplant survival by etiology of liver disease Study Etiology of Liver Disease N Pa 1-year survival 3-year survival 5-year survival 10-year survival Median survival Burra et al. (2010) ALD 9880 0.04 84 78 73 58 ALD+viral 1478 85 77 69 55 Viral 10,943 82 74 70 60 Cryptogenic 2410 78 73 69 61 Dumortier et al. (2015) ALD 305 NS 93 89 84 73 Non-ALD 289 89 84 81 75 Aguilera et al. (2009) ALD 107 90 76 67b HCV 170 <0.01 72 49 43 ALD + HCV 60 NS 86 73 63 Barber et al. (2007) PBC 704 35.8 (28.1–45.6) Autoimmune cirrhosis 148 24.5 (15.8–38.2) HBV 147 24.2 (15.0–39.2) PSC 284 26.0 (18.4–36.8) Cryptogenic cirrhosis 207 33.9 (21.9–52.7) ALD 533 15.0 (12.2–18.6) HCV 339 12.0 (9.2–15.7) Cancer 107 5.3 (3.9–7.1) Other 233 16.5 (12.0–22.9) Pageaux et al. (1999) ALD 53 NS 75 67 62 Non-ALD 48 83 66 61 Legaz et al. (2016) ALD 305 83 77 74 71 ALD + viral 93 74 67 66 65 Viral cirrhosis 247 c 68 (<0.01) 60 (NS) 58 (<0.01) 55 (<0.01) Cancer 104 75 (NS) 62 (0.01) 53 (<0.01) 50 (<0.01) Autoimmune cirrhosis 61 90 (NS) 87 (0.05) 85 (NS) 80 (NS) Fulminant hepatitis 39 69 (0.02) 64 (0.04) 64 (NS) 64 (NS) Other 177 63 (<0.01) 59 (<0.01) 55 (<0.01) 53 (<0.01) Bjornsson et al. (2005) ALD 103 NS 81 69 Non-ALD 94 87 83 Adam et al. (2003) ALD 6950 83 72 59 Viral 9486 83 72 66 Autoimmune cirrhosis 991 81 72 65 Other 2292 74 69 58 Pfitzmann et al. (2007) ALD 300 NS 96 88 76 Non-ALD 1164 97 80 72 Study Etiology of Liver Disease N Pa 1-year survival 3-year survival 5-year survival 10-year survival Median survival Burra et al. (2010) ALD 9880 0.04 84 78 73 58 ALD+viral 1478 85 77 69 55 Viral 10,943 82 74 70 60 Cryptogenic 2410 78 73 69 61 Dumortier et al. (2015) ALD 305 NS 93 89 84 73 Non-ALD 289 89 84 81 75 Aguilera et al. (2009) ALD 107 90 76 67b HCV 170 <0.01 72 49 43 ALD + HCV 60 NS 86 73 63 Barber et al. (2007) PBC 704 35.8 (28.1–45.6) Autoimmune cirrhosis 148 24.5 (15.8–38.2) HBV 147 24.2 (15.0–39.2) PSC 284 26.0 (18.4–36.8) Cryptogenic cirrhosis 207 33.9 (21.9–52.7) ALD 533 15.0 (12.2–18.6) HCV 339 12.0 (9.2–15.7) Cancer 107 5.3 (3.9–7.1) Other 233 16.5 (12.0–22.9) Pageaux et al. (1999) ALD 53 NS 75 67 62 Non-ALD 48 83 66 61 Legaz et al. (2016) ALD 305 83 77 74 71 ALD + viral 93 74 67 66 65 Viral cirrhosis 247 c 68 (<0.01) 60 (NS) 58 (<0.01) 55 (<0.01) Cancer 104 75 (NS) 62 (0.01) 53 (<0.01) 50 (<0.01) Autoimmune cirrhosis 61 90 (NS) 87 (0.05) 85 (NS) 80 (NS) Fulminant hepatitis 39 69 (0.02) 64 (0.04) 64 (NS) 64 (NS) Other 177 63 (<0.01) 59 (<0.01) 55 (<0.01) 53 (<0.01) Bjornsson et al. (2005) ALD 103 NS 81 69 Non-ALD 94 87 83 Adam et al. (2003) ALD 6950 83 72 59 Viral 9486 83 72 66 Autoimmune cirrhosis 991 81 72 65 Other 2292 74 69 58 Pfitzmann et al. (2007) ALD 300 NS 96 88 76 Non-ALD 1164 97 80 72 ALD, alcoholic liver disease; PBC, primary biliary cirrhosis; HCV, hepatitis C virus; viral, viral hepatitis; HBV, hepatitis B virus; PSC, primary sclerosing cholangitis; NS, non-significant. aSurvival difference between groups where available in manuscripts. P values are for global log-rank testing unless otherwise specified. b7-year survival, P values are pairwise log-rank tests for each etiology vs. ALD. cP values in parentheses for each time point represent the diagnosis vs. ALD (referent), based on log-rank test wherein HCV and viral hepatitis with ALD were grouped together. Causes of death A study using the European Liver Transplant Registry found that patients with ALD were more likely to die of de novo malignancy and cardiovascular-related causes than those without ALD (Burra et al., 2010) although the risks of cardiovascular and malignancy-related death are also elevated in recipients with non-alcoholic steatohepatitis (NASH) cirrhosis, an increasingly frequent indication for transplantation (Siddiqui and Charlton, 2016). In fact, cardiovascular deaths have been found to be increased among those with both ALD and NASH (Watt et al., 2010). The role that return to alcohol use after LT has played in mortality has been assessed in several studies. Among 54 subjects with ALD 5-year survival rates were similar regardless of relapse but the 10-year survival rate for patients with vs. without alcohol relapse was 45.1% vs. 85.5% (Cuadrado et al., 2005a). Among 300 recipients with ALD, the subset that returned to ‘abusive’ drinking, (defined as those with hospitalization related to alcohol and ‘heavy drinking’ based on patient and physician reports and