Early liver transplant for alcohol-associated liver disease: Current state and future directions

Abstract

Alcohol-associated liver disease (ALD) is a rapidly increasing indication for liver transplantation (LT) globally with a significant rise in transplants for ALD with limited sobriety including patients with alcohol-associated hepatitis (AH). This evolution challenges the older paradigm that mandates prolonged periods of alcohol abstinence prior to LT. Due to the limited armamentarium of effective pharmacotherapy to treat severe AH, the mortality rates are significantly higher when LT is not available. In the patients who are transplanted for ALD with limited sobriety including AH, patient and graft survival are equivalent, if not better, compared to patients transplanted for other etiologies. However, due to the risk of alcohol relapse and other psychosocial factors, public opinion regarding early LT may continue to impact how the field moves forward particularly regarding organ stewardship and the need for equitable allocation of organs. Numerous tools for psychosocial evaluations have been developed to assist liver transplant teams to identify appropriate patients in a more uniform manner. In this review, we aim to assess the available evidence to support early LT for alcohol AH and propose directions for the future as the field continues to evolve.

Key Words: Liver transplantation; Alcohol-associated liver disease; Alcohol use disorder; End stage liver disease; Alcohol relapse; Psychosocial evaluation; Public opinion; Policy

Core Tip: Liver transplantation (LT) for alcohol-associated liver disease continues to be an evolving field. As transplant centers internationally continue to increase rates of transplantation for patients with limited sobriety including alcohol-associated hepatitis, there is an ongoing need to standardize the selection process. This appraisal aims to succinctly review the current state of early LT and anticipate future direction for the field.

INTRODUCTION

Alcohol-associated hepatitis (AH) is an inflammatory condition of the liver defined by new onset of jaundice within 60 days of heavy alcohol consumption for a minimum of six months, elevated aminotransferase levels with an aspartate transaminase predominance, and exclusion of alternative causes of hepatitis (Table 1)[1]. Alcohol-associated liver disease (ALD) including AH is an increasing public health burden as rates of alcohol use disorder (AUD) in the United States continue to rise exponentially[2,3]. There has been a 51.5% (1.8 million to 2.7 million) rise in the number of alcohol-related emergency department visits from 2006 to 2014 in the United States[4]. More recently, the coronavirus disease 2019 pandemic contributed to a remarkable increase in harmful drinking and alcohol-related hospitalizations[5]. According to the 2022 Scientific Registry of Transplant Recipients annual report, ALD is now the leading indication for liver transplantation (LT)[6]. Moreover, AH constitutes more than 10% of patients with ALD waitlisted for LT with a 6.5-fold increase between 2008 and 2019[3].

Table 1 Definition of alcohol-associated hepatitis recommended by the National Institute on Alcohol Abuse and Alcoholism.

	Items
1	Onset of jaundice in the previous 8 weeks
2	Continuous alcohol consumption of > 40 (female) or > 60 (male) g/day for at least 6 months, with less than 60 days of abstinence before the onset of jaundice
3	Aspartate aminotransferase > 50, aspartate aminotransferase/alanine aminotransferase > 1.5, and both values less than 400 IU/L
4	Serum bilirubin (total) > 3.0 mg/dL
5	Liver biopsy confirmation in patients (macrovesicular steatosis, hepatocyte ballooning, and predominantly neutrophilic infiltration and Mallory-Denk bodies)
	Exclusion of other liver disease (i.e., viral hepatitis, autoimmune liver diseases, Wilson disease, drug-induced liver injury, hepatocellular carcinoma)

Given the paucity of effective pharmacologic therapies for AH, LT may be the only life-saving treatment available. However, eligibility for LT historically required at least six months of alcohol abstinence (“6-month rule”). Transplant free survival is less than 50% at one month and 30% at six months in AH patients unresponsive to medical management[1,7]. Numerous studies showing favorable outcomes for LT prior to 6 months of abstinence (early LT) and greater knowledge of AUD over the last two decades has led to shifting opinions regarding "the 6 month rule"[8]. Early LT remains controversial due to alcohol relapse risk, minimal long-term outcomes and survival statistics, and ethical concerns regarding utilization of a limited organ supply.

