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Alcohol use and smoking after liver transplantation; complications and prevention
Best Practice & Research Clinical Gastroenterology 31 (2017) 181e185
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Alcohol use and smoking after liver transplantation; complications and prevention Ursic-Bedoya, MD a, He le ne Donnadieu-Rigole, MD, Head of Addictology Department b, Jose phanie Faure, MD a, Georges-Philippe Pageaux, MD, PhD, Professor, Ste Head of Liver Transplantation Unit a, * a b
Liver Transplantation Unit, Digestive Department, Saint Eloi University Hospital, University of Montpellier, 34295, Montpellier Cedex 5, France Addictology Department, Saint Eloi University Hospital, University of Montpellier, 34295, Montpellier Cedex 5, France
a b s t r a c t Keywords: Liver transplantation Smoking Alcohol relapse Post-transplant malignancy Addiction specialist
The last thirty years have been very prosperous in the field of liver transplantation (LT), with great advances in organ conservation, surgical techniques, peri-operative management and long-term immunosuppression, resulting in improved patient and graft survival rates as well as quality of life. However, substance addiction after LT, namely alcohol and tobacco, results in short term morbidity together with medium and long-term mortality. The main consequences can be vascular (increased risk of hepatic artery thrombosis in smokers), hepatic (recurrent alcoholic cirrhosis in alcohol relapsers) and oncological (increased risk of malignancy in patients consuming tobacco and/or alcohol after LT). This issue has thus drawn attention in the field of LT research. The management of these two at-risk behaviors addictions need the implication of hepatologists and addiction specialists, before and after LT. This review will summarize our current knowledge in alcohol use and cigarette smoking in the setting of LT, give practical tools for identification of high risk patients and treatment options. © 2017 Elsevier Ltd. All rights reserved.
Introduction Liver transplantation (LT) is the most efficient treatment for end-stage liver disease and small hepatocellular carcinoma (HCC), with excellent and constantly improving survival rates [1]. As long term survival has become commonplace, physicians have been confronted to new issues such as relapse to substance addiction. This review will summarize our current knowledge in alcohol use and cigarette smoking in the setting of LT, focusing on the consequences of such behavior and the importance of a combined management with an addiction specialist.
Is cigarette smoking before LT commonplace? The prevalence of cigarette consumption among patients suffering from chronic liver disease has never been studied, while data are more abundant regarding tobacco use in the setting of LT.
* Corresponding author. E-mail address: [email protected] (G.-P. Pageaux). http://dx.doi.org/10.1016/j.bpg.2017.03.005 1521-6918/© 2017 Elsevier Ltd. All rights reserved.
In Western countries, where the most common liver cirrhosis etiologies are hepatitis C virus (HCV), alcoholic liver disease (ALD) and, more recently, NASH, studies in transplant candidates [2] or recipients [3e5] showed incidences between 42% and 60% of any cigarette smoking, with 10%e23% actively smoking at the time of LT [3e5]. Those figures might vary depending on the predominant chronic liver disease in each center, since alcohol and tobacco use are closely related, with reports revealing that up to 90% of alcohol abusers smoke [6]. For example, in our ALD-dominant center, a prospective evaluation of 173 candidates showed that barely a quarter had never smoked, while 42.2% were active smokers (data unpublished). Interestingly, most of these studies show methodological limits, since smoking habits were only self-reported and this can be considered as a bias since some patients might lie about addictive behavior fearing that candor could result in non-listing. To our knowledge, only one study focused on the reliability of selfreported smoking using a biological method (serum cotinine levels) in LT candidates. After evaluating 171 patients, authors found that 11% of those denying tobacco use had cotinine (a nicotine metabolite) levels consistent with active smoking behavior [7].