labs) had decreased survival related to ALD, but among those without return to ‘abusive’ drinking the predominant causes of death included malignancy, infection and cardiovascular complications (Pfitzmann et al., 2007). Another study of 68 ALD recipients found 8% (n = 6) returned to heavy alcohol use post-LT (defined as more than one drink a day) and 3 of these 6 patients died of acute alcoholic hepatitis within the first 3.5 years post-LT (Conjeevaram et al., 1999). In one study of 126 ALD living donor recipients three died of complications related to alcohol abuse although the authors felt the overall rate of relapse was low related to recipients feeling increased responsibility to their donors and potential feelings of guilt and betrayal that may have inhibited relapse (Ahn et al., 2014). Overall, relapse appears to contribute less to mortality than malignancy, and return to occasional alcohol use has not been associated with increased mortality (Dumortier et al., 2007). Acute alcoholic hepatitis and post-LT survival Acute alcoholic hepatitis (AAH) is a rapidly decompensating form of ALD. Mortality from AAH nonresponsive to medical therapy is high with only 30% survival at 6 months. AAH typically occurs in the context of active or recent drinking so many patients cannot achieve a period of abstinence required by most LT programs. Thus LT for AAH is uncommon and remains controversial (Dureja and Lucey, 2010). However, Mathurin et al. in a recent study compared the survival benefit conferred by LT for AAH to those who received medical therapy only. Twenty-six AAH patients, representing fewer than 2% of their AAH patients, were selected for LT after several rounds of deliberation by members of the multidisciplinary transplant team. These cases were compared to controls matched for age, sex and prognostic criteria based on biochemical data and response to therapy. They found improved 6-month survival with LT compared to medical therapy (77% vs. 23%) (P < 0.01) (Mathurin et al., 2011). These results are not surprising given the medical therapy group had overall very poor prognosis. From the United Network for Organ Sharing database (from 2004 to 2010), 55 AAH LT recipients were identified (mostly diagnosed from the explanted liver) and compared to patients with alcoholic cirrhosis (n = 165) matched on age, Model of End-stage Liver Disease and donor risk. Findings indicated that the early survival advantage of LT in AAH could be maintained with similar 5-year graft (75% vs. 73%, P = 0.97) and patient (80% vs. 78%, P = 0.90) survival for AAH and ALD, respectively (Singal et al., 2012). The authors also found that the causes of graft failure and mortality were similar between the groups (Singal et al., 2012). Despite the satisfactory transplant survival outcomes for AAH, the ethical and social acceptability of transplanting actively drinking patients will likely remain controversial. Nevertheless protocols for transplanting patients with AAH currently exist in a limited number of LT transplant programs. Cancer Cancer after transplantation is a leading cause of mortality. In LT cancer is generally divided into preexisting liver cancer and de novo malignancy (DNM). DNM after transplant has been studied with respect to etiology of liver disease. In a recent review, skin cancer and lymphoproliferative disorders were the most common tumors (Vallejo et al., 2005). Patients undergoing LT for primary sclerosing cholangitis (PSC) (particularly with inflammatory bowel disease) and ALD each have high rates of malignancies compared with patients undergoing LT for other indications. These populations are at particular risk for gastrointestinal and aerodigestive cancers, respectively (Mukthinuthalapati et al., 2016). In addition to classic risk factors such as older age, smoking and alcohol use, cancer risk is attributed to chronic exposure to immunosuppressive agents (Vallejo et al., 2005). Some observational studies found the incidence of DNM is greater in recipients with pre-transplant ALD than those with other forms of liver disease (Duvoux et al., 1999; Aguilera et al., 2009); however, the majority of these studies do not control for smoking, which is associated with both ALD and cancer. Smoking is essential to consider especially due to the synergistic carcinogenic effects of alcohol and tobacco use. Not surprisingly one study found