The availability of early LT for ALD varies significantly on a global level[9,10]. Even in Asia, where living donor transplantation is more common, early LT for ALD has not been widely adopted[11]. The prevalence of AUD in Asia is nearly half that of United States and Europe, and the lack of data regarding early LT in ALD in the Asian population may contribute to the reluctance of many healthcare institutions in the region to prioritize transplantation for ALD[11,12]. European guidelines, on the other hand, have recently adjusted to reflect the utility of early LT in patients with severe AH (SAH) who do not respond to medical therapy[13].

Considering the evolving trends in LT for AH, this review explores the current state of early LT for AH. We aim to critically evaluate recent studies on the advantages of early LT for AH, delineate nuances of the available evidence, investigate psychosocial assessment tools that identify high risk candidates who may need more personalized pre- and post-transplant care, and identify gaps in knowledge requiring further investigation.

CURRENT GUIDELINES FOR NON-SURGICAL TREATMENTS IN ALCOHOL-AH

Treatment for AH is currently centered on nutritional therapy and corticosteroids. Multiple society guidelines advise 1.2-1.5 g/kg of protein and 35-40 kcal/kg of dietary intake for AH patients[14,15]. The importance of nutritional therapy is demonstrated by the significant difference in one-year mortality rates for hospitalized patients with mild and severe malnutrition (14% vs 76%)[16]. A meta-analysis of nutritional interventions in patients with AH suggests that robust nutritional therapy reduces mortality risk by 20%[17].

The Maddrey discriminant function (mDF) has traditionally been used to identify patients who may benefit from corticosteroids[18]. However, unlike the Model of End Stage Liver Disease (MELD) and Sodium (MELD-Na) score, the mDF does not include serum creatinine or sodium levels which are known predictors of mortality[19,20]. Thus, a combination of mDF and MELD is likely more reflective of true severity and should be used in conjunction to determine appropriate candidates for corticosteroids. A meta-analysis of AH patients treated with prednisolone showed a significantly lower 28-day mortality rate (HR = 0.64, P = 0.003) though this benefit did not persist beyond 90 days[21]. Use of corticosteroids does not come without risk, particularly its use is associated with greater infection rates (13% vs 7%, P = 0.002)[22]. Contraindications for corticosteroid use include upper gastrointestinal bleeding, acute kidney injury, multiorgan failure, shock, or need for dialysis. Importantly, nearly half of AH patients treated with corticosteroids are non-responders and only have 28- and 90-day survival rates of 66% and 40%, respectively (P < 0.001)[23]. Thus, while many alternative medical therapies are now being studied for AH, LT is currently the only treatment option available for AH patients who are non-responders to the limited available therapy.

An updated version of MELD (MELD 3.0) is now used for organ allocation and it has also been found to perform better than the mDF and MELD-Na in predicting 30-day and 90-day mortality in AH. The MELD 3.0 added gender and serum albumin to the current score with updated coefficients which resulted in superior performance for predicting 30-day mortality with an area under the curve of 0.761 compared to 0.724 (P = 0.013) with mDF and 0.744 (P = 0.042) with MELD-Na; meanwhile, all three performed similarly at predicting 90-day mortality[24].

THE 6-MONTH CONUNDRUM

LT for AH patients has historically been contentious. The "6-month rule" emerged in 1998 after a consensus panel meeting with specialists from the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases[25]. The rule was initially established to allow ample time for individuals to seek AUD treatment and effectively lower the likelihood of relapse, provide adequate time to assess the patient’s commitment to alcohol abstinence, and determine if there may be spontaneous recovery without needing a LT. The origin of the stipulated length of abstinence was based on studies that were conducted in the late 1990s and early 2000s with small sample sizes, relied exclusively on self-reported measures, and lacked objective evidence of alcohol use after LT[26].

