Workup and management of liver transplantation in alcohol-related liver disease.

Alcohol-related liver disease (ALD) represents the most common indication for liver transplantation (LT) worldwide. Outcomes of LT for ALD are comparable with those of LT for other etiologies; however, ALD is still considered a controversial indication for LT, mainly because it is considered a self-inflicted disease with a high risk of return to alcohol use after LT. Pre-LT evaluation criteria have changed over time, with a progressive re-evaluation of the required pre-transplant duration of abstinence. Despite the fact that some transplant programs still require 6 months of abstinence in order to consider a patient suitable for LT, there is increasing evidence that a pre-transplant abstinence period of <6 months can be considered for well-selected patients. Early LT for severe alcohol-related hepatitis that has not responded to medical therapy has been shown to be an effective therapeutic option with high survival benefit when performed within strict and well-recognized criteria. However, high variability in LT access exists for these patients due to the presence of social and medical stigma. A psycho-social assessment, together with an evaluation by an addiction specialist, should be mandatory in patients with ALD who are potential candidates for LT in order to assess the risk of post-transplant return to alcohol use and to ensure good long-term outcomes. Finally, before LT, attention should be paid to the presence of other potential comorbidities (i.e., cardiovascular and neurological diseases), which could represent a potential contraindication to LT. Similarly, after LT, patients should be adequately monitored for the development of cardiovascular events and screened for "de novo" tumors, although standardized protocols for this monitoring do not exist at this time.

Alcohol use disorder in alcohol-associated liver disease: Two sides of the same coin.

Alcohol-associated liver disease (ALD) has emerged as the leading indication for liver transplantation (LT) worldwide, with 40% of LTs in the United States performed for ALD in 2019. The ALD-related health care burden accelerated during the COVID-19 pandemic, especially in young individuals. Alcohol use disorder (AUD), which focuses on the negative effects of alcohol on psychosocial, physical, and mental health, is present in the majority of patients with ALD, with moderate to severe AUD in 75%-80%. During the last decade, early liver transplantation (eLT) has emerged as a lifesaving treatment for selected patients with alcohol-associated hepatitis; these patients may have a higher risk of using alcohol after LT. The risk of alcohol use recurrence may be reduced during the pretransplant or post-transplant period with AUD treatment using behavioral and/or pharmacological therapies and with regular monitoring for alcohol use (self-reported and complemented with biomarkers like phosphatidylethanol). However, AUD treatment in patients with ALD is challenging due to patient, clinician, and system barriers. An integrated model to provide AUD and ALD care by hepatologists and addiction experts in a colocated clinic starting from LT evaluation and selection to monitoring listed candidates and then to following up on recipients of LT should be promoted. However, the integration of addiction and hepatology teams in an LT program in the real world is often present only during evaluation and candidate selection for LT. Data are emerging to show that a multidisciplinary integrated AUD treatment within an LT program reduces recurrent alcohol use after LT. If we want to continue using early liver transplantation for patients with severe alcohol-associated hepatitis, LT programs should focus on building integrated multidisciplinary care teams for the integrated treatment of both AUD and ALD.

Single-center experience with early liver transplantation for acute alcohol-related hepatitis-Limitations of the SALT score and directions for future study.

Alcohol-related liver disease (ALD) is the leading indication for liver transplantation worldwide. Since Mathurin et al. described their experience in providing early liver transplantation for patients with ALD in 2011, other centers have followed suit with generally favorable survival outcomes. This patient population poses a unique clinical challenge given the expedited nature of the evaluation and the lack of any significant sobriety period prior to transplantation. The SALT (Sustained Alcohol Use Post-Liver Transplant) score is a standardized psychometric tool increasingly used to help stratify the risk of relapse and guide listing decisions for these challenging clinical situations. In 2018, our center introduced a protocol for early liver transplantation for acute alcohol-related hepatitis (AAH). In this article, we offer a retrospective review of 26 patients transplanted between May 2018 and May 2021, including at least 1-year follow-up, and compare outcomes to initial SALT scores; we further identify additional factors that may impact post-transplant success. As transplant committees continue to weigh the ethical dilemma of denying lifesaving treatment against the obligation to remain stewards of a limited resource, we aim to contribute to a more nuanced understanding of risk regarding early transplantation for ALD.