pre-LT cigarette exposure to be higher in ALD LT candidates who had on average 10 more pack-years of pre-LT smoking than patients with non-alcoholic cirrhosis (Duvoux et al., 1999). Among the largest of these studies (n = 1140 LT recipients) identified 30 (2.6%) who developed DNM by a median follow-up of 69 months (Saigal et al., 2002). An increased risk of malignancy was associated with ALD (P < 0.001), although having cancer did not impact survival (Saigal et al., 2002). While this study did find increased cancer among ALD patients, it did not control for smoking or other comorbid conditions. To this point, the increased risk of DNM among those with ALD was not confirmed in a subsequent study that demonstrated that the major independent risk factors associated with post-transplant de novo solid-organ cancer included immunosuppression with tacrolimus, smoking and obesity (Carenco et al., 2015a). Similarly another large study also found smoking and tacrolimus dosing to be the strongest predictors of cancer, rather than etiology of liver disease (Carenco et al., 2015b). Similar to the findings for DNM, pre-transplant ALD has not generally been considered a risk factor for recurrent hepatocellular carcinoma after LT (Hoyos et al., 2015). Graft failure In general ALD has not proven to be a major risk factor for graft failure requiring re-transplantation (Bellamy et al., 2001; Crivellin et al., 2011; Costabeber et al., 2013). In a study of 152 LT recipients that examined biochemical markers of graft function those with ALD (28%) were not more likely to have elevated liver enzymes (aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase and total bilirubin) at 6 months post-LT (Stilley et al., 2010). Most studies that examine any alcohol use after transplant (rather than heavy use) do not find an association with graft dysfunction (Bellamy et al., 2001; Pageaux et al., 2003). However, return to heavy alcohol use/abuse after LT has been associated with graft failure, rejection and fibrosis (Conjeevaram et al., 1999; Pageaux et al., 2003; Rice et al., 2013; Dumortier et al., 2015). BEHAVIORAL AND MENTAL HEALTH ISSUES Alcohol use and risk factors One of the most highly investigated outcomes for ALD recipients is alcohol use after LT. Herein we present a brief summary of our own work in this area to illustrate some unique perspectives on alcohol use. Our group performed a meta-analysis of 50 liver transplant recipient studies published between 1983 and 2005 on relapse rates and risk factors for relapse. Alcohol relapse was examined in relation to 12 possible psychosocial risk factors, including demographics and pre-LT characteristics. Only 3 variables were significantly associated with relapse: poorer social support, family history of alcohol abuse/dependence and pre-LT abstinence of less than 6 months (Dew et al., 2008). Cumulative incidence rates of 5.6% per year for any alcohol use and 2.5% per year for heavy use were found with some studies identifying return to alcohol use many years after LT. These findings suggest that relapse rates are unlikely to level off even in the later years post-LT (Dew et al., 2008). We also conducted one of the few prospective, longitudinal studies with repeated measurement of alcohol use investigating 208 ALD LT recipients with nearly 10 years of follow-up. We found the rate of any alcohol use post-LT approached 50% at 10 years (DiMartini et al., 2010). Of those who drank 40%, or 20% of the total sample, progressed to a binge episode (6 drinks or more) within 6 months of their first drink (DiMartini et al., 2006). Nevertheless it is important to note that these relapse rates are significantly lower than what is seen following conventional treatment for alcoholism in non-transplant populations where 2-year relapse rates of 60–80% are common (Vaillant, 1997). Our detailed prospective data allowed us to further identify discrete patterns beyond basic thresholds of use. We used group-based trajectory models to identify clusters of individuals following similar patterns of consumption over time modeling alcohol use along the parameters of quantity, frequency and duration of consumption (DiMartini et al., 2010). Among the five identified trajectories of alcohol use two stood out as the most problematic; recipients characterized by early onset moderate-to-heavy alcohol use (Groups 3 and 5, see