Emphasis on a defined period of abstinence has been misleading in terms of patient selection for LT. A meta-analysis with little study-to-study heterogeneity found no difference in the rate of alcohol relapse between AH patients who received LT with more or less than six months of sobriety (OR = 1.68, P = 0.2)[26]. Presence of psychiatric co-morbidities appears to be a better predictor of alcohol relapse than length of abstinence less than 6 months (OR = 3.46, P = 0.02)[27]. Interestingly, although patients may relapse into their vices, multiple groups have continued to show higher survival in early LT patients (Table 2).

Table 2 Studies to date examining early-liver transplantation for alcohol-associated hepatitis.

Ref.	Location	Study format	Early LT candidacy criteria	n	Primary outcome	Survival rate	Relapse rate
Im et al, 2016[61]	United States	Retrospective	Mathurin et al[28] criteria (see Table 3). Inclusion of patients with recent infection and gastrointestinal bleeding	18	6-month patient survival or early LT	6 months patient: 89% (early LT) vs 11% (no LT at 6 months, matched controls; P < 0.001)	Any alcohol relapse: 25% among early LT group
Lee et al, 2017[32]	United States	Retrospective	Mathurin et al[28] criteria (see Table 3). Inclusion of patients with previous diagnosed but adequately managed mental health disorder. Inclusion of patients with recent infection and gastrointestinal bleeding	43	3-year patient survival and alcohol relapse	6 months patient: 100% (early LT) vs 88.5% (standard LT; P = 0.27). No significant difference in patient survival (P = 0.922) between early- and standard LT over 3 years	Any alcohol relapse: 23.5% (early LT) vs 29.2% (standard LT; P > 0.99). Alcohol relapse with harmful patterns: 23.5% (early LT) vs 11.5% (standard LT; P = 0.42)
Weeks et al, 2018[33]	United States	Retrospective	Mathurin et al[28] criteria (see Table 3). Inclusion of patients with previous diagnosed but adequately managed mental health disorder. Inclusion of patients with recent infection and gastrointestinal bleeding	80	1-year patient and graft survival. 1-year alcohol relapse rate	1 year patient: 97% (early LT) vs 100% (standard LT; P = 1.00). 1 year graft: 93% (early LT) vs 89% (standard LT; P = 0.70). No significant difference in patient (P = 0.60) and graft (P = 0.80) survival rate between early- and standard LT over 5 years	Any alcohol relapse: 28% (early LT) vs 24% (standard LT; P = 0.80). Alcohol relapse with harmful patterns: 17% (early LT) vs 12% (standard LT; P = 0.50)
Lee et al, 2018[29]	United States	Retrospective	Mathurin et al[28] criteria (see Table 3). The ACCELERATE-AH multi-center trial	147	1- and 3-year patient survival after early LT. Any alcohol use after early LT	1 year patient: 94% (95%CI: 89%-97%); 3 years patient: 84% (95%CI: 75%-90%)	Any alcohol relapse: 25% (95%CI: 18%-34%) at 1-year and 34% (95%CI: 25%-44%) at 3-years post-early LT