Racial and Ethnic Disparities in Liver Transplantation for Alcohol-associated Liver Diseases in the United States.

BACKGROUND: Emerging data suggest disparities exist in liver transplantation (LT) for alcohol-associated liver disease (ALD). As the incidence of ALD increases, we aimed to characterize recent trends in ALD LT frequency and outcomes, including racial and ethnic disparities. METHODS: Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data (2015 through 2021), we evaluated LT frequency, waitlist mortality, and graft survival among US adults with ALD (alcohol-associated hepatitis [AH] and alcohol-associated cirrhosis [AAC]) stratified by race and ethnicity. We used adjusted competing-risk regression analysis to evaluate waitlist outcomes, Kaplan-Meier analysis to illustrate graft survival, and Cox proportional hazards modeling to identify factors associated with graft survival. RESULTS: There were 1211 AH and 26 526 AAC new LT waitlist additions, with 970 AH and 15 522 AAC LTs performed. Compared with non-Hispanic White patients (NHWs) with AAC, higher hazards of waitlist death were observed for Hispanic (subdistribution hazard ratio [SHR] = 1.23, 95% confidence interval [CI]: 1.16-1.32), Asian (SHR = 1.22, 95% CI:1. 01-1.47), and American Indian/Alaskan Native (SHR = 1.42, 95% CI: 1.15-1.76) candidates. Similarly, significantly higher graft failures were observed in non-Hispanic Black (HR = 1.32, 95% CI: 1.09-1.61) and American Indian/Alaskan Native (HR = 1.65, 95% CI: 1.15-2.38) patients with AAC than NHWs. We did not observe differences in waitlist or post-LT outcomes by race or ethnicity in AH, although analyses were limited by small subgroups. CONCLUSIONS: Significant racial and ethnic disparities exist for ALD LT frequency and outcomes in the United States. Compared with NHWs, racial and ethnic minorities with AAC experience increased risk of waitlist mortality and graft failure. Efforts are needed to identify determinants for LT disparities in ALD that can inform intervention strategies.

Outcomes of re-referrals of patients with alcohol-associated liver disease, who were previously declined for liver transplantation.

Since 2018, our program has utilized specific psychosocial criteria and a multidisciplinary approach to assess patients for liver transplant due to alcohol-associated liver disease (ALD), rather than the 6-month abstinence rule alone. If declined based on these criteria, specific recommendations are provided to patients and their providers regarding goals for re-referral to increase the potential for future transplant candidacy. Recommendations include engagement in treatment for alcohol use disorder, serial negative biomarker testing, and maintenance of abstinence from alcohol. In our current study, we evaluate the outcomes of patients with ALD, who were initially declined upon assessment and re-referred to our program. This is a retrospective cohort study that includes 98 patients with ALD, who were previously declined for liver transplantation and were subsequently re-referred for liver transplant assessment between May 1, 2018, and December 31, 2021. We assess the outcomes of patients who were re-referred including acceptance for transplantation following a second assessment. Of the 98 patients who were re-referred, 46 (46.9%) fulfilled the recommendations made and proceeded to further medical evaluation. Nine were eventually transplanted; others are listed and are waiting for transplant. The presence of a partner was independently associated with a higher rate of acceptance (OR 0.16, 95% CI: 0.03-0.97, p = 0.05). Most of the patients who did not proceed further (n = 52) were declined again due to ALD contraindications (n = 33, 63.4%), including ongoing drinking and lack of engagement in recommended addiction treatment. Others had medical contraindications (11.2%), clinically improved (6.1%), had adherence issues (5.1%), or lack of adequate support (2%). Patients with ALD previously declined for a liver transplant can be re-referred and successfully accepted for transplantation by fulfilling the recommendations made by the multidisciplinary team. Important factors including ongoing abstinence, engagement in addiction treatment, and social support are key for successful acceptance.