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Besides, only one study evaluated nicotine addiction using a vali€m test [8]. dated scale such as Fagerstro When active smoking is detected in a LT candidate, cessation ought to be advised, although there is no data regarding potential benefit on success rates from smoking cessation therapies. Whether active smoking should represent a contraindication is debatable. A survey in the United States on smoking policies in 51 LT centers showed that cessation was mandatory before LT in 63% of them [9]. Professional societies remain vague, with AASLD stating that “all patients considered for liver transplantation should be encouraged to undergo efforts to abstain from smoking” [10], while EASL recommends that “smoking cessation should be mandatory in all transplant candidates” [11]. Irrespective of the consequences of smoking on LT outcomes, beneficial effects of smoking cessation on the liver function are expected. Indeed, it is well established that cigarette smoking participates in the progression of the fibrosis and disease severity in chronic hepatitis C [12,13], primary biliary cholangitis (PBC) [14] and ALD [15]. Moreover, there is mounting evidence linking tobacco exposure and HCC development [16,17]. The influence of donor smoking before transplantation was assessed in one German study of livers transplanted with extended donor criteria and showed that any smoking in the donor was associated with an increased risk of death after LT of 1.249 (95% CI, 1.011e1.544; P ¼ 0.04), although there was no repercussion on graft survival [18]. Alcohol use before LT In general, complete alcohol abstinence is mandatory before performing LT in patients having alcoholic liver disease (ALD) as primary indication [11]. The main objective of this rule is to allow roughly two thirdsofthepatientshavingaChild-PughCscoretorecoverwithinthe3 months-period aftera firstepisode ofdecompensationand thus avoid LT[19].Thedurationofthisabstinenceperiodhasbeensurroundedwith greatcontroversy[20],andnowadaysitisrecognizedthattheuseofa“6monthrule”aloneisnotevidence-basedanditcanhindersomelow-risk relapse candidates from getting a life-saving LT. The assessment of the risk of relapse after LT is a thorny issue, and the data are abundant and often contradictory. The most common risk factors associated with relapse are sobriety pre-LT <6 months [21e23]; family history of alcoholism [24]; psychiatric comorbidities, including other substance abuse [23e25]; diagnosis of alcohol dependence [25]; prior alcohol rehabilitation[25];andfemalegender[26]. In practice, the “High Risk Alcoholism Relapse” (HRAR) scale [27] can be useful to detect patients at greater risk of harmful relapse. This scale considers the daily alcohol consumption (9 drinks, 9e16 drinks, 17 drinks), length of the heavy drinking history (11 years, 11e24 years, 25 years), and previous inpatient alcoholism treatment history (none, one or 2), each item being graded from 0 to 2. In a French-Swiss cohort of 387 patients transplanted for ALD, an HRAR score higher than 3 was one of the independent factors associated with harmful relapse (declared alcoholic consumption level >40 g/d and the presence of physical or mental alcohol-related damage), along with a duration of abstinence <6 months and presence of psychiatric comorbidities [23]. The identification of patients at high-risk of relapse raises the question of alcohol addiction management in the pre-LT period. A randomized controlled trial conducted in 91 patients in two United States centers compared a positive reinforcement technique called Motivational Enhancement Therapy (MET), with referral to local treatment sources such as Alcoholics Anonymous. The study revealed that 25% of the patients drank alcohol before their transplant, but MET had little, if any, influence on this event [28].
Furthermore, alcohol consumption must be sought in every LT candidate, no matter what the primary indication is. Indeed, in a British single-center study, the authors evaluated lifetime alcohol consumption of 208 consecutive patients referred for LT. The assessment was conducted by a researcher completely independent of the transplant team to foster candor and they found that the referring physician had not raised the possibility of alcohol consumption as a causative factor in ten (12.5%) of the 80 patients meeting DSM-IV criteria for alcohol abuse or dependence [29]. Thus, in our center, every transplant candidate is evaluated by an independent addiction specialist. Our data revealed that up to 72% of the candidates between 2008 and 2014 have experienced excessive alcohol use at some time in their life, while merely 40% of them were labeled as “alcoholic liver disease” as the primary indication (data unpublished). Tobacco consumption after LT Do patients smoke after LT? The most thorough study of smoking behavior in LT recipients for ALD examined the course of nicotine addiction through time €m test. Authors found that smoking prevalence using the Fagerstro ranged between 39 and 58% of all LT recipients, with smokers resuming tobacco use quickly after LT and nicotine dependence increasing over time. At 9 months post-LT, 60% of smokers were €m test score [8]. dependent to nicotine according to their Fagerstro Of interest, the incidence of “de novo” smoking after LT is neglectable. For example, in a single-center study of smoking patterns before and after LT of 202 recipients, 31 patients (15%) reported smoking after LT, and only one of them had not smoked before the surgery [3]. A meta-analysis of studies examining substance use after solid organ transplantation found that the average rate of cigarette smoking relapse after LT was 9.9, or approximately 10 cases per 100 PPY (persons per year) of observation (confidence intervals 2.7e17.1) [30]. What are the repercussions of smoking in LT outcomes? Data are abundant in this regard, even though the concordance between studies is incomplete. At least two studies suggested that patient survival is hampered by cigarette smoking, assessed at the time of pre-transplant evaluation. The first study is a single-center retrospective report from Scotland that examined the outcomes of 136 consecutive liver recipients with a mean follow-up time of 8.8 years. This study found that active smokers at the time of LT had a significantly lower survival (for example, 64% vs 83% 5-year survival, p ¼ 0.04) when compared to lifelong nonsmokers, with increased cardiovascular-specific mortality and sepsis-specific mortality but not malignancy-related mortality [5]. A more recent retrospective single-center study performed in the US, classified 1275 LT recipients in active smokers (22%), previous smokers (25%) and nonsmokers (53%) at the time of listing for LT. Cox regression analysis of post-LT patient survival showed a 10-year survival of only 57% for current smokers, significantly lower than previous smokers and nonsmokers (P < 0.01; risk of death, 1.47; 95% confidence interval [1.10e1.97]). Interestingly, authors found a dosedependent relationship, as smokers with more than 20 packyears tobacco exposure exhibited a lower survival than nonsmokers and smokers with less than 20 pack-years [4]. Unlike the Scottish study, cardiovascular and sepsis-related mortality were not increased in smokers, whereas HCC recurrence and non-skin de novo malignancy were incremented in smokers.