Herrick-Reynolds et al, 2021[31]	United States	Retrospective	NIAA criteria (see Table 1)	163	3-year patient, allograft, relapse-free, hazardous relapse-free survival	1 year patient: 94.1% (early LT) vs 95.9% (standard LT; P = 0.60). 3 years patient: 83.0% (early LT) vs 78.6% (standard LT; P = 0.60). 1 year allograft: 92.7% (early LT) vs 90.5% (standard LT; P = 0.42). 3 years allograft: 81.7% (early LT) vs 74.7% (standard LT; P = 0.42)	Early LT no association with relapse (HR = 0.77, 95%CI: 0.42-1.42, P = 0.41. adjusted HR = 0.87, 95%CI: 0.46-1.63, P = 0.66). Early LT no association with hazardous relapse (HR = 0.74, 95%CI: 0.36-1.51, P = 0.41. Adjusted HR = 0.88. 95%CI: 0.42-1.86. P = 0.74). Younger age (21-30 years) associated with relapse (HR = 5.60, 95%CI: 1.32-23.68, P = 0.02) and hazardous relapse (HR = 6.92, 95%CI: 1.53-31.32, P = 0.01)
Germani et al, 2022[62]	Italy	Retrospective	Mathurin et al[28] criteria (see Table 3). Inclusion of patients with previous diagnosed but adequately managed mental health disorder. Inclusion of patients with recent infection and gastrointestinal bleeding	93	3-year patient survival rate	6-, 12-, 24, 36-month patient survival in early LT patients (100% across all points) significantly higher than patients that are non-responders to medical therapy and denied LT (41%, 41%, 38% and 35% respectively; log-rank P < 0.001). 6-, 12-, 24, 36-month patient survival in early LT patients (100% across all points) significantly higher than patients who are responders to medical therapy (77%, 67%, 65% and 55% respectively; log-rank P = 0.008)	Any alcohol relapse: 12% among early LT group
Carrique et al, 2021[30]	Canada	Retrospective	NIAA criteria (see Table 1). Inclusion of patients with decompensated ALD without SAH. Includes "intensive relapse prevention therapy" in early LT patients	155	2-year patient survival	30 days patient: 95.5% (early LT; 95%CI: 83.0%-98.8%) vs 97.3% (standard LT; 95%CI: 91.7%-99.1%). 6 months patient: 88.6% (early LT; 95%CI: 74.8%-95.1%) vs 96.3% (standard LT; 95%CI: 90.4%-98.6%). 1 year patient: 88.6% (early LT; 95%CI: 74.8-95.1%) vs 96.3% (standard LT; 95%CI: 90.4%-98.6%). 2 years patient: 88.6% (early LT; 95%CI: 74.8%-95.1%) vs 94.1% (standard LT; 95%CI: 87.3%-97.3%)	6.8% of early LT patients vs 16% of standard LT patients returned to alcohol use after transplant (P = 0.21)
Louvet et al, 2022[35]	France-Belgium	Prospective	Mathurin et al[28] criteria (see Table 3). Additional scoring criteria by study team (≥ 220 points = early LT)	161	Non-inferiority of the 2-year rate of alcohol relapse in the early LT group vs standard LT group.	24 months patient: 89.7% (early LT) vs 88.2% (standard LT; HR = 0.87, 95%CI: 0.33-2.26). 24 months patient: 70.6% (early LT) vs 28.3% (non-eligible for early LT; HR = 0.27, 95%CI: 0.16-0.47)	24 months: 34% (early LT) vs 25% (standard LT; Absolute difference = 9.1%, 95%CI: -∞ to 21.1, P = 0.45); non-inferiority of early LT for alcohol relapse not proven
Musto et al, 2024[60]	United States	Retrospective	NIAA criteria (see Table 1)	334	10-year patient adjusted survival in early LT, standard LT and non-ALD diagnoses	10 years patient: early LT (referent) vs standard LT (adjusted HR = 1.31, 95%CI: 0.79-2.17; P = 0.30)	10 years: Early LT (referent) vs standard LT (adjusted HR = 1.47, 95%CI: 0.88-2.45, P = 0.14)
						10 years patient: Early LT (referent) vs non-ALD (adjust HR = 1.68, 95%CI: 0.79-2.78, P = 0.04)

ACCELERATE-AH: American Consortium of Early Liver Transplantation for Alcoholic Hepatitis; LT: Liver transplantation; ALD: Alcohol-associated liver disease.

