Alcohol use while on the liver transplant waiting list: A single-center experience
Alcoholic liver disease (ALD) is a leading indication for liver transplantation. Our center has randomly checked blood alcohol levels (BALs) in ALD patients on the waiting list since 2004. We aimed to identify the incidence and predictors of inactivation on the transplant list due to alcohol use and to determine the utility of BAL-screening in this process. We conducted a retrospective review of patients with ALD listed for liver transplantation with at least 3 months of postlisting follow-up. Alcohol use while on the transplant list was defined as a positive BAL, an admission of alcohol use, or refusal to perform screening within 12 hours of request. Cox proportional hazards regression was used to estimate risk ratios (RRs). Of 134 patients meeting eligibility criteria, 78% were male, and mean age was 52 years. Alcohol use was documented in 23 patients (17%). Of these, 12 refused to have a random screen, 8 had detectable serum ethanol levels, and 3 had self-reported alcohol use. On multivariable analysis, a higher number of random BAL-checks [RR = 0.63(0.52, 0.76), P = 0.001] and a longer duration of prelisting abstinence [RR = 0.88(0.83, 0.94), P = 0.001] independently reduced the risk of alcohol use by patients while on the waiting list. None of the patients with >24 months of prelisting abstinence had a positive screen. In conclusion, this study supports random BAL-screening before transplantation and reinforces the importance of abstinence duration as a predictor of relapse. For patients with <24 months of prelisting abstinence, our center will increase the frequency of random BAL screening and increase the rehabilitation requirements to include an intensive 3-week rehabilitation program. We hope that these measures will reduce the rate of relapse to alcohol use post-transplantation. Liver Transpl 16:91–97, 2010. © 2009 AASLD.
Alcoholic liver disease (ALD) is a leading indication for liver transplantation.1, 2 Because of the current donor organ shortage and the potentially harmful effects of posttransplant alcohol relapse on both organ donation3 and graft function,1, 2, 4, 5 minimization of alcohol relapse remains an important target. Several risk factors for alcohol relapse have been identified, including a shorter duration of pretransplant abstinence,6–8 a first-degree relative with alcoholism, poor compliance with medical care,9 increased alcohol consumption,10 and underage children.8 Most programs require at least 6 months of abstinence prior to activation on the transplant list.9 Despite this, reported rates of posttransplant alcohol use range from 11% to 33% in North America and have been quoted to be as high as 95% in Europe.4, 11–17 A recent study from our center identified a 13% rate of abusive or problem drinking post-transplant and, in these patients, a 10% rate of death due to posttransplant alcoholic hepatitis.18 The duration of pretransplant abstinence was the only independent predictor of posttransplant problem drinking in our series.18
In an attempt to minimize the number of patients at high risk for alcohol relapse who receive an allograft, our center has randomly checked blood alcohol levels (BALs) in ALD patients on the transplant waiting list since July 2004. BAL monitoring offers a unique opportunity to survey for high-risk behavior prior to transplantation and can therefore potentially reduce the rates of alcohol relapse post-transplantation. To our knowledge, data regarding the incidence and predictors of alcohol use by patients while on the waiting list are limited.
We hypothesized that a shorter duration of prelisting abstinence would be predictive of relapse by patients while on the waiting list. Accordingly, the objectives of this study were to identify the incidence and predictors of inactivation on the transplant waiting list due to alcohol use and to determine the utility of BAL screening in this process.
PATIENTS AND METHODS
After approval was obtained from the Health Research Ethics Board of the University of Alberta (#7500), a retrospective review of prospectively collected electronic patient health record data was conducted for patients with ALD over the age of 18 years who were waitlisted for a liver transplant at the University of Alberta Hospital (Edmonton, Canada). Data were collected from the start of BAL screening in July 2004 to December 31, 2008.
A diagnosis of ALD was based on consistent histological, laboratory, and clinical data. All patients included in the current study had one of the following: 1) major life area affected by alcohol use (finances, relationships, employment, legal issues, previous alcohol treatment or counseling, and alcohol use as a coping mechanism as adapted from the criteria of Diagnostic and Statistical Manual of Mental Disorders, 4th ed.) (93% of patients), 2) ALD as the only identified etiology of cirrhosis, or 3) a history of daily alcohol use greater than the recommended allowance (2 drinks per day for women and 4 drinks per day for men).19 One drink was estimated to equal 5 oz of wine, 12 oz of beer, or 1.5 oz of hard liquor. Patients were excluded if they did not have at least 1 random screening test performed before they were delisted, were transplanted, or died or if they did not have at least 3 months of follow-up. We required a minimum of 3 months of follow-up to allow a period of time for the detection of relapse back to alcohol use not picked up by the BAL screens.