Dual alcohol and metabolic-related liver disease: Results from a population of liver transplant patients.

BACKGROUND & AIMS: If alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are now the two main indications for liver transplantation (LT), it has been recognized that both conditions can coexist in varying degrees and the concept of dual-aetiology fatty liver disease (DAFLD) has been proposed. This retrospective study aimed to evaluate, in a cohort of patients transplanted for ALD and NAFLD, the prevalence of DAFLD before LT and the impact on liver graft outcome. METHODS: From 1990 to 2010, all patients who underwent LT for the so-called ALD or NAFLD in our centre were included. Before LT, DAFLD was defined as patients with a history of excessive alcohol consumption and obesity associated with either diabetes or hypertension. Before LT, patients were separated into three groups: DAFLD, ALD, and NAFLD. Fatty liver graft disease was classified according to the FLIP algorithm. RESULTS: Out of 907, adult LT recipients were identified: 33 DAFLD patients, 333 ALD patients, and 24 NAFLD patients. After LT, ALD patients experienced significantly more alcohol relapse than DAFLD patients, who had twice more post-LT metabolic syndrome. Out of 926, post-LT biopsies, DAFLD patients had significantly more fatty liver graft disease due to metabolic syndrome features than ALD patients. CONCLUSION: Our results support that DAFLD recently emerged as an indication of LT. In the future, this particular population needs to be identified as a specific entity since post-LT outcome on the graft is different from ALD and more similar to NAFLD patients.

Alcohol Use in Liver Transplant Recipients With Alcohol-related Liver Disease: A Comparative Assessment of Relapse Prediction Models.

BACKGROUND: The selection of liver transplant (LT) candidates with alcohol-related liver disease (ALD) is influenced by the risk of alcohol relapse (AR), yet the ability to predict AR is limited. We evaluate psychosocial factors associated with post-LT AR and compare the performance of high-risk alcoholism risk (HRAR), sustained alcohol use post-LT (SALT), and the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) scores in predicting relapse. METHODS: A retrospective analysis of ALD patients undergoing LT from 2015 to 2021 at a single US transplant center was performed. Risk factors associated with post-LT AR were evaluated and test characteristics of 3 prediction models were compared. RESULTS: Of 219 ALD LT recipients, 23 (11%) had AR during a median study follow-up of 37.5 mo. On multivariate analysis, comorbid psychiatric illness (odds ratio 5.22) and continued alcohol use after advice from a health care provider (odds ratio 3.8) were found to be significantly associated with post-LT AR. On sensitivity analysis, SIPAT of 30 was optimal on discriminating between ALD LT recipients with and without post-LT AR. SIPAT outperformed both the HRAR and SALT scores (c-statistic 0.67 versus 0.59 and 0.62, respectively) in identifying post-LT AR. However, all scores had poor positive predictive value (<25%). CONCLUSIONS: AR after LT is associated with comorbid psychiatric illness and lack of heeding health care provider advice to abstain from alcohol. Although SIPAT outperformed the HRAR and SALT scores in predicting AR, all are poor predictors. The current tools to predict post-LT AR should not be used to exclude LT candidacy.

The changing epidemiology of adult liver transplantation in the United States in 2013-2022: The dominance of metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease.

