Because liver transplantation (LT) continues to improve in both efficacy and outcome, demand for liver allografts will exceed supply by a growing margin. Alcoholic liver disease (ALD) is the second most common cause of end-stage liver disease (ESLD) leading to LT, after viral hepatitis (1). However, in light of an overall organ shortage, ALD is a controversial indication for LT. The crux of the issue is the definition of alcoholic dependency. On one hand, many consider alcoholism a behavioral choice and one with negative moral implications. By this standard, patients who develop ALD should be given lower priority for organ allocation, because their illness is merely a consequence of their actions (2). Interestingly, the same moral concerns have not been raised about patients with hepatitis B, hepatitis C, and obese patients with nonalcoholic steatohepatitis whose disease, in many cases, is also a consequence of a behavioral choice. On the other hand, mental health and addiction specialists regard alcoholism as a distinct mental disorder, with excellent reliability and validity of Diagnostic and Statistical Manual of Mental Disorders, 4th Edition and International Classification of Diseases, 10th Revision criteria for diagnosing alcohol dependence (3). As such, others argue that patients with ALD as a sequela of their dependency deserve equal consideration for treatment of their medical condition, LT included, compared with those with ESLD from any other process (4).
Overall survival of patients with ALD undergoing LT is similar to patients with other causes of ESLD, although survival has been shown to be compromised in patients who return to alcohol after LT (5, 6). Although patients actively consuming alcohol are universally excluded from consideration for LT, much of the screening process for transplant candidates is designed to assess the likelihood of the patient resuming alcohol postoperatively. Despite numerous studies examining risk factors, no reliable factor, including the 6 months of pretransplant abstinence that is required by the majority of transplant centers (7), has been found to predict relapse to alcohol consistently in patients with ALD undergoing LT.
More than one fifth of all LT performed in Kentucky since 1988 has been for ALD, a percentage second only to Wisconsin (8). Because of the high prevalence of ALD in our patient population, we wanted to determine the role of demographic, psychosocial, and behavioral factors in predicting relapse to alcohol after LT. In addition, few studies have investigated the prevalence of illicit drug use before and after LT. Therefore, an additional aim of this study was to determine factors predictive of illicit drug use after LT in patients with ALD.
At our institution, patients were selected for LT if thought to be at low risk for alcohol relapse by the transplant team, which included a psychiatrist or a social worker. Patients were not listed for LT if they had acute alcoholic hepatitis, had been abstinent for less than 6 months, or if they did not satisfactorily complete an alcohol rehabilitation program if abstinent for less than a year. Patients were also screened for illicit drugs at the time of evaluation and routinely while awaiting LT, and were inactivated from listed status if there was evidence of continuing substance abuse. After LT, patients were followed up at weekly intervals for 3 months and annually thereafter by the transplant surgeons. Patients also had weekly laboratory tests, including liver enzymes, for 3 months after liver transplantation, biweekly until 1 year after LT, and monthly to quarterly thereafter, monitored by the transplant team.
Patients who underwent LT for ALD between 1995 and 2007 were identified by retrospective review of medical records. All patients included in the analysis were determined to have a diagnosis of ALD by the hepatologist or transplant surgeon based on their history, physical examination, and laboratory and pathologic evaluations. The demographic and other variables examined included recipient age, gender, race, marital status, employment status, education level, family history of alcoholism, quantity and duration of alcohol consumed, length of abstinence before LT, history of substance abuse, history of depression, participation in substance rehabilitation, presence of hepatocellular carcinoma (HCC) or hepatitis C virus, and relapse to alcohol or illicit drugs after LT. History of depression was defined by having significant prior clinical depression treated with medication, outpatient therapy, or hospitalization. Any amount of alcohol use after liver transplantation as revealed during follow-up with members of the transplant team was considered a relapse event. Pretransplant substance abuse was defined as a history of using narcotics, cocaine, marijuana, or intravenous drugs, while prescribed narcotics were excluded from substance abuse after LT. The number of grams of alcohol consumed daily was calculated based on the following assumptions: one beer constituted 355 mL of 4% alcohol; one glass of wine was 148 mL of 11.5% alcohol; and one mixed drink represented 37 mL of 40% alcohol, with 0.789 g/mL.
Analyses were performed using SPSS 15.0 for Windows. Survival curves, determined by the Kaplan-Meier method, were compared using log-rank test. Multivariate analysis for predictors of survival was performed using Cox proportional hazards model. Fisher’s exact test was used for univariate analysis of dichotomous variables. Multivariate analysis was then carried out using stepwise logistic regression. Analysis of variance was used to compare means. Data are reported as mean or median±SD. A P value less than 0.05 was considered significant in all cases.