All patients underwent a detailed pretransplant psychosocial evaluation and assessment by an alcohol rehabilitation program. As part of our program's routine policy, ALD patients listed for liver transplantation during this time were made aware that they would be subject to random alcohol screening and that refusing to take a random screening test within 12 hours of request was considered equivalent to having a positive result. Those who admitted to alcohol use without a positive screen were also counted as using alcohol while on the waiting list. Those with known episodes of encephalopathy had calls placed to a support person. All random screening calls were made by an independent individual not directly involved in the care of the patient or management of the transplant waitlist. The calls were made on average every 4 to 6 weeks; however, serial levels were occasionally obtained. If a patient was delisted, he had the possibility of being reconsidered for transplantation if a repeat 6-month period of abstinence was proved and rehabilitation was carried out. For the purposes of this study, however, all patients were included only once.
The primary exposure was the length of prelisting abstinence. This was defined as the time from the patient's last self-reported alcohol use, with corroboration by family if possible, until the date on which the patient was listed for transplantation. Prelisting abstinence is different from the more commonly examined variable, pretransplant abstinence, which refers to the time from last self-reported alcohol use until the date on which the patient undergoes transplantation. All other variables considered to be of potential importance for the prediction of alcohol use were selected a priori. A BAL screening was considered positive if the value was above the upper limit of detection in our laboratory (3 mmol/L); it was found either by random screening or on presentation to the emergency department. The total follow-up time for all patients was defined as the time between listing for liver transplantation and the development of an outcome while on the transplant list (alcohol use, delisting, death, or transplantation). For those patients not developing an outcome, their end of study follow-up was taken to be December 31, 2008. Posttransplant relapse to alcohol use was taken as any alcohol use in the posttransplant period.
Statistical analyses were performed with STATA version 8.1. Variable distributions were described with means and standard deviations. Cox proportional hazards regression was used to estimate risk (hazard) ratios (RRs) of predictors for alcohol use by patients while on the transplant waitlist. All variables with a P value of <0.05 on univariate modeling were introduced into the multivariable regression model. A P value of <0.05 was considered statistically significant.
Of the 243 patients with a referral diagnosis of ALD referred for liver transplant assessment during this study, 40 were never actively listed, 31 had no screens performed prior to developing a study endpoint (transplantation, death, or delisting), 28 did not meet our criteria for ALD diagnosis, 9 had less than 3 months of follow-up, and 1 did not consent to random alcohol screening.
Of the final group of 134 patients meeting the eligibility criteria, 78% were male; the mean age was 52.3 ± 6.8 years, and the mean prelisting Model for End-Stage Liver Disease score was 13.2 ± 5.5 (Table 1). Fifty-three percent (71/134) of the patients had a coexisting liver disease (59 had a hepatitis C virus infection, 3 had an alpha-1-antitrypsin deficiency, 3 had primary sclerosing cholangitis, 3 had primary biliary cirrhosis, 1 had hemochromatosis, 1 had autoimmune cirrhosis, and 1 had nonalcoholic fatty liver disease). Nineteen percent (26/134) had concurrent hepatocellular carcinoma. Fifty-eight percent of the patients were married or were in common-law relationships, and 81% were not working at the time of the transplant assessment. One quarter of our patients with children had a child less than 18 years of age. The mean follow-up for patients while on the transplant waitlist was 15.6 ± 11.4 months.