BACKGROUND: The high prevalence of obesity in the United States drives the burden of NASH, recently renamed as metabolic dysfunction-associated steatohepatitis (MASH). We assessed the most recent trends in liver transplantation in the United States. METHODS: The Scientific Registry of Transplant Recipients (SRTR 2013-2022) was used to select adult (18 years or above) candidates who underwent liver transplant. RESULTS: There were 116,292 candidates who underwent liver transplant with known etiology of chronic liver disease. In candidates without HCC, the most common etiology was alcohol-associated liver disease (ALD), increasing from 23% (2013) to 48% (2022), followed by NASH/MASH, which increased from 19% to 27%; the rates of viral hepatitis decreased (chronic hepatitis C: 28%-4%; chronic hepatitis B: 1.8%-1.1%) (all trend p<0.01). The proportion of HCC decreased from 25% (2013-2016) to 17% (2021-2022). Among HCC cohort, the proportion of chronic hepatitis C decreased from 60% (2013) to 27% (2022), NASH/MASH increased from 10% to 31%, alcohol-associated liver disease increased from 9% to 24% (trend p<0.0001), and chronic hepatitis B remained stable between 5% and 7% (trend p=0.62). The rapid increase in the proportion of NASH/MASH in HCC continued during the most recent study years [20% (2018), 28% (2020), 31% (2022)]; the trend remained significant after adjustment for age, sex, ethnicity, obesity, and type 2 diabetes. CONCLUSIONS: Liver transplant etiologies in the United States have changed over the last decade. Alcohol-associated liver disease and NASH/MASH remain the 2 most common indications for transplantation among those without HCC, and NASH/MASH is the most common in patients with HCC.

Outcomes following liver transplant for alcohol-associated liver disease: comparing alcohol-associated hepatitis and cirrhosis.

BACKGROUND: Liver transplant (LT) is a highly effective therapy for refractory severe alcohol-associated hepatitis (SAH), but optimal selection criteria remain unknown. We aim to evaluate the outcomes of patients who received LT for alcohol-associated liver disease at our center following the introduction of updated selection criteria, including the removal of the minimum sobriety requirement. METHODS: Data were collected on all patients who underwent LT for alcohol-associated liver disease from January 1, 2018, to September 30, 2020. Patients were divided into SAH and cirrhosis cohorts based on disease phenotype. RESULTS: One hundred twenty-three patients underwent LT for alcohol-associated liver disease, including 89 (72.4%) for cirrhosis and 34 (27.6%) for SAH. There was no difference in 1- (97.1 ± 2.9% vs. 97.7 ± 1.6%, p = 0.97) and 3-year (97.1 ± 2.9% vs. 92.4 ± 3.4%, p = 0.97) survival between SAH and cirrhosis cohorts. Return to alcohol use was more frequent in the SAH cohort at 1 year (29.4 ± 7.8% vs. 11.4 ± 3.4%, p = 0.005) and 3 years (45.1 ± 8.7% vs. 21.0 ± 6.2%, p = 0.005) including higher frequencies of both slips and problematic drinking. Unsuccessful alcohol use counseling (HR 3.42, 95% CI 1.12-10.5) and prior alcohol support meetings (HR 3.01, 95% CI 1.03-8.83) predicted a return to harmful alcohol use patterns in early LT recipients. Both duration of sobriety (c-statistic 0.32 (95% CI 0.34-0.43) and SALT score (c-statistic 0.47, 95% CI 0.34-0.60) were independently poor predictors of return to harmful drinking. CONCLUSION: Survival following LT was excellent in both SAH and cirrhosis cohorts. Higher rates of return to alcohol use highlight the importance of further individualized refinement of selection criteria and improved support following LT.

Long-term outcomes of liver transplantation for alcohol-related liver disease.