Between July 1995 and November 2007, 387 patients underwent LT at the University of Kentucky. From this group, 147 patients with ALD were identified, representing 38% of the total. Five patients (3.4%) experienced perioperative mortality and were excluded from analysis of recurrence. The majority of patients were male and white (89.4% and 93.7%, respectively). The median age at transplant was 52 years, with a range of 26 to 69 years. The median body mass index was 28.2. Fifty-three patients (37.3%) had concomitant HCV. More than half (64.4%) of the patients were married or had a stable partner. Only 18.4% of patients were working at the time of evaluation. Primary payer was private insurance for 25.7% of patients. Twenty-six percent of these patients were living alone. Ten patients were found to have HCC in their explanted livers. The mean waiting time for patients with HCC was not significantly different from those without tumors (P=0.6). Additional patient characteristics are summarized in Table 1.
Factors Affecting Patient Survival
The overall survival of patients undergoing LT for ALD was 96.2%, 89.6%, and 84.4% at 1, 3, and 5 years, respectively, with a median follow-up of 41.2±36.6 months (Fig. 1). A history of depression (P=0.01) was the only significant factor associated with decreased survival on univariate analysis. Multivariate analysis controlling for relapse to alcohol (which trended toward significance [P=0.059] and has been found in other series to influence survival) demonstrated that depression and recurrence of alcohol intake after LT were independently associated with decreased survival (P=0.008 and 0.017, respectively). Figures 2 and 3 show survival in patients with and without relapse to alcohol and illicit drugs, respectively. There were 23 deaths (16.2%) during the follow-up period. The most common primary causes of death were cancer, sepsis, and recidivism (Table 2). Only three of the eight patients who died from cancer had HCC recurrence. Patients with HCC had decreased survival compared with those without HCC, but this difference did not reach statistical significance. Lung cancer was responsible for the other five cancer-related deaths, and all of these patients were smokers before transplantation.
Analysis of Relapse to Alcohol after Transplantation
All but one patient had more than 6 months of abstinence from alcohol before LT, and 78% were abstinent longer than 12 months before transplantation. Sixty-three patients underwent substance abuse rehabilitation before LT. Twenty-seven patients (19%) were found objectively to have returned to alcohol consumption after LT. The average duration of pretransplant abstinence among subsequent relapsers was 23.4±16.4 months, compared with 50.1±52 months among nonrelapsers (P=0.009). On univariate analysis, abstinence for less than 12 months before LT (P=0.019) and participation in rehabilitation (P=0.026) were identified as potential risk factors for alcohol relapse. On multivariate analysis of these two factors, duration of abstinence less than 12 months was the only independent predictor of relapse (P=0.037).
Illicit Drug Use among Patients With Alcoholic Liver Disease
Pretransplant substance abuse was found to be common in our population, with 65 of 137 patients (47.4%) having previous or current use of one or more drugs. Table 3 lists the prevalence for each substance. After LT, 25 patients (17.2%) had objective evidence of illicit drug use. Numerous factors associated with posttransplant substance use were identified by univariate analysis, including government insurance (Medicare or Medicaid, P=0.001), age more than 50 (P=0.019), body mass index more than 35 (P=0.014), working status (P=0.019), HCV (P<0.001), and previous substance abuse (P<0.001). Multivariate analysis showed that history of substance abuse was the only independent factor to predict the use of illicit drugs after LT (P=0.017).
In the United States, ALD is responsible for the second-largest percentage of ESLD among patients receiving LT; ALD was the sole cause in 12.6% and was a cofactor with hepatitis C in 5.2% of all primary LT performed since 1988 (1). However, transplantation in this group of patients is socially controversial, as organ resources are scarce and ALD is considered by many to be a self-destructive behavior. In addition, while most patients will experience a positive outcome, it is nearly inevitable that some will return to alcohol consumption after LT. The percentage of recidivism varies in the literature, ranging in one review from 7% to 95% (9). This is most likely due to the broad spectrum of definitions used to characterize post-LT alcohol use (10).
It is difficult to identify factors that are consistently and predictably related to alcohol relapse. Capturing the true extent of alcohol consumption can be difficult, since in the majority of cases it hinges on the honesty of the patient or family members. This is a pervasive limitation, as it potentially weakens both pretransplant history and posttransplant follow-up (11). Yates et al. (12) evaluated patient alcohol history reliability and found it acceptable, although the possibility of inaccuracy remains.
Since the first LT performed at the University of Kentucky in 1995, we have included patients with ALD in the evaluation process, and like other programs, have experienced the challenges of defining the most appropriate selection criteria for LT in this group of patients. We were able to identify 147 patients with ALD among the 387 total LT recipients, representing 38% of our recipient population, a proportion higher than national and international averages (1, 13, 14).
It is important to consider the differences in definitions used to determine relapse when evaluating published data. Some authors have differentiated harmful and more benign drinking after transplantation, based loosely on quantity (15). In our series, recidivism was discovered by posttransplant screening, or admission by the patient or a family member. By this definition, 27 of the 142 patients reviewed were found to have returned to alcohol consumption, representing a relapse rate of 19%.
