Risk Factors, Scoring Systems, and Interventions for Alcohol Relapse After Liver Transplantation for Alcoholic Liver Disease

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1 REVIEW Risk Factors, Scoring Systems, and Interventions for Alcohol Relapse After Liver Transplantation for Alcoholic Liver Disease Jane Lim, M.D.,* and Vinay Sundaram, M.D., M.Sc. Alcoholic liver disease (ALD) is the second most common indication for liver transplantation (LT) in the United States. 1 Transplantation for ALD can be controversial, partially because of concerns regarding alcohol relapse. 1 In patients with ALD, rates of post-lt drinking approach 50%, with 20% of recipients returning to harmful drinking. 2 Although overall survival rates posttransplantation for ALD are comparable with non-ald, 1,3 clinical outcomes for those with slips are different from those who return to harmful drinking. A slip is defined as consumption of a limited amount of alcohol, followed by immediate procedures to reestablish abstinence, whereas harmful drinking is defined as consumption of four or more drinks in 1 day or drinking for 4 or more days consecutively. 1 Occasional slips are not associated with graft loss or reduced overall survival, 1,4 but harmful drinking can increase risk for advanced allograft fibrosis, graft loss, recurrent alcoholic cirrhosis, and reduced survival. 4,5 Therefore, it is essential to identify factors associated with alcohol relapse, evaluate scoring systems for predicting relapse, and establish interventions to reduce the risk for relapse after transplantation. RISK FACTORS Several patient risk factors have been associated with alcohol relapse after transplantation (Table 1). Duration of abstinence is often an important consideration for transplant listing. 1,6 However, although certain transplant centers require a minimum of 6 months of abstinence to be listed for LT, there are conflicting findings whether this duration of sobriety predicts a lower risk for relapse. 3,6,7 Therefore, the Abbreviations: AA, Alcoholics Anonymous; ALD, alcoholic liver disease; ARRA, Alcohol Relapse Risk Assessment; HRAR, High-Risk Alcoholism Relapse scale; LT, liver transplantation; MAPS, University of Michigan Alcoholism Prognosis Score; MET, motivational enhancement therapy; RCT, randomized controlled trial; SIPAT, Stanford Integrated Psychosocial Assessment for Transplant. From the *Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, and Division of Gastroenterology and Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA. Potential conflict of interest: Nothing to report. Received 1 September 2017; accepted 8 January 2018 View this article online at wileyonlinelibrary.com VC 2018 by the American Association for the Study of Liver Diseases 105 CLINICAL LIVER DISEASE, VOL 11, NO 5, MAY 2018 An Official Learning Resource of AASLD