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However, the findings suggesting that tobacco use influences survival after LT are not supported by another retrospective singlecenter study that analyzed the outcome of 2260 adult patients with chronic liver disease evaluated for liver transplantation at the University of Michigan. Authors found that smoking was not associated with increased mortality risk at any time point in those evaluated or receiving transplants, even though a trend toward decreased survival beyond 2 years post-LT in active and previous smokers existed when compared to nonsmokers [31]. The relationship between cigarette smoking and cardiovascular complications varies greatly between studies. In 2002, Pungpapong et al. reported that smokers had a higher rate of hepatic artery thrombosis, while cessation of smoking for at least two years before grafting reduced vascular events [32]. Nonetheless, a more recent report examining metabolic and cardiovascular events after LT contradicts these findings. Indeed, only age, diabetes, prior history of CVD and serum troponin >0.07 ng/mL were independently associated with CVD in the long term [33]. Albeit, one possible bias in this study is that smoking was considered as a binary variable (any history of smoking vs never smoked) and the only consumption studied was the one that occurred before transplantation. Biliary complications after LT are frequent and can be related to arterial microvasculature defects. Thus, Mathur et al. hypothesized that smoking could lead to biliary complications (bile leaks, strictures or bile casts). They found that those who smoked actively within the three months before transplant had higher rates of biliary complications (51.4%) compared with lifetime nonsmokers (35.6%) and previous smokers having quit at least three months before LT (35.6%) [34]. Other complications after LT have been found to be associated with smoking cigarettes: development of inflammatory bowel disease in patients transplanted for primary sclerosing cholangitis (PSC) [35], shorter recurrent viral hepatitisefree survival [36], higher incidence of one-year post-LT diabetes mellitus [37] and increased bone fracture risk [38].
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respectively [1]. After LT, the graft is more prone to damage, either it originates from viral insults such as hepatitis C recurrence [46] or from alcohol-mediated aggressions. Hence, histopathological studies have shown that steatosis, steatohepatitis, and rapidly progressive fibrosis were associated with alcohol relapse [47e49]. Whether the relapse to drinking hampered the survival rates was a matter of debate for many years due to contradictory reports [23,40,43,50]. Nonetheless, more recent studies support the fact that excessive alcohol relapse significantly increases mortality beyond 5 years [41,42], especially when the graft exhibits lesions of recurrent alcoholic cirrhosis (10-year survival of 49.7% vs. 69.9%, p<0.001, for the patients with and without recurrent alcoholic cirrhosis, respectively) [41]. Of interest, the negative effect on survival of excessive alcohol consumption after LT affects patients regardless of the primary indication [42]. Are tobacco and alcohol use involved in malignancy after LT?
Alcohol use after LT
When compared to general population, LT recipients are at higher risk of developing skin malignancy, lymphoproliferative disorders and solid-organ malignancy [51e55], mainly because these patients are exposed to immunosuppressive therapy. Moreover, cancer has emerged as a major long-term cause of death in liver transplant recipients [1,56,57]. Tobacco and alcohol consumption are known risk factors for oral, pharyngeal, laryngeal, esophageal, and upper airway tumors in the general population, with a synergistic effect when the patients are exposed to both substances [58,59]. Unsurprisingly, numerous studies reported a link between the occurrence after LT of non-cutaneous solid organ malignant tumors and alcohol consumption [60,61] and cigarette smoking [57,62e65]. Furthermore, we demonstrated that a synergistic effect exists between the degree of exposure to tacrolimus the first year after LT and tobacco use before LT. For example, a patient smoking before LT who had a first-year mean tacrolimus concentration of 10 ng/mL had a 40% probability of development of a solidorgan cancer, compared to only 10e15% in the same situation but without a history of smoking pre-LT [62].
Is relapse a frequent event?
Importance of an addiction team before and after LT
Back in the 1980's, pioneer transplant programs were extremely confident in the positive effect of LT on alcohol cessation [39]. This assurance has decreased in the last decades, and it is now acknowledged that no matter how stringent the selection is, there will still be a considerable number of patients who will resume drinking after LT. However, relapse rates vary greatly between the studies, depending on the definition of relapse and the method(s) used to detect it. When any alcohol consumption is considered, including minor and controlled episodes (“slips”), rates can climb up to 48% [40], but when only consumption believed to be harmful to the graft (usually higher than 20e40 g of alcohol per day for a period longer than 6 months), these rates approach 12e26% [23,41e43]. A meta-analysis published in 2008 by Dew et al found that any alcohol relapse rates were 5.6 cases per 100 patients per year (PPY), and 2.5 cases per 100 PPY for relapse with heavy alcohol use [30]. Although data are limited, relapse rates after living donor LT seem lower, with any alcohol consumption rates between 10% and 23% [44,45].