OUTCOMES IN EARLY LT

Patients with SAH pose a challenge to the "6-month rule" since the majority of these patients will not be fortunate enough to live beyond six months. The landmark Franco-Belgian study (inclusion criteria reported in Table 3) reported a six-month survival rate of 23% in SAH patients compared to 77% in the early LT cohort[28]. The results of this study led to significant interest in early LT in the United States which have been reported in subsequent retrospective studies (Table 2). The American Consortium of Early LT for Alcoholic Hepatitis trial included twelve LT programs in the United States that reported 1- and 3-year survival rates of 94% and 84%, respectively, in early LT patients[29]. There were no significant differences in 2- or 3-year survival rates between early and standard LT for AH[28,29]. To date, there have been no studies reporting a statistical difference in one-year mortality rates for those transplanted with AH compared to those transplanted for all other etiologies. There is a need for prospective, long-term studies to ensure survival benefit for early LT in AH patient.

Table 3 Mathurin et al[29] inclusion criteria for early liver transplantation in alcohol-associated hepatitis patients.

	Severe alcohol-associated hepatitis is defined as follows
1	DF > 32
2	Non-response to medical therapy: Lille score > 0.45 after 7 days of medical treatment or continued increase in MELD score
3	Severe AH as the first liver-decompensating event
4	Presence of supportive family structure
5	Absence of psychiatric co-morbidities
6	Agreement by patients to lifelong total alcohol abstinence
7	Complete consensus for early LT by multidisciplinary team

LT: Liver transplantation; AH: Alcoho-associated hepatitis; DF: Maddrey's discriminant function; MELD: Model for End-Stage Liver Disease.

Another main concern of early LT is the inherent risk of alcohol relapse in AH patients. While the “6-month rule” was intended to facilitate AUD rehabilitation efforts and minimize the likelihood of alcohol relapse, most studies have not identified significant differences in alcohol relapse between early and standard LT groups (Table 2). The range of "any alcohol relapse" was 6%-34% in early LT groups and 16%-29% in standard LT groups[28-33]. However, direct comparisons between studies is not possible as relapse definitions differ among centers. The alcohol timeline follow-back (TLFB) tool is considered the gold standard for assessing drinking in alcohol consumption research[34]. In a recent prospective multi-center, non-randomized, non-inferiority-controlled trial examining alcohol relapse events in AH patients found no difference between early and standard LT regimens (absolute difference 9.1%; P = 0.45) using the TLFB tool for standardization[35]. Taken together, the evidence suggests no difference in the risk of alcohol relapse in AH patients among early and standard LT groups. Further research is warranted to explore standardizations in terminology of what is considered a relapse and how it impacts survival outcomes.

Based on the non-inferiority of early LT and the dearth of high-quality data to support the “6-month rule”, transplant candidacy for AH patients should not be predetermined by the length of alcohol abstinence. Moreover, numerous medical societies recommend against using a defined period of abstinence to determine LT candidacy[13,15]. This shift in policy will allow for greater focus on determining likelihood of recovery and placing an emphasis on finding methods to mitigate the psychosocial factors that increase risk of alcohol relapse.

PSYCHOSOCIAL EVALUATIONS

The LT psychosocial assessment requires a multidisciplinary approach with team members including psychiatrists, psychologists, therapists, case managers, and social workers. The psychosocial assessment tools (Table 4) have been created to identify the likelihood of alcohol relapse, issues with medication compliance or medical care, and poor social support.

Table 4 Psychosocial assessment scores for liver transplant candidacy and risk of alcohol recidivism.