Fig. 1). These groups were characterized by having less pre-LT sobriety, a positive family history of alcoholism and a diagnosis of alcohol dependence. Moderate-to-heavy drinkers were also characterized by histories of substance use other than alcohol. On average members of these two groups began drinking within months post-LT and drank from 3.5 standard drinks per week to 3.7 drinks a day. They were also significantly more likely to experience poorer early outcomes, with more frequent steatohepatitis or evidence of acute rejection on biopsy, and higher likelihood of graft failure or death from recurrent ALD (DiMartini et al., 2010). Those most likely to drink in these early problematic patterns also reported experiencing more stress, more pain, less vitality and felt their health was worse after LT. Fig. 1. View largeDownload slide Specific alcohol use trajectories from the point of transplant. (From DiMartini A, Dew MA, Day N, et al. (2010) Trajectories of alcohol consumption following liver transplantation. Am J Transplant10:2308–12; used with permission.) Fig. 1. View largeDownload slide Specific alcohol use trajectories from the point of transplant. (From DiMartini A, Dew MA, Day N, et al. (2010) Trajectories of alcohol consumption following liver transplantation. Am J Transplant10:2308–12; used with permission.) Although current DSMV criteria evaluate alcohol use disorders along a continuum, by the original DSM-IV and ICD-10 nosology used at the time of our study, alcohol use disorders were divided into alcohol dependence, the more severe form of the disorder or alcohol abuse. Of ALD LT recipients, roughly three quarters met DSM-IV criteria for alcohol dependence prior to transplant, while most remaining patients met DSM-IV criteria for alcohol abuse (DiMartini et al., 2008). Those with a pre-LT diagnosis of alcohol dependence were 2.6 times more likely to drink post-LT than those with alcohol abuse (DiMartini et al., 2006). However, we considered whether there may be additional approaches to consider risk for drinking after transplant beyond the DSM’s broad diagnostic categories. Our novel approach was to examine whether specific phenotypes exist based on clustering of their alcohol disorders diagnostic criteria. Using cluster analyses we identified four distinct clusters of diagnostic symptoms, three clusters representing those with alcohol dependence and one cluster with alcohol abuse (DiMartini et al., 2008). A discriminant analysis compared these four clusters against a subset of nine prospective correlates. This analysis identified two dimensions along which the clusters varied: the first dimension separated respondents in cluster Group 1, (those with the most diagnostic criteria) from cluster Group 4, (those with the least diagnostic criteria), with Groups 2 and 3 in the middle, while the second dimension was between Groups 2 and 3, (those with primarily social or role-related alcohol symptoms), and separated them from both other groups. The most important factors distinguishing the most vs. less severely symptomatic groups were lower education, historically consuming more ethanol on average, having attended rehab and having a history of comorbid non-alcoholic substance abuse/dependence. Along the second dimension, respondents in social/role-related groups were most likely to be younger and have worked in blue-collar occupations. Interestingly, despite much heterogeneity between the three alcohol dependent clusters regarding their symptoms, when compared against each other, there was no predictive value for relapse between them. However, those in the alcohol abuse cluster were significantly less likely to drink than those in the clusters with a diagnosis of dependence. Thus, whereas a patient’s subcategory of alcohol dependence was unimportant for risk stratification, the diagnosis of alcohol dependence as opposed to alcohol abuse most accurately predicted relapse (DiMartini et al., 2008). Depression Depression is one of the more common mental health disorders and is especially important to consider due to increasing evidence of its negative impact on post-transplant survival (Corruble et al., 2010; DiMartini et al., 2011; Rogal et al., 2013; Dew et al., 2015). Depression is highly prevalent (up to 63%) in advanced liver disease, particularly those with ALD (Ewusi-Mensah et al., 1984), with 30–40% of LT