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

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)

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.

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.

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.