Scoring system	Method	Risk factors measured
PACT (1989)	8-item exam; Rated on 5-point scale; Final independent score given to rater's overall impression of candidates' acceptability of a transplant	Knowledge and receptiveness to education; Compliance with medical treatment; Drug and alcohol use; Healthy lifestyle habits and sustainable practices; Risk for psychopathology; Psychopathology, stable personality factors; Family/support system stability
MAPS (1990)	12-item exam; Items vary from yes/no questions and scaled items; Final score assesses risk of alcohol relapse	Acceptance of alcoholism; Prognostic indices; Social stability
PLS (1991)	7-item exam; 3-point scale; Final score examines psychological vulnerability	Past psychiatric history; Quality of family/social support; Prior coping history; Coping with disease/treatment, ability to anticipate problems; Quality of affect; Mental status
TERS (1993)	10-item exam; 3-point scale; Final score indicates functioning level	Prior psychiatric history; Substance abuse; Compliance; Health behaviors; Quality of social support; Prior coping history
HRAR (1993)	3-item exam; Each item stratified into 3 groups of varying severity; Single score given based on risk of alcoholism	Duration of heavy drinking in years; Number of drinks per day; Number of prior alcoholism inpatient hospitalizations
SIPAT (2012)	18-item exam; 4 psychosocial themes evaluated; Varying number of questions for each theme ranging from 3-5 questions; Final score determines risk of candidates for transplantation	Patient's readiness level and illness management; Social support system level of readiness; Psychological stability and psychopathology; Lifestyle and effect of substance use
ARRA (2013)	9-item exam; Final score determines placement into 1 of 4 groups (ARRA I-IV) based on rates of post LT alcohol use	Presence of hepatocellular carcinoma; Tobacco, alcohol dependent; Motivation for alcohol treatment, stress management skills; Rehabilitation, social support status, nonmedical behaviors, amount of alcohol in social activities
HPSS (2017)	11-item exam; 3-point scale; post-hoc analysis of patients with severe alcoholic hepatitis vs alcoholic cirrhosis with > 6 months of abstinence; Final score shows risk of alcohol relapse after transplant	Self-admission to hospital; drinks/day prior to period of abstinence; Insight to diagnosis; Marital status; Abstinence before transplant; Psychiatric comorbidity; History of other substance use; History of failed rehabilitation attempt; Family history of alcoholism; Employment status prior to hospitalization; Alcohol-related legal history
SALT (2018)	Machine learning technique through the multi-center, ACCELERATE-AH cohort; Outcome of interest was sustained alcohol use post LT	Drinks per day at initial hospitalization; Multiple prior rehabilitation attempts; Prior alcohol-related legal issues; Prior illicit substance abuse
HALT (2020)	Retrospective review obtained of liver transplant patients; Final score predicts risk of alcohol relapse after transplant	Age at liver transplant; Non-alcohol related criminal history; Pre-transplant abstinence period; Drinks per day

PACT: Psychosocial Assessment of Candidates for Transplantation; MAPS: Michigan Alcoholism Prognostic Scale; PLS: Psychosocial Levels System; TERS: Transplant Evaluation Rating Scale; HRAR: High-Risk Alcoholism Relapse; SIPAT: Stanford Integrated Psychosocial Assessment for Transplant; ARRA: Alcohol Relapse Risk Assessment; HPSS: Hopkins Psychosocial Scoring System; SALT: Sustained Alcohol Use Post-Liver Transplant; HALT: Harmful Alcohol Post-Transplant score; LT: Liver transplant; ACCELERATE-AH: American Consortium of Early Liver Transplantation for Alcoholic Hepatitis.

Machine learning techniques were used to develop the Sustained Alcohol Use Post-Liver Transplant (SALT) score which identified four characteristics that predicted post LT alcohol consumption, including consumption of ten drinks per day when admitted to the hospital for AH (+ 4 points), two or more failed rehabilitation attempts (+ 4 points), prior alcohol-related legal issues (+ 2 points), and prior illicit drug use (+ 1 point). In the initial study, SALT score < 5 was found to be most useful in identifying appropriate patients for early LT from a psychosocial standpoint (95% negative predictive value)[36]. A later study confirmed a SALT score ≥ 7 to be a significant predictor of alcohol relapse and time to relapse (HR = 2.30, P = 0.02)[37].

