INTRODUCTION — Historically, physicians were reluctant to offer liver transplantation to patients with alcohol-associated liver disease. However, in appropriately selected patients, it is clear that transplantation offers an excellent survival advantage similar to that for other disease indications. Prior reluctance stemmed from the perception that the disease was self-inflicted and from concern regarding the risk of alcohol-related damage to sites outside the liver [1,2]. There was also concern that relapse and medication noncompliance would lead to graft failure.
Alcohol-associated cirrhosis was responsible for 21 percent of all orthotopic liver transplants in 2015 in the United States, according to the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients (OPTN/SRTR) report . Liver transplantation appears to be cost-effective for alcohol-associated liver disease, albeit possibly less so than for transplantation for some indications such as primary biliary cholangitis and primary sclerosing cholangitis [1,4,5].
The COVID-19 pandemic has led to an increase in both alcohol-associated liver disease as well as a 50 percent increase in waiting list registrations for liver transplantation [6-8]. The underlying reasons are not clear, but could reflect an increase in alcohol use, worsening of liver disease due to COVID-19, and/or increasing awareness and availability of liver transplantation for alcohol-associated liver disease.
This topic will review liver transplantation for alcohol-associated liver disease. The diagnosis and treatment of alcohol use disorder and the pathogenesis, diagnosis, and treatment of alcohol-associated liver disease are discussed separately.
The allocation of donor livers by the Model for End-stage Liver disease (MELD) is also discussed separately. (See "Model for End-stage Liver Disease (MELD)".)
DEFINING ALCOHOL USE AFTER TRANSPLANTATION — While abstinence is the expectation both before and after liver transplantation, there is a range of patterns of alcohol use. Quantification of alcohol consumption after liver transplantation is not standardized, although several terms are used to describe alcohol use:
●Abstinence – No alcohol use.
●Slips – Occasional consumption of limited amounts of alcohol with immediate measures to re-establish abstinence .
●Harmful and excessive drinking – Referred to as relapses and defined as more than 40 g alcohol per day; four or more drinks in one day; or drinking for at least four consecutive days [9,10].
The Diagnostic and Statistical Manual of Mental Disorders Version V (DSM-5) criteria for the diagnosis of alcohol use disorder are discussed separately. (See "Risky drinking and alcohol use disorder: Epidemiology, clinical features, adverse consequences, screening, and assessment", section on 'Diagnosis'.)
Timing of referral — Early referral for transplantation is an important determinant of success, and we recommend that patients with alcohol-associated liver disease who are transplant candidates are referred for transplantation evaluation. With progressively longer waiting times until a suitable donor liver is available, delayed referral may prevent the patient from surviving the evaluation and waiting period [11,12].
The presence of cirrhosis alone is not sufficient to warrant transplantation. Transplantation is generally considered when a patient has suffered either a complication of portal hypertension or a manifestation of compromised hepatic function. The indications for liver transplantation are discussed separately. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation", section on 'Indications'.)
Early referral for liver transplantation is not always accomplished, in part because of active drinking or a perception among referring clinicians that liver transplantation is not a viable option. However, it is unclear how often patients who are transplant candidates are not being referred for evaluation . In a study of nearly 200 potential liver transplantation candidates according to the American Association for the study of Liver Diseases (AASLD) guidelines, patients with alcohol-associated liver disease were less likely to receive counseling regarding liver transplantation compared with patients with cirrhosis of another etiology (OR 0.10, 95% CI 0.02-0.57) . In this cohort, 41 patients with cirrhosis (21 percent) were referred for transplant evaluation and the most common reason for not referring patients was active alcohol use.
Overall risk of alcohol relapse — In appropriately selected patients, the alcohol relapse rate after transplantation generally ranges from 10 to 30 percent [14-20]. In two studies of over 600 patients, 5 percent of patients resumed excessive drinking [21,22]. However, there are conflicting data on whether such patients can be identified with accuracy in advance.
Two groups have proposed multivariate models to better predict alcohol relapse after transplant, incorporating readily definable behaviors and psychosocial factors [10,23]. Further studies are needed to establish their validity.
Risk factors for alcohol relapse — There are several patient-related factors that affect the likelihood that alcohol use will be resumed following transplantation:
●Social factors – Lack of social support is a risk factor for alcohol relapse [15,16,23,24].