EASL 2016 guidelines on liver transplantation state that “it is important to assess social network, psychiatric illness and addiction in order to evaluate adherence of the recipient” [11]. There is data supporting the fact that this assessment should be made by an addiction specialist. Indeed, an Italian study showed that the relapse and mortality rates of patients transplanted for ALD decreased after the implementation of an “Alcohol Addiction Unit”, consisting of internists, physicians in training and psychologists, with expertise in alcoholism, hepatology, and neuroscience [66]. Moreover, after LT, early recognition of addictive disorder is crucial, before any dependence or harm is developed. In the context, reliability of self-report is insufficient, so to maximize this detection, transplant physician must have recourse to biomarkers of recent drinking (such as serum methanol or ethyl glucuronide [67,68]), standardized tests such as AUDIT-C (Alcohol Use Disorders Identification Test-Consumption) and addiction specialist interviews. We recently published a prospective study performed in our center, showing that there was a discrepancy between hepatologist's interview, the AUDIT-C score, and the addiction specialist visit in 30% of the 141 LT patients evaluated for alcohol consumption after LT. Hence, hepatologist's interview allowed the detection of only 21.9% of patients drinking alcohol, while addiction specialist detected this disorder in 41% of patients [69].
What are the consequences of alcohol relapse after LT? Survival rates after LT for ALD are excellent and similar to those observed with other indications. For example, data from over 89000 LT originating from the European Liver Transplant Registry (ELTR) show 1-, 5- and 10-year survival rates of 86%, 73%, and 59%,
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Practice points Alcohol and tobacco consumption are common before and after LT, so they should be tracked down in every patient, regardless of the primary indication. Heavy alcohol relapse after LT is frequent, leads to a faster damage of the graft and an increased medium and longterm mortality. Alcohol consumption and cigarette smoking in the setting of LT are recognized risk factors of solid-organ cancer.
Research agenda It is unclear whether LT patients having a history of smoking and/or alcohol use should have an intensive screening of solid-organ cancer. Potential benefit of smoking cessation therapies or strategies should be evaluated in LT candidates.
Conflict of interest - Georges-Philippe Pageaux: board membership Astellas and Novartis. - Other authors: none.
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J. Ursic-Bedoya et al. / Best Practice & Research Clinical Gastroenterology 31 (2017) 181e185 re L, Guitard J, Ribes D, et al. [37] Oufroukhi L, Kamar N, Muscari F, Lavayssie Predictive factors for posttransplant diabetes mellitus within one-year of liver transplantation. Transplantation 2008;85:1436e42. http://dx.doi.org/ 10.1097/TP.0b013e31816f1b7c. [38] Hardinger KL, Ho B, Schnitzler MA, Desai N, Lowell J, Shenoy S, et al. Serial measurements of bone density at the lumbar spine do not predict fracture risk after liver transplantation. Liver Transpl 2003;9:857e62. http://dx.doi.org/ 10.1053/jlts.2003.50135. [39] Starzl TE, Van Thiel D, Tzakis AG, Iwatsuki S, Todo S, Marsh JW, et al. Orthotopic liver transplantation for alcoholic cirrhosis. JAMA 1988;260:2542e4. [40] Dimartini A, Dew MA, Day N, Fitzgerald MG, Jones BL, Devera ME, et al. Trajectories of alcohol consumption following liver transplantation. Am J Transpl 2010;10:2305e12. http://dx.doi.org/10.1111/j.1600-6143.2010.03232.x. [41] Dumortier J, Dharancy S, Cannesson A, Lassailly G, Rolland B, Pruvot F-R, et al. Recurrent alcoholic cirrhosis in severe alcoholic relapse after liver transplantation: a frequent and serious complication. Am J Gastroenterol 2015;110:1160e6. http://dx.doi.org/10.1038/ajg.2015.204. quiz 1167. [42] Faure S, Herrero A, Jung B, Duny Y, Daures JP, Mura T, et al. Excessive alcohol consumption after liver transplantation impacts on long-term survival, whatever the primary indication. J Hepatol 2012;57:306e12. http:// dx.doi.org/10.1016/j.jhep.2012.03.014. brega E, Casafont F, Pons-Romero F. Alcohol recidivism impairs [43] Cuadrado A, Fa long-term patient survival after orthotopic liver transplantation for alcoholic liver disease. Liver Transpl 2005;11:420e6. http://dx.doi.org/10.1002/ lt.20386. [44] Saigal S, Choudhary NS, Yadav SK, Saraf N, Kumar N, Rai R, et al. Lower relapse rates with good post-transplant outcome in alcoholic liver disease: experience from a living donor liver transplant center. Indian J Gastroenterol 2016;35: 123e8. http://dx.doi.org/10.1007/s12664-016-0646-z. [45] Egawa H, Nishimura K, Teramukai