BACKGROUND: Liver transplantation (LT) is being increasingly performed for alcohol-related liver disease (ALD). It is unclear whether the increasing frequency of LTs in ALD patients has a negative impact on deceased-donor (DDLT) allocation and whether the current policy of 6 months of abstinence before transplantation effectively prevents recidivism after transplantation or improves long-term outcomes. METHODS: A total of 506 adult LT recipients, including 97 ALD patients, were enrolled. The outcomes of ALD patients were compared with those of non-ALD patients. The 97 ALD patients were further divided into group A (6-month abstinence) and group N (nonabstinence) based on the pretransplant alcohol withdrawal period. The incidence of relapsed drinking and the long-term outcomes were compared between the two groups. RESULTS: The prevalence of LT for ALD significantly increased after 2016 (27.0% vs 14.0%; p < 0.01), but the frequency of DDLT for ALD remained unchanged (22.6% vs 34.1%, p = 0.210). After a median follow-up of 56.9 months, patient survival was comparable between the ALD and non-ALD patients (1, 3, and 5 years posttransplant: 87.6%, 84.3%, and 79.5% vs 82.8%, 76.6%, and 72.2%, respectively; p = 0.396). The results were consistent irrespective of the transplant type and disease severity. In ALD patients, 22 of the 70 (31.4%) patients reported relapsed drinking after transplantation, and the prevalence in group A had a higher tendency than that in group N (38.3% vs 17.4%, p = 0.077). Six months of abstinence or nonabstinence did not result in a survival difference, and de novo malignancies were the leading cause of late patient death in ALD patients. CONCLUSION: LT achieves favorable outcomes for ALD patients. Six months of abstinence pretransplant did not predict the risk of recidivism after transplantation. The high incidence of de novo malignancies in these patients warrants a more comprehensive physical evaluation and better lifestyle modifications to improve long-term outcomes.

Long-term survival after liver transplantation for alcohol-related liver disease in the Nordic countries.

OBJECTIVES: Alcohol-related liver disease (ALD) is among the most common indications for liver transplantation (LTX) in Europe and North America, with good five-year survival rates post-LTX. Here we evaluated survival up to and beyond 20 years after LTX for patients with ALD compared to a comparison group. METHODS: Patients with ALD and a comparison group transplanted in the Nordic countries between 1982 and 2020 were included. Data were analyzed using descriptive statistics, Kaplan-Meier curves and predictors of survival were assessed with Cox-regressions. RESULTS: 831 patients with ALD and 2979 patients in the comparison group were included in the study. Patients with ALD were older at the time of LTX (p < .001) and more likely to be male (p < .001). The estimated median follow-up time was 9.1 years for the ALD-group and 11.1 years for the comparison group. 333 (40.1%) patients with ALD and 1010 (33.9%) patients in the comparison group died during follow-up. The overall survival was impaired for patients with ALD compared to the comparison group (p < .001) and was evident for male and female patients, patients transplanted before and after 2005, and observed in all age-groups except patients over 60 years. Age at transplant, waiting time, year of LTX and country of LTX were associated with decreased survival after LTX for patients with ALD. CONCLUSIONS: Patients with ALD have a decreased long-term survival following LTX. This difference was evident in most sub-groups of patients and warrants close follow-up of liver transplanted patients with ALD with focus on risk reduction.

Liver transplantation in alcohol-associated liver disease: ensuring equity through new processes.

Worsened by the COVID-19 pandemic, alcohol use is one of the leading causes of preventable death in the US, in large part due to alcohol-associated liver disease. Throughout history, liver transplantation for this population has been controversial, and many policies and regulations have existed to limit access to lifesaving transplant for patients who use alcohol. In recent years, the rates of liver transplantation for patients with alcohol-associated liver disease have increased dramatically; however, disparities persist. For instance, many criteria used in evaluation for transplant listing, such as social support and prior knowledge of the harms of alcohol use, are not evidence based and may selectively disadvantage patients with alcohol use disorder. In addition, few transplant providers have adequate training in the treatment of alcohol use disorder, and few transplant centers offer specialized addiction treatment. Finally, current approaches to liver transplantation would benefit from adopting principles of harm reduction, which have demonstrated efficacy in the realm of addiction medicine for years. As we look toward the future, we must emphasize the use of evidence-based measures in selecting patients for listing, ensure access to high-quality addiction care for all patients pretransplant and posttransplant, and adopt harm reduction beliefs to better address relapse when it inevitably occurs. We believe that only by addressing each of these issues will we be able to ensure a more equitable distribution of resources in liver transplantation for all patients.