●Psychiatric disorder – Current or previous psychiatric illness is a risk factor for alcohol relapse after liver transplantation; assessment for comorbid psychiatric condition may help identify at-risk patients [10,23-25].
In a study of 387 patients who underwent liver transplantation for alcohol-associated liver disease, patients with psychiatric illness (ie, anxiety or depressive disorder) were more likely to resume harmful alcohol use (ie, >40 g per day) after transplantation (OR 7.8, 95% CI 3.1-20) .
●Family history of alcohol dependence – Family history of alcohol dependence correlated with risk of alcohol relapse in one meta-analysis, but the strength of the correlation was modest .
●Noncompliance – In a study of 195 patients with alcohol-associated liver disease who underwent liver transplantation, noncompliance with office visits after transplantation was a nonsignificant risk factor for alcohol relapse (OR 4.36, 95% 0.92-15.43) [26,27].
●Hepatitis C virus infection – Liver disease due to both alcohol and hepatitis C virus (HCV) infection is not uncommon, but the presence of HCV does not result in greater risk of alcohol relapse following transplantation. In a study of 167 post-transplant patients with a history of either alcohol-associated liver disease alone or HCV and alcohol-associated liver disease, there was no significant difference in alcohol relapse rates (18 versus 8 percent) .
●Younger age – Younger age is not consistently associated with a higher rate of alcohol relapse [14,15,20,29].
●Duration of abstinence pre-transplant – Longer periods of abstinence pre-transplant appear to be associated with lower risks of alcohol relapse. (See 'Pre-transplant abstinence and monitoring' below.)
A score incorporating several factors (age at liver transplantation, nonalcohol-related criminal history, pre-transplantation alcohol abstinence, and number of drinks per day) has been developed and has shown promise for identifying patients at increased risk for alcohol relapse .
Pre-transplant abstinence and monitoring
Six-month rule — Six months of abstinence is still a requirement prior to placement on the transplantation waiting list at many programs for two reasons :
●To identify patients who are at risk for relapse
●To allow time for liver recovery from ongoing alcohol-related injury
The six-month rule affects the eligibility of patients with alcohol-associated liver disease for transplantation. Some transplantation programs and society guidelines suggest that no absolute interval of abstinence is required because some patients who are otherwise suitable candidates will not survive a period of six months. (See 'Patients with severe alcohol-associated hepatitis (AH)' below.)
Based on the available studies, it is increasingly less certain that the six-month abstinence requirement significantly reduces the rate of relapse after transplantation or improves outcomes [10,14,23,32,33]. While the six-month abstinence requirement is somewhat arbitrary, some [10,32,34] but not all [14,23,33] studies have found that longer duration of abstinence before transplant is associated with lower alcohol relapse rates after transplant. For example, in one study, for every month of pre-transplantation abstinence, there was a 5 percent decrease in the adjusted relapse rate . However, in a cohort study comparing earlier liver transplant (ie, <6 months) with standard transplant (ie, adherence to the six-month rule), there were no significant differences in rates of patient survival, graft survival, and relapse-free survival between groups .
An additional consideration is that patient-reported alcohol use may not be accurate. In a study of 40 patients with alcohol-associated liver disease who were referred for liver transplant evaluation, urine toxicological screening was positive for any substance in 15 patients (38 percent) and for alcohol in eight patients (20 percent) . However, only 3 percent of the patients admitted to using alcohol.
Alcohol treatment program — In addition to adhering to the six-month rule, some transplant centers require that patients enroll in a substance abuse treatment program such as Alcoholics Anonymous. In a study of 118 patients who underwent liver transplantation, participation in a substance disorder treatment program both before and after liver transplantation lowered the post-transplant alcohol relapse rate compared with those who only participated in a treatment program before transplant or those who received no treatment (16 percent versus 45 and 41 percent, respectively) .