S, Yamamoto M, Umeshita K, Furukawa H, et al. Risk factors for alcohol relapse after liver transplantation for alcoholic cirrhosis in Japan. Liver Transpl 2014;20:298e310. http://dx.doi.org/10.1002/ lt.23797. [46] Neumann UP, Berg T, Bahra M, Seehofer D, Langrehr JM, Neuhaus R, et al. Fibrosis progression after liver transplantation in patients with recurrent hepatitis C. J Hepatol 2004;41:830e6. http://dx.doi.org/10.1016/j.jhep.2004.06.029. [47] Conjeevaram HS, Hart J, Lissoos TW, Schiano TD, Dasgupta K, Befeler AS, et al. Rapidly progressive liver injury and fatal alcoholic hepatitis occurring after liver transplantation in alcoholic patients. Transplantation 1999;67:1562e8. http://dx.doi.org/10.1097/00007890-199906270-00010. [48] Rice JP, Eickhoff J, Agni R, Ghufran A, Brahmbhatt R, Lucey MR. Abusive drinking after liver transplantation is associated with allograft loss and advanced allograft fibrosis. Liver Transpl 2013;19:1377e86. http://dx.doi.org/ 10.1002/lt.23762. [49] Burra P, Mioni D, Cecchetto A, Cillo U, Zanus G, Fagiuoli S, et al. Histological features after liver transplantation in alcoholic cirrhotics. J Hepatol 2001;34: 716e22. http://dx.doi.org/10.1016/S0168-8278(01)00002-2. [50] Pageaux G-P, Bismuth M, Perney P, Costes V, Jaber S, Possoz P, et al. Alcohol relapse after liver transplantation for alcoholic liver disease: does it matter? J Hepatol 2003;38:629e34. http://dx.doi.org/10.1016/S0168-8278(03)00088-6. [51] Ducroux E, Boillot O, Ocampo MA, Decullier E, Roux A, Dumortier J, et al. Skin cancers after liver transplantation: retrospective single-center study on 371 recipients. Transplantation 2014;98:335e40. http://dx.doi.org/10.1097/ TP.0000000000000051. [52] Duvoux C, Pageaux G-P, Vanlemmens C, Roudot-Thoraval F, Vincens-Rolland Azode C, et al. Risk factors for lymphoproliferative disorders after liver L, He transplantation in adults: an analysis of 480 patients. Transplantation 2002;74: 1103e9. http://dx.doi.org/10.1097/00007890-200210270-00008. [53] Collett D, Mumford L, Banner NR, Neuberger J, Watson C. Comparison of the incidence of malignancy in recipients of different types of organ: a UK registry
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6
Alcohol use and smoking after liver transplantation; complications and prevention Ursic-Bedoya, MD a, He le ne Donnadieu-Rigole, MD, Head of Addictology Department b, Jose phanie Faure, MD a, Georges-Philippe Pageaux, MD, PhD, Professor, Ste Head of Liver Transplantation Unit a, * a b
Liver Transplantation Unit, Digestive Department, Saint Eloi University Hospital, University of Montpellier, 34295, Montpellier Cedex 5, France Addictology Department, Saint Eloi University Hospital, University of Montpellier, 34295, Montpellier Cedex 5, France
a b s t r a c t Keywords: Liver transplantation Smoking Alcohol relapse Post-transplant malignancy Addiction specialist
The last thirty years have been very prosperous in the field of liver transplantation (LT), with great advances in organ conservation, surgical techniques, peri-operative management and long-term immunosuppression, resulting in improved patient and graft survival rates as well as quality of life. However, substance addiction after LT, namely alcohol and tobacco, results in short term morbidity together with medium and long-term mortality. The main consequences can be vascular (increased risk of hepatic artery thrombosis in smokers), hepatic (recurrent alcoholic cirrhosis in alcohol relapsers) and oncological (increased risk of malignancy in patients consuming tobacco and/or alcohol after LT). This issue has thus drawn attention in the field of LT research. The management of these two at-risk behaviors addictions need the implication of hepatologists and addiction specialists, before and after LT. This review will summarize our current knowledge in alcohol use and cigarette smoking in the setting of LT, give practical tools for identification of high risk patients and treatment options. © 2017 Elsevier Ltd. All rights reserved.
Introduction Liver transplantation (LT) is the most efficient treatment for end-stage liver disease and small hepatocellular carcinoma (HCC), with excellent and constantly improving survival rates [1]. As long term survival has become commonplace, physicians have been confronted to new issues such as relapse to substance addiction. This review will summarize our current knowledge in alcohol use and cigarette smoking in the setting of LT, focusing on the consequences of such behavior and the importance of a combined management with an addiction specialist.
Is cigarette smoking before LT commonplace? The prevalence of cigarette consumption among patients suffering from chronic liver disease has never been studied, while data are more abundant regarding tobacco use in the setting of LT.