Patient reflections, challenges, and supports related to early liver transplant for severe alcohol-associated liver disease.

Transplant centers conventionally require at least 6 months of alcohol abstinence before offering liver transplants for alcohol-associated liver disease. However, early liver transplant (ELT)-proceeding with a transplant when clinically necessary without first meeting the conventional requirement-is increasingly gaining attention. In our study, we qualitatively assessed ELT recipients' perceived challenges and supports regarding alcohol-associated liver disease, transplant, and posttransplant survivorship. To diversify perspectives based on gender, race/ethnicity, age, time since ELT, and pretransplant abstinence duration, we purposively recruited ELT recipients and conducted semistructured interviews. Recruitment continued until data saturation. We analyzed transcripts using inductive thematic analysis. We interviewed 20 ELT recipients between June and December 2020 and identified themes within 3 participant-characterized time periods. Three themes emerged in life before severe illness: (1) alcohol as a "constant" part of life, (2) alcohol use negatively affecting relationships and work life, and (3) feeling "stuck" in the cycle of drinking. Two themes emerged during the severe illness period: (4) rapidity of health decline and (5) navigating medical care and the 6-month abstinence requirement. Finally, in life after transplant, 4 themes emerged: (6) feelings of shame or stigma and new self-worth, (7) reconnecting with others and redefining boundaries, (8) transplant as a defining point for sobriety, and (9) work-related challenges. Overall, participants expressed gratitude for receiving a gift of life and acknowledged their responsibilities to the new liver. ELT recipient experiences reveal complex psychosocial challenges related to addiction, inadequate support system, and stigma, particularly in the posttransplant period. The care of ELT recipients would be incomplete if focused solely on optimizing patient or graft survival.

Adverse outcomes after non-hepatic surgeries in patients with alcoholic liver diseases: a propensity-score matched study.

BACKGROUND: The influence of alcoholic liver disease (ALD) on the postoperative outcomes is not completely understood. Our purpose is to evaluate the complications and mortality after nonhepatic surgeries in patients with ALD. METHODS: We conducted a retrospective cohort study included adults aged 20 years and older who underwent nonhepatic elective surgeries using data of Taiwan's National Health Insurance, 2008-2013. Using a propensity-score matching procedure, we selected surgical patients with ALD (n = 26,802); or surgical patients without ALD (n = 26,802) for comparison. Logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of postoperative complications and in-hospital mortality associated with ALD. RESULTS: Patients with ALD had higher risks of acute renal failure (OR 2.74, 95% CI 2.28-3.28), postoperative bleeding (OR 1.64, 95% CI 1.34-2.01), stroke (OR 1.51, 95% CI 1.34-1.70) septicemia (OR 1.47, 95% CI 1.36-1.58), pneumonia (OR 1.43, 95% CI 1.29-1.58), and in-hospital mortality (OR 2.64, 95% CI 2.24-3.11) than non-ALD patients. Patients with ALD also had longer hospital stays and higher medical expenditures after nonhepatic surgical procedures than the non-ALD patients. Compared with patients without ALD, patients with ALD who had jaundice (OR 4.82, 95% CI 3.68-6.32), ascites (OR 4.57, 95% CI 3.64-5.74), hepatic coma (OR 4.41, 95% CI 3.44-5.67), gastrointestinal hemorrhage (OR 3.84, 95% CI 3.09-4.79), and alcohol dependence syndrome (OR 3.07, 95% CI 2.39-3.94) were more likely to have increased postoperative mortality. CONCLUSION: Surgical patients with ALD had more adverse events and a risk of in-hospital mortality after nonhepatic surgeries that was approximately 2.6-fold higher than that for non-ALD patients. These findings suggest the urgent need to revise the protocols for peri-operative care for this population.