2 TABLE 1. RISK FACTORS FOR ALCOHOL RELAPSE AFTER LIVER TRANSPLANTATION Lack of social support 3,8 Comorbid psychiatric condition 6,9 Cigarette smoking 8 Noncompliance 9 6-month rule is not a reliable predictor of post-lt sobriety. Strong social support, such as a life companion or a support system of friends or family, is protective against drinking post-lt. 8 Comorbid psychiatric illnesses including anxiety, depression, and personality disorders are associated with a higher risk for relapse. 6,9 In addition, cigarette smoking at time of LT evaluation was shown to be an independent predictor of alcohol use post-lt. 8 Lastly, pretransplant noncompliance is strongly associated with an increased risk for relapse. 9 In one prospective study, 75% of LT recipients with a single missed clinic appointment without notification, missed medication dose, or missed refill of prescriptions relapsed to drinking post-lt. 9 ALCOHOL RELAPSE SCORING SYSTEMS Several scoring systems have been proposed to predict posttransplant alcohol relapse (Table 2). The High Risk Alcoholism Relapse scale (HRAR) assesses three variables: duration of heavy drinking, number of drinks per day, and number of prior alcoholism inpatient treatment experiences 10 (Table 1). A few studies have evaluated the association between the HRAR score and post-lt alcohol relapse. In a prospective trial, an HRAR score 4 was associated with an increased risk for harmful drinking post-lt. 6 Another retrospective study, however, did not find an association between HRAR score and alcohol use post-lt, although the study had limitations regarding sample size and generalizability of the study population. 11 Therefore, further prospective studies are needed to validate the HRAR. The Alcohol Relapse Risk Assessment (ARRA) assesses nine factors that were associated with post-lt alcohol use in a single-center retrospective study. 8 Patients are categorized into four groups based on total number of points. Patients in groups ARRA III (4-6 points) and ARRA IV (7-9 points) had significantly higher rates of alcohol relapse. 8 The ARRA scale has not been validated by other studies. The Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) is a comprehensive tool that was developed to standardize pretransplant psychosocial evaluations. 12 It has not been validated for predicting post-lt alcohol relapse, but it was found to be associated with increased rejection episodes, hospitalizations, infection rates, and psychiatric decompensations in a prospective study of heart, lung, liver, and kidney transplant recipients. 12 The SIPAT may be a promising tool, and further prospective trials are needed to study its association with alcohol relapse. Lastly, the University of Michigan Alcoholism Prognosis Score (MAPS) was developed to stratify potential transplant candidates into low- and high-risk categories for alcohol relapse. 13 It evaluates insight into alcoholism, social stability, and presence of factors that suggest a favorable sobriety prognosis. However, a single-center retrospective study found that there was no significant association between pre- LT MAPS and alcohol use post-lt. 14 INTERVENTIONS TO PREVENT RELAPSE Few studies have evaluated specific psychosocial interventions to prevent alcohol relapse after LT. A randomized controlled trial (RCT) found that pre-lt motivational enhancement therapy (MET) combined with encouragement to attend Alcoholics Anonymous (AA) and case management meetings reduced drinks per day in the pretransplant period compared with treatment as usual, which included referral for intensive outpatient therapy and AA or Narcotics Anonymous. The impact of MET on post-lt relapse was not determined because of the small number of patients who underwent LT. 15 Being followed by an addiction psychiatrist integrated within the liver transplant center may also significantly lower rates of relapse. 7 Participating in a structured addiction program before and after LT may reduce the risk for relapse by more than 50%. 3 In regard to pharmacological interventions, baclofen is the only medication that has been studied in patients with alcoholic cirrhosis, and none has been studied after LT. 16 In an RCT of 84 patients with alcohol dependence and cirrhosis, baclofen significantly improved abstinence and reduced relapse compared with placebo. 16 Disulfiram and naltrexone are approved for alcohol dependence but carry a risk for hepatotoxicity. 17 Topiramate and ondansetron are also promising agents due to reduced risk for hepatotoxicity, but they have not been studied in patients with advanced liver disease. 17 Although no standardized psychosocial or pharmacological interventions are part of the LT protocol, the American Association for the Study of Liver Diseases 106 CLINICAL LIVER DISEASE, VOL 11, NO 5, MAY 2018 An Official Learning Resource of AASLD

3 TABLE 2. SCORING SYSTEMS TO PREDICT ALCOHOL RELAPSE AFTER LIVER TRANSPLANTATION FOR ALCOHOLIC LIVER DISEASE Scoring Scale Scoring System Risk Factors Points Interpretation Validation HRAR Duration of heavy drinking (years) Total score range: 0-6 One prospective study found that a HRAR score <11 0 Score Group 4 is independently associated with harmful <4 Low-risk alcoholism risk drinking post-lt 6 > High-risk alcoholism risk No. of drinks per day One retrospective study did not find the HRAR to <9 0 be associated with alcohol use post-lt >17 2 No. of prior alcoholism inpatient treatment experiences >1 2 ARRA 1. Absence of hepatocellular carcinoma 1 Total score range: 0-9 One retrospective study found that groups ARRA 2. Tobacco dependence 1 Score Group III and IV had significantly greater rates of 3. Continued alcohol use after liver disease 1 0 ARRA I post-lt alcohol use 8 : diagnosis ARRA I: 0% 4. Low motivation for alcohol treatment ARRA II ARRA II: 8% 5. Poor stress management skills ARRA III ARRA III: 57% 6. Lack of rehabilitation ARRA IV ARRA IV: 75% 7. Limited social support 1 8. Lack of nonmedical behavioral consequences 1 9. Engagement in social activities with alcohol 1 SIPAT Patient s readiness level and illness Total score range: One prospective study found that higher management pre-lt SIPAT scores were associated with 1. Knowledge and understanding of medical 0-4 Score Interpretation increased rejection episodes, hospitalizations, illness process infection rates, and psychiatric 2. Knowledge and understanding of the process of Excellent candidate decompensations 12 transplantation 3. Willingness/desire for treatment (transplant) Good candidate 4. History of treatment adherence/compliance Minimally acceptable candidate 5. Lifestyle factors Poor candidate 107 CLINICAL LIVER DISEASE, VOL 11, NO 5, MAY 2018 An Official Learning Resource of AASLD