* Corresponding author. E-mail address: [email protected] (G.-P. Pageaux). http://dx.doi.org/10.1016/j.bpg.2017.03.005 1521-6918/© 2017 Elsevier Ltd. All rights reserved.
In Western countries, where the most common liver cirrhosis etiologies are hepatitis C virus (HCV), alcoholic liver disease (ALD) and, more recently, NASH, studies in transplant candidates [2] or recipients [3e5] showed incidences between 42% and 60% of any cigarette smoking, with 10%e23% actively smoking at the time of LT [3e5]. Those figures might vary depending on the predominant chronic liver disease in each center, since alcohol and tobacco use are closely related, with reports revealing that up to 90% of alcohol abusers smoke [6]. For example, in our ALD-dominant center, a prospective evaluation of 173 candidates showed that barely a quarter had never smoked, while 42.2% were active smokers (data unpublished). Interestingly, most of these studies show methodological limits, since smoking habits were only self-reported and this can be considered as a bias since some patients might lie about addictive behavior fearing that candor could result in non-listing. To our knowledge, only one study focused on the reliability of selfreported smoking using a biological method (serum cotinine levels) in LT candidates. After evaluating 171 patients, authors found that 11% of those denying tobacco use had cotinine (a nicotine metabolite) levels consistent with active smoking behavior [7].
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Besides, only one study evaluated nicotine addiction using a vali€m test [8]. dated scale such as Fagerstro When active smoking is detected in a LT candidate, cessation ought to be advised, although there is no data regarding potential benefit on success rates from smoking cessation therapies. Whether active smoking should represent a contraindication is debatable. A survey in the United States on smoking policies in 51 LT centers showed that cessation was mandatory before LT in 63% of them [9]. Professional societies remain vague, with AASLD stating that “all patients considered for liver transplantation should be encouraged to undergo efforts to abstain from smoking” [10], while EASL recommends that “smoking cessation should be mandatory in all transplant candidates” [11]. Irrespective of the consequences of smoking on LT outcomes, beneficial effects of smoking cessation on the liver function are expected. Indeed, it is well established that cigarette smoking participates in the progression of the fibrosis and disease severity in chronic hepatitis C [12,13], primary biliary cholangitis (PBC) [14] and ALD [15]. Moreover, there is mounting evidence linking tobacco exposure and HCC development [16,17]. The influence of donor smoking before transplantation was assessed in one German study of livers transplanted with extended donor criteria and showed that any smoking in the donor was associated with an increased risk of death after LT of 1.249 (95% CI, 1.011e1.544; P ¼ 0.04), although there was no repercussion on graft survival [18]. Alcohol use before LT In general, complete alcohol abstinence is mandatory before performing LT in patients having alcoholic liver disease (ALD) as primary indication [11]. The main objective of this rule is to allow roughly two thirdsofthepatientshavingaChild-PughCscoretorecoverwithinthe3 months-period aftera firstepisode ofdecompensationand thus avoid LT[19].Thedurationofthisabstinenceperiodhasbeensurroundedwith greatcontroversy[20],andnowadaysitisrecognizedthattheuseofa“6monthrule”aloneisnotevidence-basedanditcanhindersomelow-risk relapse candidates from getting a life-saving LT. The assessment of the risk of relapse after LT is a thorny issue, and the data are abundant and often contradictory. The most common risk factors associated with relapse are sobriety pre-LT <6 months [21e23]; family history of alcoholism [24]; psychiatric comorbidities, including other substance abuse [23e25]; diagnosis of alcohol dependence [25]; prior alcohol rehabilitation[25];andfemalegender[26]. In practice, the “High Risk Alcoholism Relapse” (HRAR) scale [27] can be useful to detect patients at greater risk of harmful relapse. This scale considers the daily alcohol consumption (9 drinks, 9e16 drinks, 17 drinks), length of the heavy drinking history (11 years, 11e24 years, 25 years), and previous inpatient alcoholism treatment history (none, one or 2), each item being graded from 0 to 2. In a French-Swiss cohort of 387 patients transplanted for ALD, an HRAR score higher than 3 was one of the independent factors associated with harmful relapse (declared alcoholic consumption level >40 g/d and the presence of physical or mental alcohol-related damage), along with a duration of abstinence <6 months and presence of psychiatric comorbidities [23]. The identification of patients at high-risk of relapse raises the question of alcohol addiction management in the pre-LT period. A randomized controlled trial conducted in 91 patients in two United States centers compared a positive reinforcement technique called Motivational Enhancement Therapy (MET), with referral to local treatment sources such as Alcoholics Anonymous. The study revealed that 25% of the patients drank alcohol before their transplant, but MET had little, if any, influence on this event [28].