patients affected post-LT (Miller et al., 2013; Dew et al., 2015; Fineberg et al., 2016). For LT patients in general, pre-LT depression consistently predicts post-LT depression and poorer quality of life (Miller et al., 2013; Fineberg et al., 2016). Although in chronic illness depression is associated with non-adherence, longer hospital stays and lower health status, these outcomes in ALD LT are infrequently studied with respect to depression. In a retrospective cohort analysis of liver transplant patients, depressed patients were more likely, although not significantly, to have ALD. Depressed patients required more psychiatric care post-LT. Additionally those diagnosed with depression pre-LT and treated with an antidepressant at the time of LT had a lower rate of acute cellular rejection comparatively to those untreated (Rogal et al., 2011). Another prospective study similarly assessed depressive symptoms 3 months post-transplant and evaluated survival after 5 years. An increase of one point on the Beck Depression Inventory (BDI) score was associated with a 17% increase in mortality. Interestingly, a pre-LT diagnosis of ALD was not found to contribute to poorer survival (Corruble et al., 2010). In a cohort of ALD LT recipients, DiMartini et al. examined the effect of depressive symptoms during the first year of transplantation on survival. Using cluster analyses, three trajectories of depressive symptoms were identified: consistently low depressive symptoms, increasing depressive symptoms and consistently high depressive symptoms. Even after controlling for medical factors known to be associated with poorer outcomes, those in the increasing and consistently high depression group were more than twice as likely to die. The decline in survival rates from 66% in the low depression group to 46% and 43% in the two groups with depressive symptoms demonstrates how strong a risk factor depression is for poorer survival (DiMartini et al., 2011). A prior history of depression, co-infection with HCV and limited social supports, particularly single marital status, were found to be significant risk factors for developing depressive symptoms. Notably, no association between post-LT alcohol use and depression was established. As depression has been recognized as a potentially modifiable risk factor for survival, Rogal et al. further analyzed the effect of treatment with an antidepressant on long-term survival rates for these ALD recipients. Over a median follow-up of 9.5 years, survival rates were 52% and 56%, respectively, of those adequately treated depression or patients not depressed, compared to 32% in the inadequately treated group (Rogal et al., 2013). Treating depression in the first post-LT year was associated with improved survival, while untreated depression was the factor most strongly linked to long-term mortality (2.44 times greater odds) compared to non-depressed recipients (Rogal et al., 2013). In sum, these studies suggest early depression screening post-LT and treatment of depression can improve survival for ALD LT recipients and may improve adherence to the post-LT regimen. Tobacco Use In liver transplant patients tobacco use has been correlated with graft loss, cardiovascular disease and higher rates of de novo cancer (Mangus et al., 2015). Tobacco use impedes wound healing and leads to higher rates of vascular complications and infections. Hepatic artery thrombosis is a devastating vascular complication post-LT and cessation of tobacco use 2 years prior to transplantation can significantly decrease this risk by 58% (Pungapong et al., 2002). Comorbid use of alcohol and tobacco in advanced liver disease is associated with a higher incidence of squamous cell carcinoma and heavier pack year history (Ehlers et al., 2004). In a single center study, although a diagnosis of ALD was not reported, 60% of LT patients smoked pre-LT with 5.8 times higher odds for those who drank alcohol to also be pre-LT smokers (CI 2.21–15.3, P = 0.0001) (Ehlers). Those who resumed smoking after LT were 1.79 times more likely to also drink alcohol (CI 0.75–4.27, P = 0.026) (Ehlers et al., 2004). In a meta-analysis of studies reporting on patients with pre-transplant histories of substance use disorders or diseases indicative of substance use (e.g. ALD), three studies of LT cohorts determined that the highest prevalence rate of post-LT substance