The Stanford Integrated Psychosocial Evaluation for Transplant (SIPAT) score was developed to standardize the pre-transplant psychosocial assessment process and is now one of the most commonly used tools amongst LT centers. SIPAT is predictive of transplant outcomes, rejection rates, hospitalizations, infections, and social support system failure[38]. In ALD patients, a SIPAT score ≥ 21 was significantly associated with alcohol relapse following LT (HR = 6.40, P = 0.019)[37]. Of note, likely due to the greater degree of granularity provided by the SIPAT score, it is a better tool for predicting alcohol relapse compared to SALT score (area under the receiver operating characteristic 0.71 vs 0.62)[37]. The SIPAT score is associated with medication non-adherence including immunosuppression [SIPAT ≥ 21, adjusted OR (aOR) = 2.92, 95%CI: 1.69-5.03] and allograft rejection (SIPAT Readiness domain score > 5, aOR = 2.66, 95%CI: 1.20-5.91) in ALD patients[39]. The use of SIPAT is in line with the Dallas Consensus Conference recommendations on psychosocial domains that should be assessed in AH transplant candidates[40].

While these scoring systems can provide some degree of objectivity, they are not intended to supplant a LT selection committee’s clinical judgment. Instead, scoring methods should be utilized to identify individuals who may need additional psychosocial support before and after LT. For instance, the readiness domain score of the SIPAT provides an assessment on a patient’s insight into AUD which aids in identifying more vulnerable patients that would benefit additional psychiatric or addiction medicine care. Future research must continue to challenge the validity of these tools as the pool of early LT candidates for AH expands and greater objectivity is needed during the psychosocial assessment.

ETHICAL CONSIDERATIONS

Public perception of LT for ALD has had a tumultuous course. High-profile cases like those of George Best, a renowned British soccer player who obtained a LT for alcohol-related disease after pledging a life of abstinence but later relapsed and died within 3 years, may lead to negative perceptions of the liver allocation process[41,42]. Questions emerged about the use of a very limited resource to individuals with AUD not only amongst the lay public but also amongst physicians[43]. Given the publicity surrounding organ shortage and deaths on the waitlist, it is feared that widespread adoption of early LT for AH could lead to public distrust in how the donor pool is distributed if they believe one is responsible for their disease. Despite these concerns, the public’s hesitant attitudes towards early LT seem to be waning with time. In a public survey, three-quarters of participants indicated that they would be an organ donor even for an individual who needed a LT for alcohol-related reasons[8].

Additionally, while early LT for AH does provide more expedient treatment, it does effectively divert organs away from non-AH patients with equally severe liver disease. There are concerns that patients with AH may receive preferential treatment as they often have more favorable characteristics as a surgical candidate; that is, they often are younger, less frail, and have more robust physiologic reserve compared to their older, non-AH counterparts. This may play a role in the 6.5-fold increase in waitlist additions due to AH and greater waitlist survival by 33% between 2008-2020[5]. Introducing comprehensive psychological evaluations to assess long-term treatment of alcoholism and addiction may contribute to achieving a more equitable situation. A recent study comparing SIPAT evaluation in ALD vs non-ALD patients for LT found that SIPAT scores had a stronger influence than MELD-Na scores in determining which patients were listed for LT for ALD patients but not the non-ALD patients[44].

The Organ Procurement and Transplantation Network (OPTN) is the regulatory entity in the United States that establishes membership criteria for LT centers, specifying key personnel and procedural mandates that must be followed to conduct LTs. At the national level there is presently no set of standardized practices or qualitative indicators from OPTN that ensures a consistently equitable allocation of transplantable liver organs among LT centers and therefore the ALD population[45]. Individual LT centers in the United States generally have their own unique criteria for early LT eligibility for ALD and fewer than 60% of LT centers have protocols for monitoring alcohol consumption after early LT despite the established detrimental effects of severe AUD on graft and patient outcomes[10]. The absence of national standards for best practices and auditing procedures likely contributes to disparities in LT-related care and outcomes in this population[45].

Published recommendations and expert opinions aimed at standardizing early LT for ALD practices, ensuring precise data collecting and implementing interventions to optimize post LT outcomes, have yet to be adopted by OPTN. Field experts assert that the dissemination of OPTN best practices and guidelines on early LT for ALD will mitigate disparities in access and outcomes among LT centers nationwide[10,45]. It is imperative that medical decision-making and organ stewardship are data driven, while also engaging the community to preserve public confidence in the organ donation process. Clinicians, researchers, and patient advocacy groups must continue to analyze both short- and long-term outcomes to best serve and advocate for disadvantaged patients.