Table 1. Baseline Characteristics (n = 134 Unless Stated Otherwise)
|Age (years)||52.3 ± 6.8|
|53.0 (49.0, 56.0)|
|Male gender||104/134 (77.6%)|
|Child-Pugh class C||43/134 (32.1%)|
|MELD at assessment||13.2 ± 5.5|
|12.0 (10.0, 16.0)|
|Hepatitis C virus||59/134 (44.0%)|
|Hepatocellular carcinoma||26/134 (19.4%)|
|Financially independent or living off savings versus the need for government assistance||44/134 (32.8%)|
|Currently employed||25/134 (18.7%)|
|Marital status|| |
| Single||15/134 (11.2%)|
| Divorced/separated||42/134 (35.1%)|
| Married/common law||77/134 (57.5%)|
|Living with family versus living alone or with a friend||92/134 (68.7%)|
|Children < 18 years old||25/100 (25.0%)|
|Smoking history|| |
| Never||30/134 (22.4%)|
| Exsmoker||44/134 (32.8%)|
| Current smoker||60/134 (44.8%)|
|Street drugs (use ever)||56/134 (41.8%)|
|Depression (ever)||49/134 (36.6%)|
|Previous suicide attempt||10/134 (7.5%)|
|Prelisting Alcohol Use History|| |
|Daily alcohol intake as drinks per day (n = 124)*||12.6 ± 8.6|
|12.0 (6.0, 16.0)|
|Years of drinking before listing (n = 128)||25.6 ± 9.2|
|28.5 (20.0, 30.0)|
|Age at first drink < 15 years||26/104 (25.0%)|
|Prelisting abstinence||23.5 ± 36.5|
|10.0 (7.0, 20.3)|
|Reason for abstinence (medically encouraged versus self-initiated)||103/134 (76.9%)|
|Number of times that residential rehab was attended before listing (n = 133)||0.45 ± 0.87|
|0 (0, 1.0)|
|Number of relapses after a period of abstinence (n = 133)||0.61 ± 1.1|
|0 (0, 1.0)|
|Number of MLAs affected by alcohol intake (n = 124)||1.8 ± 1.2|
|1.2 (1.0, 2.0)|
|MLA: legal and DUI||39/124 (31.5%)|
|MLA: employment and finances||41/123 (33.3%)|
|MLA: relationships||57/124 (46.0%)|
|MLA: attended EtOH rehab||46/123 (37.4%)|
|MLA: EtOH coping||34/123 (27.6%)|
Prelisting Alcohol Use History
The mean prelisting abstinence period was 23.5 ± 36.5 months. As for the a priori alcohol use variables studied in this population, 25% of the patients had consumed their first drink of alcohol at less than 15 years of age, 37% had at least 1 relapse to alcohol use after a period of abstinence, and 34% had previously attended a residential alcohol rehabilitation program. The most common major life area affected by alcohol was relationships (46% of patients), and this was followed by legal issues (32%), employment and finances (31%), and use of alcohol as a method of coping (28%; Table 1).
Alcohol Use While on the Transplant Waiting List
Alcohol use was documented in 17% of the patients (23/134). Of these, 12 patients refused to have a random screening test performed, 4 had a serum ethanol level > 3 mmol/L on random screening, 4 had a serum ethanol level > 3 mmol/L on presentation to the emergency department, and 3 had self-reported alcohol use. The amount of time on the transplant waitlist at the time of detection of alcohol use ranged from a minimum of 3 months to a maximum of 23 months with a mean of 11.6 ± 6.6 months.
Predictors of Alcohol Use While on the Transplant Waiting List
Through univariate Cox proportional hazards modeling, the unadjusted relative risk of the identified variables was determined. In the univariate model, 3 predictors had unadjusted RRs with P values < 0.05: the number of random BAL tests performed, the number of months of prelisting abstinence, and the number of times that a patient had attended a residential rehabilitation program (Table 2).
Table 2. Univariate Analysis for Predictors of Alcohol Use While on the Transplant Waiting List
|Age||0.98 (0.92, 1.04)||0.44|
|Male gender||1.90 (0.56, 6.44)||0.30|
|Child-Pugh class C||1.38 (0.53, 3.56)||0.51|
|MELD at assessment||0.95 (0.85,1.05)||0.32|
|Hepatitis C virus infection||0.82 (0.35, 1.93)||0.65|
|Hepatocellular carcinoma||1.79 (0.73, 4.39)||0.20|
|Financially independent or living off savings versus the need for government assistance||1.71 (0.75,3.88)||0.20|
|Currently employed||1.88 (0.79, 4.47)||0.16|
|Marital status|| || |
| Divorced/separated||1.03 (0.22, 4.91)||0.90|
| Married/common law||1.10 (0.25, 4.89)|| |
|Living with family versus living alone or with a friend||0.86 (0.36, 2.04)||0.73|
|Children||2.36 (0.70, 7.95)||0.17|
|Children < 18 years old (n = 100)||0.94 (0.37, 2.52)||0.94|
|Smoking history|| || |
| Exsmoker||0.36 (0.09, 1.45)||0.74|
| Current smoker||1.18 (0.45, 3.06)|| |