use was for tobacco use, at a rate of nearly 10% per year (Dew et al., 2008). This tobacco use rate in LT recipients was notably higher than a prior rate determined for all solid-organ transplant recipients of only 3.4% per year (Dew et al., 2007). In an ALD cohort followed prospectively, nearly 60% were smoking by the first post-LT year (DiMartini et al., 2005). They resumed smoking within months after LT, typically smoked daily, and increased their cigarette consumption over time (DiMartini et al., 2005) demonstrating the highly addictive nature of cigarettes. Adherence to the post-transplant regimen Few studies have addressed the significant concern of whether the use of alcohol impacts adherence to the transplant regimen. One early study of 118 ALD LT recipients followed for a mean of 4.5 years found that although nearly 20% drank (defined as any alcohol use) by 5 years after LT, adherence to the post-LT regimen, including immunosuppression and attending appointments was not different between drinking and non-drinking groups (Berlakovich et al., 2000). Sixteen percent were defined as non-adherent to immunosuppressive medication based on being either below or above the target range for immunosuppression blood levels. Only three patients were non-adherent to clinic appointments, none of whom drank alcohol. The percentages of those with late acute rejection, used as an indicator of immunosuppression non-adherence, were similar between those who drank (7%) and those who did not (8%). The authors concluded that rates of non-adherence were overall low and alcohol use was not associated with poorer adherence (Berlakovich et al., 2000). In another study of 54 ALD LT regardless of alcohol use no recipients had an episode of acute rejection attributable to immunosuppression non-adherence and compliance with immunosuppression assessed by clinical interview and therapeutic drug monitoring reached 100% in both groups (Cuadrado et al., 2005b). Our meta-analysis examining substance use after transplantation (mostly ALD LT recipients) determined a lower rate of immunosuppressant medication non-adherence than we found in our earlier analysis of general liver transplant samples (2.6% vs. 6.7% per year, respectively) and lower non-adherence rates for attending clinic appointments compared to all solid-organ transplant recipients (1.9% vs. 5.8%, respectively) (Dew et al., 2007, 2008). These results seem to refute concerns over patients with substance use disorders being at higher risk for medical non-adherence compared to others. QUALITY OF LIFE AFTER ALD LT Pre- to post-comparisons Quality of life (QOL) has been shown to improve from pre- to post-transplant. The degree of improvement appears to be largely driven by the severity of illness at the point of LT rather than the etiology of liver disease that led to LT, with ALD recipients achieving similar levels of QOL compared to those with other types of liver disease (Estraviz et al., 2007). Similarly, a meta-analysis of studies using the Short Form Health Survey (SF-36) found significant pre- to post-LT gains in most areas of QOL but no difference comparing ALD recipients to other types of liver diseases (Tome et al., 2008). A study specifically examining sleep disturbance in LT patients found that patients with ALD had the most disturbed sleep pre-LT compared to other diseases, but that post-LT they experienced dramatically improved sleep parameters compared to their pre-LT parameters and had significantly better sleep satisfaction compared to those transplanted for HCV (Bhat et al., 2015). Prospective QOL from the point of LT While LT can dramatically improve QOL in the short term, the potential for LT to provide sustained QOL is less clear. Using the NIDDK-Liver Transplant database on longitudinal QOL outcomes (which included three centers and 381 LT recipients with prospective QOL surveys), found that, although QOL improvements can be largely sustained over a 12-year post-LT period, there are gradual and consistent decrements in QOL over time (Ruppert et al., 2010). Neither a diagnosis of ALD before LT nor post-LT use of alcohol or tobacco (reported by only 5% across all recipients) were associated with poorer QOL outcomes. Recipients with comorbid ALD and HCV had the worst QOL outcomes across all domains at 1 year post-LT and had the greatest rate of physical decline over