Monitoring for alcohol use — We monitor patients with alcohol-associated liver disease for alcohol use both prior to and following liver transplantation by clinical interview and by testing of urine ethyl glucuronide (uEtG) during outpatient visits and randomly, if needed. Urine ethyl glucuronide can be detected for up to 80 hours after complete ethanol elimination from the body and after consumption of less than 5 g of ethanol, and has low false positive rates [38,39]. In one study of 121 patients with alcohol-associated liver disease who were either candidates for or recipients of liver transplantation, alcohol consumption was detected by clinical interview (using a validated screening tool) or by patient response to abnormal tests (ie, urine or blood markers of alcohol use) in 31 percent of patients . Urine ethyl glucuronide was the strongest marker of alcohol consumption (OR 415, 95% CI 51 to >1000).
Additional methods for monitoring patients for alcohol use include assessment of blood or breathalyzer alcohol levels [41-43]. The available data suggest that the serum marker phosphatidylethanol is more sensitive for detecting chronic alcohol use compared with other blood tests (eg, carbohydrate deficient transferrin) [44,45].
Some centers randomly check blood alcohol levels in patients on the transplant waiting list. In a study of 134 such patients in whom alcohol use was defined as a positive blood alcohol level, self-reported alcohol use or refusal to check a blood alcohol level within 12 hours of the request, alcohol use was less likely in patients with a higher number of random blood alcohol level checks (RR 0.63, 95% CI 0.52-0.76) and with a longer duration of prelisting abstinence (RR 0.88, 95% 0.83-0.94) . This study did not address whether this practice reduced post-transplant alcohol relapse.
Carbohydrate deficient transferrin is a laboratory test that is elevated in the setting of sustained heavy alcohol use (ie, six standard drinks for two weeks or more), but it can also be elevated in patients with advanced liver disease who are abstinent. Thus, carbohydrate deficient transferrin levels should be interpreted with caution. (See "Risky drinking and alcohol use disorder: Epidemiology, clinical features, adverse consequences, screening, and assessment", section on 'Laboratory evaluation'.)
Smoking cessation — Smoking remains an independent and significant risk factor for post-transplant morbidity and mortality [47,48]. Long-term follow-up of patients who have undergone liver transplantation for alcohol-associated liver disease has shown an increased rate of lung, liver, and oropharyngeal cancer compared to patients transplanted for other indications [49,50]. It is likely that this association is due to the relatively high prevalence of smoking in this population combined with the impact of immunosuppression on tumor surveillance. Moreover, long-term morbidity and mortality are also linked to continued smoking, which accelerates cardiovascular and cancer risk .
Increasing emphasis or insistence on enrollment of patients into smoking cessation programs has been advocated to reduce morbidity post-transplantation [51,52]. (See "Overview of smoking cessation management in adults".)
Some authorities have advocated removing patients from the transplant waiting list who continue to smoke despite these interventions. Roughly 20 percent of transplant centers report that they will refuse to list patients due to smoking . One report found that up to 40 percent of patients who had undergone transplantation for alcohol-associated liver disease resumed smoking early in the post-transplant course, underscoring the need for continued counseling and monitoring after transplantation .
Other goals of pre-transplant evaluation — The goal of the pre-transplantation evaluation is to assess the patient's ability to tolerate the stress of surgery, immunosuppression, and the demands of post-transplantation care. The details of the extensive cardiopulmonary, psychosocial and screening evaluation are discussed separately. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation", section on 'Pretransplantation evaluation'.)
PATIENTS WITH SEVERE ALCOHOL-ASSOCIATED HEPATITIS (AH) — Liver transplantation may be the only treatment option for patients with severe AH who do not respond to glucocorticoids, and transplantation has been lifesaving for some patients [55-57]. The number of patients undergoing liver transplantation for acute AH has been steadily increasing in the United States, with marked geographic variation because a limited number of centers perform transplantation for this indication [8,55,58,59]. Patients who are transplanted for AH are generally younger, have higher MELD scores, and are more frequently on renal dialysis compared with patients transplanted for other indications . (See "Management and prognosis of alcoholic hepatitis", section on 'Liver transplantation'.)
It has been suggested that the six-month period of abstinence be reconsidered in patients with severe AH and that methods to identify risk factors for alcohol relapse are needed . While recurrent harmful alcohol use is associated with post-transplant morbidity, the risk for alcohol relapse is not well defined and may be similar to patients who complete a six-month period of abstinence prior to transplantation .