|Street drugs (use ever)||1.13 (0.45, 2.58)||0.76|
|Depression (ever)||1.10 (0.46, 2.63)||0.83|
|Suicide attempt (ever)||0.84 (0.20, 3.60)||0.81|
|Daily alcohol intake (continuous)||1.0 (0.96, 1.06)||0.81|
|Years of drinking before listing||1.03 (0.98, 1.09)||0.20|
|Age at first drink < 15 years||1.58 (0.62, 4.03)||0.34|
|Prelisting abstinence (months)||0.92 (0.85, 0.995)||0.04|
|Reason for abstinence (medically encouraged versus self-initiated)||1.57 (0.54, 4.63)||0.41|
|Number of times that residential rehab was attended (continuous)||1.42 (1.03, 1.97)||0.04|
|Number of relapses after abstinence (continuous)||1.30 (0.98, 1.72)||0.071|
|Number of MLAs affected (continuous)||1.21 (0.87, 1.68)||0.27|
|MLA: legal and DUI||1.50 (0.64, 3.50)||0.36|
|MLA: employment and finances||1.29 (0.55, 3.04)||0.55|
|MLA: relationships||2.04 (0.85, 4.87)||0.11|
|MLA: attended EtOH rehab||1.13 (0.47,2.68)||0.79|
|MLA: EtOH coping||0.87 (0.34, 2.23)||0.77|
|Number of random blood alcohol levels||0.81 (0.75, 0.88)||0.001|
Two variables remained statistically significant in the multivariable model (Table 3). First, the number of random BAL checks performed remained significant, with a 37% reduction in the rate of positive alcohol screening for each level drawn [RR = 0.63 (0.52, 0.76), P = 0.001]. Second, for each month of prelisting abstinence, there was a 12% reduction in the rate of positive alcohol screening [RR = 0.88 (0.83, 0.94), P = 0.001]. The proportion of patients with a positive screen decreased with increasing abstinence, and none of the patients with >24 months of abstinence before listing used alcohol while on the waiting list (Table 4).
Table 3. Multivariable Analysis for Predictors of Alcohol Use While on the Transplant Waiting List
|Abstinence (months)||0.88 (0.83, 0.94)||0.001|
|Number of levels drawn||0.63 (0.52, 0.76)||0.001|
|Number of times that residential rehab was attended||1.21 (0.81, 1.84)||0.35|
Table 4. Increased Risk of Alcohol Use While on the Transplant Waiting List with a Shorter Duration of Prelisting Abstinence
|EtOH screen||Negative||3 (60%)||53 (79.1%)||16 (76.2%)||16 (88.9%)||23 (100%)|
|Positive||2 (40%)||14 (20.9%)||5 (23.8%)||2 (11.1%)||0 (0%)|
Seventeen percent of the patients (23/134) in this study were removed from the transplant waitlist because of alcohol use. Nine of these patients were relisted for transplantation after proving 6 months of abstinence again and undergoing residential alcohol rehabilitation. Of these 9 patients, 4 underwent transplantation and have not relapsed post-transplant, 3 were again delisted for alcohol use, and 2 died on the waiting list. The remaining 14 patients who were initially delisted were never relisted (7 had ongoing alcohol use or refused to attend alcohol rehabilitation, 3 died, 2 developed hepatocellular carcinoma outside the transplant criteria, 1 had psychiatric contraindications, and 1 did well with a transjugular intrahepatic portosystemic shunt and no longer required transplantation).
Of the patients who were not delisted, 7.5% (10/134) died on the waiting list. Thirty-eight percent (51/134) went on to receive a liver transplant during the study follow-up period. Of those patients who underwent transplantation, 11.8% (6/51) had a documented relapse back to alcohol use. In these 6 patients, 1 had 26 months of prelisting abstinence, 1 had 24 months, and the remaining 4 had <10 months of abstinence. The mean follow-up time post-transplant was 22.9 ± 12.6 months.
In most transplant centers across North America, the risk of relapse back to alcohol use weighs heavily in the decision about whether or not a patient with ALD should be listed for a transplant. This need for rationalization of donor organs stems in large part from the disparity between the transplant waitlist and donation rates, the potential for harm to the hepatic allograft with posttransplant alcohol use, and the negative public opinion associated with alcohol relapse in a liver transplant recipient. With the use of random BAL measurements, the current study demonstrates a substantial pretransplant delisting rate of 17%. Although it strengthens the association between abstinence duration and the likelihood of relapse to alcohol use, it also demonstrates a strong association between prelisting abstinence and alcohol use while patients are on the waiting list.