time when compared to those with either etiology alone or other etiologies of liver disease (Ruppert et al., 2010). EMPLOYMENT AND SOCIAL REINTEGRATION AFTER ALD LT Employment and social reintegration after LT appear to be comparable to patient’s transplanted for other types of liver diseases. One of the earliest reports comparing alcohol dependent and nondependent LT recipients found no difference between the groups with respect to social stability (rated by the Strauss Bacon social stability index), disability, return to work, future work plans or inability to do housework (Beresford et al., 1992). Between 30% and 50% of recipients in either group felt their ability to work had been impaired by the LT. While there was a trend toward higher rates of disability or work-related problems among the alcohol dependent group than among the nondependent group, this difference did not reach statistical significance. Additionally there were no differences between the groups in rates of reported physical problems interfering with their functioning, loss of recreational functioning or experiencing worse health than previously (Beresford et al., 1992). Of ALD LT recipients who noted life changes associated with the transplant procedure, the majority reported better family relationships and better spiritual or religious lives but worse employment and financial status (Beresford et al., 1992). Most subsequent studies support these findings that ALD recipients have similar employment outcomes compared to non-ALD recipients. A meta-analysis of 8 studies examining return to work from 1 to 3 years after transplant found comparable rates of employment between ALD and non-ALD recipients (Bravata et al., 2001), although in a subsequent review the authors recommended caution when interpreting the combined results due to the varying definitions of part-time employment, full-time employment and homemaking between studies (Bravata and Keeffe, 2001b). They also found the proportion of working non-ALD recipients was similar pre- to post-LT whereas 30% fewer ALD LT recipients were working at least 1 year following LT than worked prior to LT (Bravata et al., 2001). However, non-ALD recipients were significantly younger than ALD recipients, which could confound the results given that younger patients may be more likely to return to work. Although few studies have examined alcohol use and employment, the combined data in the meta-analyses from these studies showed no association between post-LT alcohol use and employment in either ALD or non-ALD recipients (Bravata and Keeffe, 2001). Another single center survey of adult LT recipients explored the relationship between health insurance and employment over a median of 3.4 years post-LT and found a high rate of post-LT employment at 55%. This was perhaps due to the survey’s definition of employment including full-time, part-time and student/homemaker. Pre-LT employment and post-LT functional status predicted return to work post-LT but liver disease diagnosis including ALD did not predict employment (Rongey et al., 2005). Health insurance coverage also did not have an impact on employment post-LT (Rongey et al., 2005). In a more recent single center cross-sectional study of 353 LT living recipients at a mean of 8 years post-LT, working aged recipients with ALD or PSC were most likely to resume work compared to recipients transplanted for other diseases, although the majority of recipients did not return to work due to early retirement/disability. Additionally, the authors note that their center’s stringent selection practices (i.e. <1% of end-stage ALD candidates were selected for LT) may have influenced their results (Aberg, 2016). However, analyses of the United Network for Organ Sharing (UNOS) data set examining 21,942 working aged LT recipients over a 7-year period found three quarters of LT recipients did not return to work within 24 months post-LT (Huda et al., 2012). Pre-LT employment and no functional limitations were associated with significantly higher odds of employment but having ALD was associated with significantly lower odds of working post-LT, though the reasons for not working were unknown (Huda et al., 2012). A cross-sectional single center study examined societal reintegration including employment and participation in volunteer work, support groups or other social/community