Furthermore, alcohol consumption must be sought in every LT candidate, no matter what the primary indication is. Indeed, in a British single-center study, the authors evaluated lifetime alcohol consumption of 208 consecutive patients referred for LT. The assessment was conducted by a researcher completely independent of the transplant team to foster candor and they found that the referring physician had not raised the possibility of alcohol consumption as a causative factor in ten (12.5%) of the 80 patients meeting DSM-IV criteria for alcohol abuse or dependence [29]. Thus, in our center, every transplant candidate is evaluated by an independent addiction specialist. Our data revealed that up to 72% of the candidates between 2008 and 2014 have experienced excessive alcohol use at some time in their life, while merely 40% of them were labeled as “alcoholic liver disease” as the primary indication (data unpublished). Tobacco consumption after LT Do patients smoke after LT? The most thorough study of smoking behavior in LT recipients for ALD examined the course of nicotine addiction through time €m test. Authors found that smoking prevalence using the Fagerstro ranged between 39 and 58% of all LT recipients, with smokers resuming tobacco use quickly after LT and nicotine dependence increasing over time. At 9 months post-LT, 60% of smokers were €m test score [8]. dependent to nicotine according to their Fagerstro Of interest, the incidence of “de novo” smoking after LT is neglectable. For example, in a single-center study of smoking patterns before and after LT of 202 recipients, 31 patients (15%) reported smoking after LT, and only one of them had not smoked before the surgery [3]. A meta-analysis of studies examining substance use after solid organ transplantation found that the average rate of cigarette smoking relapse after LT was 9.9, or approximately 10 cases per 100 PPY (persons per year) of observation (confidence intervals 2.7e17.1) [30]. What are the repercussions of smoking in LT outcomes? Data are abundant in this regard, even though the concordance between studies is incomplete. At least two studies suggested that patient survival is hampered by cigarette smoking, assessed at the time of pre-transplant evaluation. The first study is a single-center retrospective report from Scotland that examined the outcomes of 136 consecutive liver recipients with a mean follow-up time of 8.8 years. This study found that active smokers at the time of LT had a significantly lower survival (for example, 64% vs 83% 5-year survival, p ¼ 0.04) when compared to lifelong nonsmokers, with increased cardiovascular-specific mortality and sepsis-specific mortality but not malignancy-related mortality [5]. A more recent retrospective single-center study performed in the US, classified 1275 LT recipients in active smokers (22%), previous smokers (25%) and nonsmokers (53%) at the time of listing for LT. Cox regression analysis of post-LT patient survival showed a 10-year survival of only 57% for current smokers, significantly lower than previous smokers and nonsmokers (P < 0.01; risk of death, 1.47; 95% confidence interval [1.10e1.97]). Interestingly, authors found a dosedependent relationship, as smokers with more than 20 packyears tobacco exposure exhibited a lower survival than nonsmokers and smokers with less than 20 pack-years [4]. Unlike the Scottish study, cardiovascular and sepsis-related mortality were not increased in smokers, whereas HCC recurrence and non-skin de novo malignancy were incremented in smokers.
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However, the findings suggesting that tobacco use influences survival after LT are not supported by another retrospective singlecenter study that analyzed the outcome of 2260 adult patients with chronic liver disease evaluated for liver transplantation at the University of Michigan. Authors found that smoking was not associated with increased mortality risk at any time point in those evaluated or receiving transplants, even though a trend toward decreased survival beyond 2 years post-LT in active and previous smokers existed when compared to nonsmokers [31]. The relationship between cigarette smoking and cardiovascular complications varies greatly between studies. In 2002, Pungpapong et al. reported that smokers had a higher rate of hepatic artery thrombosis, while cessation of smoking for at least two years before grafting reduced vascular events [32]. Nonetheless, a more recent report examining metabolic and cardiovascular events after LT contradicts these findings. Indeed, only age, diabetes, prior history of CVD and serum troponin >0.07 ng/mL were independently associated with CVD in the long term [33]. Albeit, one possible bias in this study is that smoking was considered as a binary variable (any history of smoking vs never smoked) and the only consumption studied was the one that occurred before transplantation. Biliary complications after LT are frequent and can be related to arterial microvasculature defects. Thus, Mathur et al. hypothesized that smoking could lead to biliary complications (bile leaks, strictures or bile casts). They found that those who smoked actively within the three months before transplant had higher rates of biliary complications (51.4%) compared with lifetime nonsmokers (35.6%) and previous smokers having quit at least three months before LT (35.6%) [34]. Other complications after LT have been found to be associated with smoking cigarettes: development of inflammatory bowel disease in patients transplanted for primary sclerosing cholangitis (PSC) [35], shorter recurrent viral hepatitisefree survival [36], higher incidence of one-year post-LT diabetes mellitus [37] and increased bone fracture risk [38].