The use of BAL has been described for the routine screening of nontransplant patients after alcohol rehabilitation20 and for the surveillance of ALD patients after liver transplantation.7 To our knowledge, published data for the pretransplant population are limited to a single study in which the alcohol relapse group of 4 patients was too small to be analyzed independently of patients delisted for alternate reasons.21 The use of random BAL monitoring was introduced into our transplant program in July 2004 in an attempt to identify high-risk patients not detected in the screening and selection process. Since the initiation of random BAL screening, the rates of delisting due to alcohol use have increased from 5% (6/115; January 1, 2000 to June 30, 2004) to 17% (23/134; July 1, 2004 to December 31, 2008). The delisting rate of 17% is higher than we expected, given that each potential recipient is subjected to a detailed psychosocial evaluation, an assessment by an alcohol rehabilitation program, and multiple follow-up visits by a transplant hepatologist from our program. Any concerns regarding risk of relapse are brought up prior to listing at our multidisciplinary transplant group meeting. Interestingly, however, the 17% rate of pretransplant alcohol use is within the range of previous estimates of posttransplant recidivism and therefore may just be a reflection of the natural history of alcoholism and its associated risk for relapse. Moreover, as the BAL sampling was random, it is possible that the rate of 17% may even be an underestimation.
In our series of patients, a higher number of BAL measurements was predictive of a lower rate of alcohol use by patients while on the transplant waiting list. Initially, we thought that this could be related to increased time on the waitlist and thus increased months of pretransplant abstinence; however, it remained significant even after we accounted for time with Cox proportional hazards modeling. The reason behind this association, therefore, remains unclear. It is possible that more frequent testing offers little opportunity for the patients to “put their guard down,” so they may have an increased fear of being caught and potentially may reflect more on their accountability to the transplant program. Although we found no studies assessing the impact of BAL screening on alcohol use by patients while on the transplant waiting list, a recent Cochrane review assessing the effectiveness of Alcoholics Anonymous and other counseling methods in the general population found that any intervention at all was found to be of at least some benefit.22 Therefore, it is possible that BAL screening as a form of intervention may assist with ongoing abstinence by patients while on the waitlist.
Prelisting abstinence was identified as a second independent predictor of a positive BAL. For each additional month of prelisting abstinence, there was a 12% reduction in the rate of a positive alcohol screen. Although the data regarding the utility of pretransplant abstinence with respect to the rates of posttransplant relapse have been inconsistent, pretransplant abstinence was the only independent predictor of problem drinking in a recent study from our center.18 The association between pretransplant abstinence and posttransplant relapse has been confirmed at other sites as well.7, 8 The current study substantiates the importance of the duration of pretransplant abstinence by confirming its correlation with pretransplant alcohol relapse. Although a shorter duration of abstinence was not necessarily associated with alcohol use in all patients, none of the patients with more than 24 months of prelisting sobriety were delisted for a positive BAL.
We note several study limitations. In order to meet the inclusion criteria, patients were required to have at least 1 random alcohol screening test performed. This limited the population to those well enough to be out of the hospital; this was reflected by the mean Model for End-Stage Liver Disease score of 13. Nevertheless, this was certainly the population of interest for screening. Although the program screening policy indicated that random calls were to be made approximately every 6 weeks, there was considerable variation in the frequency of screening. This was related to social variables that prevented patient contact (such as limited phone access) or local laboratory availability (for patients from remote centers) and may have introduced bias into the results. Of the 8 patients with elevated BALs, 3 had levels ranging from 6 to 8 mmol/L, and the remaining 5 had levels ranging from 18 to 39 mmol/L. Elevated BALs in cirrhosis have been case-reported with the use of nonalcoholic 0.5% beer23; however, this was not the situation for any of the patients in this group who had a positive BAL. Furthermore, as a refusal to submit to a BAL screening accounted for 52% of those patients (12/23) who were delisted, the study may be criticized for considering refusal as equivalent to a detectable alcohol level. We feel that this measure was justified as the patients were well informed (oral and written communication with patient and family) about the ramifications of missing a test, they were given 12 hours in which to act, and lastly, without this consequence, the BAL testing program would be rendered impotent because patients could then choose to go for testing only when they had not been drinking. We recognize therefore that this study identifies predictors of inactivation on the transplant waiting list due to presumed and not definite alcohol use. For ease of discussion, the term alcohol use has been used instead of presumed alcohol use. Lastly, as in all retrospective chart reviews, there was the potential for missing data and recall bias. Attempts were made to minimize bias by the data being obtained from the same sections of the patient charts by 1 investigator. The investigator was blinded to the alcohol screen result while collecting the variable data.
In conclusion, this study provides strong data for the utility of random BAL screening before transplantation and reinforces the importance of abstinence duration as a predictor of relapse to alcohol use. Given the data from this study, our center will increase the frequency of random BAL screening, particularly in patients with less than 24 months of prelisting abstinence. Furthermore, we have increased the rehabilitation requirements for patients with less than 24 months of prelisting abstinence to include an intensive 3-week rehabilitation program. We hope that these measures will ultimately result in a decreased rate of relapse to alcohol use post-transplantation.