At most transplant centers, criteria for selecting patients with AH require that there is no prior history of liver decompensation because prior decompensation has been associated with higher risk of mortality and alcohol relapse [62,63]. In a study including 241 patients who underwent liver transplantation for severe AH, patients with a prior history of decompensation had higher risk of mortality and harmful alcohol use after transplantation compared with no prior decompensation (adjusted hazard ratio [aHR] 2.72, 95% CI 1.61-4.59 and aHR 1.77, 95% CI 1.07-2.94, respectively) . However, rates of overall survival at one and three years among patients with prior decompensation were good (86 and 78 percent, respectively). Criteria for patient selection remain highly variable among centers, and additional studies with long-term follow-up are needed to optimize criteria for liver transplantation.
In general, patients who have AH are infrequently transplanted because the diagnosis of AH implies recent harmful alcohol use and because some patients will improve without transplantation. In principle, the chronic inflammatory state associated with AH has the potential to increase perioperative complications, although most studies found that long-term morbidity is related primarily to recurrent alcohol use disorder rather than acute complications of transplantation [5,10,15,64]. (See "Alcoholic hepatitis: Clinical manifestations and diagnosis".)
Management — The general management of patients following liver transplantation including the approach to immunosuppression and its complications, preventative medicine, and diagnosis and treatment of acute cellular rejection are discussed separately:
Mortality and graft survival — Short term patient and graft survival rates following liver transplantation for alcohol-associated liver disease are similar to rates following transplantation for nonalcohol-related diagnoses; however, the 10-year patient and graft survival rates are lower for patients with alcohol-associated liver disease [65-68]. In a cohort study of the United Network of Organ Sharing database including 9438 patients with alcohol-associated liver disease who were transplanted, the following outcomes were reported :
●Patient survival – Patient survival rates at one year and at five years were similar for patients with alcohol-associated liver disease compared with patients with nonalcohol-associated disease (one year: 91 versus 90 percent; five years: 79 versus 80 percent). However, patient survival rates at 10 years were lower for patients with alcohol-associated liver disease compared with those with a nonalcohol-related diagnosis (63 versus 68 percent).
●Graft survival – Graft survival rates at one and at five years were similar for patients with alcohol-associated liver disease compared with patients with nonalcohol-associated disease (one year: 91 versus 89 percent; five years: 79 versus 80 percent). However, graft survival rates at 10 years were lower for patients with alcohol-associated liver disease compared with those with a nonalcohol-related diagnosis (60 versus 63 percent).
The increase in mortality at 10 years after liver transplant in patients with alcohol-associated liver disease suggests the need for long-term follow-up studies to identify risk factors for mortality, so that patient selection for transplantation and post-transplant care can be optimized for long-term survival . (See "Liver transplantation in adults: Long-term management of transplant recipients".)
Recurrent harmful alcohol use — Despite comprehensive pre-transplant evaluation and adherence to the six-month rule by most centers, some patients will resume alcohol use following liver transplantation. (See 'Overall risk of alcohol relapse' above.)
A model has been developed to identify individuals who drink heavily and are at high risk for liver disease progression that incorporates patient sex, baseline fibrosis levels, onset of heavy drinking, amount of alcohol intake, and body mass index .
Complications — Graft rejection, graft loss and recurrent alcohol-associated liver disease are potential complications of alcohol relapse after liver transplantation . Excessive drinking after liver transplantation may be associated with rapidly progressive liver injury, allograft failure, and fatal alcohol-associated hepatitis (AH) [22,70-72]. In a study of 300 patients with alcohol-associated liver disease who underwent transplantation, patients who relapsed were more likely to develop steatohepatitis (OR 6.2, 95% CI 1.7-22.7) and advanced (stage three or higher) fibrosis (OR 23.2, 95% CI 3.1-177.3) compared with those who maintained abstinence . In another study, 128 of 712 patients who underwent liver transplantation for alcohol-associated cirrhosis had a severe alcohol relapse . Among the patients with a severe relapse, 41 (32 percent) developed recurrent alcohol-associated cirrhosis after a median of 5.1 years. Survival at 10 and 15 years was lower among patients with severe alcohol relapse compared with those who did not have a severe relapse (50 versus 70 percent at 10 years and 21 versus 41 percent at 15 years). A separate report also suggested impaired survival after 10 years in patients who resumed drinking, possibly because of an increased risk of death from cancer and cardiovascular events . However, in one study, alcohol use in the immediate pre-transplant period was not associated with lower long-term survival .