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respectively [1]. After LT, the graft is more prone to damage, either it originates from viral insults such as hepatitis C recurrence [46] or from alcohol-mediated aggressions. Hence, histopathological studies have shown that steatosis, steatohepatitis, and rapidly progressive fibrosis were associated with alcohol relapse [47e49]. Whether the relapse to drinking hampered the survival rates was a matter of debate for many years due to contradictory reports [23,40,43,50]. Nonetheless, more recent studies support the fact that excessive alcohol relapse significantly increases mortality beyond 5 years [41,42], especially when the graft exhibits lesions of recurrent alcoholic cirrhosis (10-year survival of 49.7% vs. 69.9%, p<0.001, for the patients with and without recurrent alcoholic cirrhosis, respectively) [41]. Of interest, the negative effect on survival of excessive alcohol consumption after LT affects patients regardless of the primary indication [42]. Are tobacco and alcohol use involved in malignancy after LT?
Alcohol use after LT
When compared to general population, LT recipients are at higher risk of developing skin malignancy, lymphoproliferative disorders and solid-organ malignancy [51e55], mainly because these patients are exposed to immunosuppressive therapy. Moreover, cancer has emerged as a major long-term cause of death in liver transplant recipients [1,56,57]. Tobacco and alcohol consumption are known risk factors for oral, pharyngeal, laryngeal, esophageal, and upper airway tumors in the general population, with a synergistic effect when the patients are exposed to both substances [58,59]. Unsurprisingly, numerous studies reported a link between the occurrence after LT of non-cutaneous solid organ malignant tumors and alcohol consumption [60,61] and cigarette smoking [57,62e65]. Furthermore, we demonstrated that a synergistic effect exists between the degree of exposure to tacrolimus the first year after LT and tobacco use before LT. For example, a patient smoking before LT who had a first-year mean tacrolimus concentration of 10 ng/mL had a 40% probability of development of a solidorgan cancer, compared to only 10e15% in the same situation but without a history of smoking pre-LT [62].
Is relapse a frequent event?
Importance of an addiction team before and after LT
Back in the 1980's, pioneer transplant programs were extremely confident in the positive effect of LT on alcohol cessation [39]. This assurance has decreased in the last decades, and it is now acknowledged that no matter how stringent the selection is, there will still be a considerable number of patients who will resume drinking after LT. However, relapse rates vary greatly between the studies, depending on the definition of relapse and the method(s) used to detect it. When any alcohol consumption is considered, including minor and controlled episodes (“slips”), rates can climb up to 48% [40], but when only consumption believed to be harmful to the graft (usually higher than 20e40 g of alcohol per day for a period longer than 6 months), these rates approach 12e26% [23,41e43]. A meta-analysis published in 2008 by Dew et al found that any alcohol relapse rates were 5.6 cases per 100 patients per year (PPY), and 2.5 cases per 100 PPY for relapse with heavy alcohol use [30]. Although data are limited, relapse rates after living donor LT seem lower, with any alcohol consumption rates between 10% and 23% [44,45].
EASL 2016 guidelines on liver transplantation state that “it is important to assess social network, psychiatric illness and addiction in order to evaluate adherence of the recipient” [11]. There is data supporting the fact that this assessment should be made by an addiction specialist. Indeed, an Italian study showed that the relapse and mortality rates of patients transplanted for ALD decreased after the implementation of an “Alcohol Addiction Unit”, consisting of internists, physicians in training and psychologists, with expertise in alcoholism, hepatology, and neuroscience [66]. Moreover, after LT, early recognition of addictive disorder is crucial, before any dependence or harm is developed. In the context, reliability of self-report is insufficient, so to maximize this detection, transplant physician must have recourse to biomarkers of recent drinking (such as serum methanol or ethyl glucuronide [67,68]), standardized tests such as AUDIT-C (Alcohol Use Disorders Identification Test-Consumption) and addiction specialist interviews. We recently published a prospective study performed in our center, showing that there was a discrepancy between hepatologist's interview, the AUDIT-C score, and the addiction specialist visit in 30% of the 141 LT patients evaluated for alcohol consumption after LT. Hence, hepatologist's interview allowed the detection of only 21.9% of patients drinking alcohol, while addiction specialist detected this disorder in 41% of patients [69].
What are the consequences of alcohol relapse after LT? Survival rates after LT for ALD are excellent and similar to those observed with other indications. For example, data from over 89000 LT originating from the European Liver Transplant Registry (ELTR) show 1-, 5- and 10-year survival rates of 86%, 73%, and 59%,
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Practice points Alcohol and tobacco consumption are common before and after LT, so they should be tracked down in every patient, regardless of the primary indication. Heavy alcohol relapse after LT is frequent, leads to a faster damage of the graft and an increased medium and longterm mortality. Alcohol consumption and cigarette smoking in the setting of LT are recognized risk factors of solid-organ cancer.
Research agenda It is unclear whether LT patients having a history of smoking and/or alcohol use should have an intensive screening of solid-organ cancer. Potential benefit of smoking cessation therapies or strategies should be evaluated in LT candidates.
Conflict of interest - Georges-Philippe Pageaux: board membership Astellas and Novartis. - Other authors: none.
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