activities. There was no difference in employment between ALD and non-ALD recipients, although ALD recipients had significantly lower median incomes (Cowling et al., 2004). Similar percentages of each group were homemakers, students and supported other dependents. ALD recipients reported significantly less participation in social/community groups than non-ALD recipients (57% vs. 82%) (Cowling et al., 2004). CONCLUSIONS AND RECOMMENDATIONS FOR FUTURE IMPROVEMENT IN CARE Overall medical and psychosocial outcomes for ALD LT recipients compare favorably to patients transplanted for other types of liver diseases. In general survival is as good if not better for ALD recipients especially in comparison to patients transplanted for viral hepatitis. A few studies showed the combination of ALD and HCV portends worse survival. With the newer HCV treatments these survival differences will likely diminish. Of particular interest, the causes of death for ALD recipients are different than other LT recipients with cardiovascular and malignancies being more common. Perhaps this is due to the higher rates of smoking seen in ALD LT candidates and recipients. In addition for those who return to heavy drinking the long-term survival is predictably lower. Beyond survival, quality of life is as good as for recipients transplanted for other types of liver disease. Post-LT re-employment and social reintegration are also comparable. Given similar outcomes where might we recommend improvements? Post-LT return to alcohol use remains a critical concern. The first post-LT year is both highly stressful period and the period of highest risk for return to drinking. As stress and distress can precipitate relapse, monitoring strategies during that first year may provide early identification so appropriate interventions can be provided. Additionally after LT hospital discharge patients should quickly re-establish their addiction recovery treatment plan. This may prove challenging in the early aftermath of the transplant surgery as patients focus on their medical/surgical care. Using an innovative treatment delivery approach to overcome such a barrier, Addolorato et al. (2013) embedded an addiction treatment team within the transplant program, and demonstrated reduced post-LT alcohol consumption for those who participated. ALD LT recipients are more likely to be smokers. Resumption of smoking is a significant risk factor for poor post-LT medical outcomes and may lead to relapse to alcohol use (Ehlers et al., 2004). Concurrent alcohol and tobacco use produces unique challenges in relapse prevention. In the general population implementation of brief interventions to address smoking has been shown to facilitate smoking cessation and such strategies could have a significant impact on LT morbidity and mortality (Ehlers et al., 2004). Transplant programs should consider the requirement of smoking cessation prior to LT with additional support after surgery to prevent resumption of smoking. In addition to substance use early diagnosis and treatment of depression may improve long-term survival. Currently available literature shows promising data on the benefit of treatment to reduce the rates of acute graft rejection and improve survival. Depression may increase activity of the hypothalamic-pituitary-adrenal axis and glucocorticoid resistance, which are pathways involved in rejection. Antidepressants may down regulate pro-inflammatory cytokines thought to favorably affect acute rejection. In summary although ALD LT medical and psychosocial outcomes are comparatively good there are notable areas for improvement in this special patient population. Emphasis on early monitoring for alcohol and tobacco use as well as depression identification may be important first steps. Effective treatments exist for these disorders and early detection could provide clinicians with essential information to improve outcomes. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES Aberg F. ( 2016) From prolonging life to prolonging working life: tackling unemployment among liver-transplant recipients. World J Gastroenterol 22: 3701– 11. Google Scholar CrossRef Search ADS PubMed Adam R, McMaster P, O’Grady JG, et al. . 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Alcohol and Alcoholism – Oxford University Press
Published: Mar 1, 2018
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