The continued use of alcohol by patients after liver transplantation may also increase the likelihood that they will be lost to follow-up, leading to an underestimate of the impact of alcohol use on outcomes.
Monitoring — We monitor patients with a history of alcohol-associated liver disease for recurrent alcohol use following liver transplantation by clinical interview and by testing of urine ethyl glucuronide (uEtG) at each follow-up outpatient visit and randomly, if needed. (See 'Monitoring for alcohol use' above.)
Prevention and treatment — Patients with either alcohol-associated liver disease who did not complete an alcohol treatment program prior to liver transplantation or with acute severe AH are required to sign a patient contract prior to transplantation. They also must complete an alcohol treatment program when medically appropriate following transplantation (usually three to six months postoperatively).
Few studies have addressed the utility of post-liver transplantation alcohol treatment programs in preventing relapse. In a study of 103 patients with alcohol-associated liver disease who underwent transplantation, participation in an alcohol treatment program resulted in lower rates of any alcohol use during a four-year follow-up period (22 versus 48 percent) . In the United Kingdom, all patients who undergo transplantation for alcohol-associated liver disease are followed by an addiction treatment psychiatrist [75,76]. Such a program is recommended but not mandatory in the United States.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Liver transplantation".)
SUMMARY AND RECOMMENDATIONS
●Background – Alcohol-associated cirrhosis was responsible for 21 percent of all orthotopic liver transplants in 2015 in the United States, according to the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients (OPTN/SRTR) report. (See 'Introduction' above.)
Transplantation is an appropriate treatment option for some patients with alcohol-associated liver disease and is generally considered when a patient has suffered either a complication of portal hypertension or a manifestation of compromised hepatic function. Such patients should be referred for transplantation as early referral is an important determinant of success. (See 'Timing of referral' above.)
●Pre-transplant abstinence and monitoring – Abstinence is an expectation for patients on the transplant waiting list. Some studies suggest that longer durations of abstinence pre-transplantation are associated with reduced rates of relapse after transplant; six-month abstinence is a common requirement in many centers. In addition, other centers monitor patients for alcohol use and/or require that patients participate in an alcohol treatment program. The efficacy of these measures in preventing alcohol relapse after transplantation and improving other outcomes is uncertain. (See 'Pre-transplant abstinence and monitoring' above.)
●Post-transplant management and outcomes
•Mortality and graft survival – One- and five-year patient and graft survival rates following liver transplantation for alcohol-associated liver disease are similar to rates following transplantation for nonalcohol-related diagnoses. However, 10-year patient and graft survival rates are lower for patients with alcohol-associated liver disease, while the cause for this is not well-defined. (See 'Mortality and graft survival' above.)
•Recurrent harmful alcohol use – Alcohol relapse after transplantation occurs in 10 to 30 percent of patients and has been associated with increased risk of graft rejection, graft loss, and recurrent alcohol-associated liver disease as well as decreased survival. The accuracy of predictors of relapse is incompletely understood but, poor social support, a family history of alcohol dependence, and pre-transplantation abstinence of ≤6 months are some of the predictors that may be important. (See 'Risk factors for alcohol relapse' above and 'Recurrent harmful alcohol use' above.)
We suggest that patients with a history of alcohol-associated liver disease participate in an alcohol treatment program following liver transplantation. (See 'Prevention and treatment' above.)
•Smoking cessation – Smoking is a significant risk factor for post-transplant morbidity and mortality. We suggest that patients with alcohol-associated liver disease who smoke undergo counseling and treatment for smoking cessation (Grade 2B). (See 'Smoking cessation' above.)
●Patients with severe alcohol-associated hepatitis (AH) – Liver transplantation may be an option for patients with severe AH who do not respond to glucocorticoids. It has been suggested that the six-month period of abstinence be reconsidered in patients with severe AH and that methods to identify transplant candidates who are at low risk of relapse are needed. (See 'Patients with severe alcohol-associated hepatitis (AH)' above.)
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