Overall survival rates in patients undergoing LT for ALD at our center are comparable with patients with other diagnoses (16). However, we identified several factors associated with decreased survival. Many of our patients had a psychiatric comorbidity by history, with depression being the most common. Clinical depression often accompanies alcohol and substance dependence disorders, and several studies have found psychiatric history (particularly anxiety or depression), to be a predictor of alcohol relapse (15, 17). In our study, a pre-LT diagnosis of depression maintained significance by multivariate analysis in predicting decreased survival. Singh et al. (18) found decreased survival in depressed versus euthymic patients before LT, but no difference after LT. It is likely that many of the factors they describe in pre-LT patients, such as decreased compliance and perceived poor quality of life, continue to play a role after LT.
Analyzing survival in ALD patients is particularly important, since it has implications for the efficacy and thus legitimacy of LT for this indication. Although no statistically different survival rates were appreciated between patients undergoing LT for ALD versus nonalcoholic disease, our study found post-LT relapse to alcohol to be an independent factor related to decreased survival, which is in accordance with several previous studies. Pfitzmann et al. (6), in one of the largest series of ALD patients, found significantly better survival among abstinent patients. In addition, among those recidivists who resumed heavy drinking, 14 of 16 died as a direct consequence of alcohol intake. Cuadrado et al. (5) similarly found post-LT drinking to compromise survival, especially after 10 years. In their series, while 25.9% of patients relapsed to alcohol, 58.3% of deaths were among recidivists. Pageaux et al. (19) followed 128 ALD patients and while actuarial survival between relapsers and nonrelapsers was not significantly different, many deaths were directly or indirectly caused by alcohol. None of the patients who resumed alcohol after LT died from acute alcoholic hepatitis, but from a combination of factors such as noncompliance, chronic alcoholic liver disease, and infection. Interestingly, the presence of HCC did not significantly affect survival in our series, possibly because of the small patient cohort.
The strongest predictor of alcohol relapse after LT in our series was a duration of pretransplant abstinence less than 1 year. Twenty-nine patients were abstinent less than 12 months, and 11 had documented relapse after LT. In addition, the mean period of abstinence was significantly shorter among those who relapsed compared with those who did not. The length of pre-LT sobriety as a predictor of post-LT sobriety is, though not universally, supported in the literature. In a prospective study assessing time to relapse in initial alcohol consumption and binge drinking after LT, DiMartini et al. (20) found that number of months sober was the strongest independent factor predicting both types of event. Retrospective studies by Foster et al. (21) and Perney et al. (22) also found length of pretransplant abstinence to be strongly predictive of relapse, although mean time periods differed greatly from ours, with 5.6 and 6 months among relapsers and 22 and 21 months among abstainers, respectively. In contrast, Kelly et al. (15) found neither length of abstinence nor abstinence less than 1 year to be predictive of relapse after LT using harmful drinking as an outcome.
Although length of sobriety is usually considered a strong predictor of recidivism, the so-called “6-month rule” is controversial. Most transplant centers require a minimum pretransplant sobriety of 6 months (14). Therefore, few patients will undergo LT outside this criterion, making assessment of its validity challenging (23, 24). Interestingly, a recent meta-analysis of risk factors for relapse to alcohol including 54 selected studies demonstrated a mild but statistically significant predictive value of abstinence less than 6 months (25). The authors of that review caution that bias exists in the selection of patients reported, as those patients presumably at highest risk for relapse (having not reached 6 months) are not listed, not transplanted, and not included in analyses. We identified a significant association between pretransplant sobriety and relapse, both at a breakpoint of 12 months, and when comparing mean sobriety among all patients who relapsed to patients who remained abstinent.
At our institution, patients with current or recent history of illicit drug abuse are required to have negative random urine screens and participate in rehabilitation before being considered for LT. We found that nearly half of our patients with ALD had a history of illicit drug use, whether remote or at evaluation, and 25 patients have used drugs after transplantation. In a previous study, Foster et al. (21) found a significant association between comorbid drug abuse and relapse to alcohol after LT. Although we did not observe this in our population, we performed separate analyses to determine predictors of drug use after LT. We found that pretransplant drug use was the only independent predictor of post-LT drug use. Although we could not analyze duration of pre-LT drug abstinence because of incomplete data, this finding appears to be in parallel with post-LT alcohol use: patient behavioral patterns before LT are the best predictors of compliance following LT.
In conclusion, ALD is a prevalent indication for LT, but presents ethical and moral dilemmas for transplant centers and society. Although survival rates and outcomes for ALD are comparable with other indications, some patients will eventually return to alcohol consumption, with detrimental effects on survival. Refining and redefining patient selection criteria by incorporating predictive factors may improve outcomes even further. In our series, the duration of abstinence before LT, especially when less than 1 year, predicted recidivism after LT. Similarly, we found pre-LT drug use to be the best predictor for using illicit drugs after LT. These factors do not replace a thorough psychosocial assessment. Nevertheless, they are extremely valuable predictors of post-LT behavior and should be taken into consideration when evaluating patients with ALD.
The authors wish to thank Liz Corio-Parsons, MSW, LCSW; Dana Grantz, RN, BSN; Lynne Polly, RN; Fran Stone, RN, BSN; and Jennifer Watkins, RN for their assistance with this study.
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