4 TABLE 2. CONTINUED Scoring Scale Scoring System Risk Factors Points Interpretation Validation Social support system level of readiness >70 High-risk candidate 1. Availability of social support system Functionality of social support system Appropriateness of physical living space and 0-4 environment Psychological stability and psychopathology 1. Presence of psychopathology (other than 0-8 personality disorders and organic psychopathology) a. Assessment of depression 0-3 b. Assessment of anxiety History of organic psychopathology or 0-5 neurocognitive impairment a. Assessment of current cognitive functioning Influence of personality traits versus disorder Effect of truthfulness versus deceptive 0-8 behavior 5. Overall risk for psychopathology 0-4 Lifestyle and effect of substance use 1. Alcohol use, abuse, and dependence Alcohol abuse: risk for recidivism Substance use/abuse/dependence Substance abuse/abuse/dependence: 0-4 risk for recidivism 5. Nicotine use/abuse/dependence 0-5 MAPS Acceptance of alcoholism Total score range: 5-20 One retrospective study found no association between the MAPS and post-lt relapse Patient and family 4 Higher score indicates reduced risk for relapse 2. Patient only 3 3. Family only 2 4. Neither CLINICAL LIVER DISEASE, VOL 11, NO 5, MAY 2018 An Official Learning Resource of AASLD

5 TABLE 2. CONTINUED Scoring Scale Scoring System Risk Factors Points Interpretation Validation Prognostic indices 1. Substitute activities 2. Behavioral consequences 3. Hope/Self-esteem 4. Social relationship Social stability 1. Steady job 1 2. Stable residence 1 3. Does not live alone 1 4. Stable marriage CLINICAL LIVER DISEASE, VOL 11, NO 5, MAY 2018 An Official Learning Resource of AASLD

6 guidelines for LT evaluation recommend early referral of patients with ALD to a transplant center to initiate psychosocial assessment and addiction treatment goals. Patients with ALD should ideally be evaluated by clinicians skilled in mental health and addiction experience. 18 CONCLUSION Identifying patient factors that are associated with alcohol relapse and establishing interventions to prevent relapse are important for improving outcomes in patients who underwent transplant for ALD. Although length of sobriety has an uncertain association with relapse risk, poor social support, psychiatric comorbidities, tobacco use, and noncompliance are all associated with increased risk for alcohol relapse. Scoring systems have been proposed to predict risk for alcohol relapse after LT, but validation studies are lacking. In addition, pharmacological interventions are limited for this population. Therefore, psychosocial interventions are the cornerstone for relapse prevention. There are a limited number of studies for specific psychosocial interventions; however, pre-lt MET was more effective than treatment as usual for reducing drinking in the pre-lt period. Pre- and post-lt structured addition management was associated with reduced alcohol relapse after LT. Lastly, follow-up with an addiction psychiatrist integrated within the transplant center was more efficacious than those not affiliated with a liver transplant center. CORRESPONDENCE Jane Lim, M.D., Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA jane.lim@cshs. org REFERENCES 1) Lucey MR. Liver transplantation in patients with alcoholic liver disease. Liver Transpl 2011;17: ) DiMartiniA,DayN,DewMA,JavedL,FitzgeraldMG,JainA,etal.Alcohol consumption patterns and predictors of use following liver transplantation for alcoholic liver disease. Liver Transpl 2006;12: ) Bjornsson E, Olsson J, Rydell A, Fredriksson K, Eriksson C, Sjoberg C, et al. 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