DIRECTIONS FOR THE FUTURE

Standard definitions for alcohol relapse or descriptors of the type of alcohol relapse (e.g., slip, hazardous use) are needed to allow for interstudy comparisons. Although the definition of AUD is standardized by the DSM-V criteria[46], alcohol relapse definitions vary widely in the literature. For this reason, the National Institute on Alcohol Abuse and Alcoholism has proposed operational definitions to define recovery from alcohol use disorder[47].

Biomarkers and promotion of their use

Biomarkers are needed for objective indicators of alcohol use rather than relying on self-reporting from patients or caregivers. Serum phosphatidyl ethanol and urinary ethyl glucuronide and ethyl sulfate are able to identify alcohol use up to weeks or days, respectively[48]. These biomarkers provide an objective measure to supplement the patient history of alcohol use and need to be incorporated into pre- and post-transplant monitoring protocols to allow for earlier detection when the patient’s self-reported history is not reliable. Further investigations are required to standardize the timing of its use during the evaluation process and in post LT follow-up.

Ongoing need for novel therapeutic agents

The landscape of therapeutics for AH treatment continues to evolve and should be monitored closely if agents are available to improve transplant-free survival[49-53].

Identify the role that living donor LT may play for AH patients

Although living donor LT for AH shows potential, studies from Asian countries may not be extrapolated to the US population as Asian countries have more experience with LDLT and different societal norms regarding alcohol use and different family structures providing support after transplant[54,55]. Future research is needed to determine outcomes and post LT alcohol relapse rates in AH patients undergoing LDLT in the United States.

Identifying potential sources of inequity

Inequities in access to liver transplantation have been identified in prior studies[3,56,57]. As early LT for AH is adopted at more liver transplant center globally, future research is warranted to investigate how social determinants of health (SDOH) may disadvantage marginalized patient groups.

Standardized and multidisciplinary care for AUD among LT candidates

As the prevalence of AUD increases and more AH patients are referred for early LT, hepatologists and surgeons must develop strategies on how to identify and manage AUD, psychiatric co-morbidities, and relevant psychosocial interventions. There is a need for structured post LT care planning which requires a multidisciplinary team including but not limited to a psychiatrist, addiction medicine provider, peer support personnel, and substance use navigators. Implementation of a program integrating hepatology treatment with direct access to mental health and addiction therapies has been shown to reduce cost and frequency of emergency department visits and inpatient re-admissions[58,59]. With more state and federal payors supporting early LT for AH patients, it is vital that insurance coverage for these patients include mental and addiction medicine care.

CONCLUSION

As the prevalence of AUD rises, early LT has emerged as a feasible option for AH patients to improve survival in situations where existing pharmacological therapies have been ineffective. Many trials have proven equivalent survival and alcohol relapse rates irrespective of the “6-month rule”. Intriguingly, the most recent and possibly largest trial to date showed that ALD patients who underwent early LT may have similar or better 10-year survival rates compared to patients with other liver disease diagnoses[60]. The promise of these studies, however, is contingent on careful psychosocial assessment tools. SALT and SIPAT have been adopted at many United States transplant centers to assess ALD patients for LT candidacy, and they have been shown to predict the likelihood of alcohol relapse and other graft- and patient-related outcomes. Larger long-term, prospective studies with standardized protocols are needed to truly understand and prove the benefit of early LT in AH. Notwithstanding, numerous global societies have amended their guidelines to strongly recommend early LT in select patients with SAH who are unresponsive to medical treatment if they present with favorable psychosocial evaluations[13,15]. As the transplant community continues to grow more accepting of early LT for AH, careful examination of SDOH will be needed to avoid further exacerbation of preexisting inequities in LT.