Management of Alcohol-Associated Liver Disease and Alcohol Use Disorder in Liver Transplant Candidates and Recipients: Challenges and Opportunities

Abstract

Alcohol-associated liver disease (ALD) poses a significant global health burden, with rising alcohol consumption and prevalence of alcohol use disorder (AUD) contributing to increased morbidity and mortality. This review examines the challenges and opportunities in the care of liver transplant (LT) candidates and recipients with AUD. Despite advancements in post-transplant patient survival, the risk of disease recurrence and alcohol relapse remains substantial. Several challenges have been identified, including (1) rising disease burden of ALD, variable transplant practices, and systemic barriers; (2) disparities in mental health therapy access and the impact on transplant; (3) variable definitions, underdiagnosis, and stigma affecting access to care; and (4) post-LT relapse, its risk factors, and consequential harm. The review focusses on the opportunities to improve AUD care for LT candidates and recipients through effective biochemical monitoring, behavioral and pharmacologic approaches, creating Centers of Excellence for post-LT AUD care, advocating for policy reforms, and ensuring insurance coverage for necessary services as essential steps toward improving patient outcomes. The review also highlights unmet needs, such as the scarcity of addiction specialists, and calls for further research on personalized behavioral treatments, digital health, and value-based care models to optimize AUD care in the LT setting.

Introduction:

Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality on a global scale. Approximately 25 million individuals have cirrhosis attributable to alcohol, of whom 10% have decompensated cirrhosis and hepatocellular carcinoma, accounting for 1% of deaths annually.^1,2 Over the last decade, ALD has become the leading indication for liver transplantation (LT) in the United States (U.S.).³ Despite excellent 1- and 5- year post-transplant patient survival among carefully selected patients,³ the risk of harmful alcohol use after LT is significant.⁴

The landscape of transplant practices in patient selection, treatment of concurrent alcohol use disorder (AUD) and mental health disease, and support in the transplant settings varies widely. Addressing this variability, aligning terminology, and defining best practices for ALD and AUD are crucial steps for enhancing care. This comprehensive review is framed around the challenges and opportunities in the management of AUD among LT candidates and recipients with ALD (Table 1) and highlights the need for a paradigm shift towards value-based care models and additional clinical training to address the unique challenges in managing AUD after LT.

Table 1:

Key challenges, disparities and opportunities in liver transplantation for alcohol-associated liver disease and their root causes

Challenges	Root Cause(s)	Examples of Opportunities for Future Implementation and Research
Geographic variation in transplant rates for ALD	Differences in regional availability and accessibility of transplant centers, donor organs, and addiction services	Creating Centers of Excellence via Hub and Spoke or Colocated models Testing hybrid telem edicine/in-person models of AUD care
Lower transplant rates for Black patients with ALD	Barriers to referral and evaluation for transplant - lack of insurance, social support, and transportation, possible implicit/explicit bias	Shifting payor policies, Medicaid expansion Leveraging EHR to identify at-risk patients within health systems Understanding patient-, provider-, and system-level barriers to engagement in AUD treatment
Lower transplant rates for women with ALD	Higher mortality and dropout rates on the waitlist, possibly due to more advanced disease, lower MELD scores, and higher rates of infection and sepsis, possible implicit/explicit bias	Increasing provider education and public education about evolving transplant practices Leveraging EHR to identify at-risk patients within health systems
Lower transplant rates for older patients with ALD	Age-related comorbidities, frailty, and reduced life expectancy
Lower post-transplant survival for patients with ALD	Relapse to alcohol use, medication nonadherence, and psychosocial issues	Multidisciplinary programs to reduce post-LT relapse Optimal screening and monitoring strategies for return to alcohol use Standardization of best practices and center resources for addiction support Testing safety and comparative effectiveness of AUD pharmacotherapy in the transplant recipients

Challenge #1: The rising disease burden of ALD and variable transplant evaluation and listing practices affect access and outcomes.

The annual average alcohol consumption per person has increased by 25% in women and 39% in men leading to 2.2% of age-standardized female deaths and 6.8% of age-standardized male deaths in 2016.⁵ Among persons 15-49 years old, alcohol constituted 3.8% and 12.2% of deaths for females and males, respectively.⁶ In the U.S., the COVID-19 pandemic was associated with a 20% increase in alcohol-related mortality (78,927 to 99,017 deaths) and liver mortality (24,106 to 29,504 deaths).⁷

In parallel with rising disease burden, ALD has become the leading indication for LT.⁸ LTs are also increasingly performed for patients with alcohol-associated hepatitis (AH) and ALD who have not demonstrated prolonged sobriety.⁹ Despite these changes, there remains considerable variability in access to LT for many ALD patients. Compared to physicians with specialized LT training, those without often require patients to demonstrate a longer length of sobriety prior to LT referral or do not refer for LT at all (OR 1.81, 95% CI 1.27-1.55).¹⁰ An international multi-center cohort study demonstrated that compared to non-ALD etiologies, patients with ALD were often referred late for specialty liver care (OR 14.1, 95% CI 10.5-18.9).¹¹

Despite increased acceptance of early LT for AH, evaluation practices and selection criteria are variable.¹² Systemic barriers exist in the form of payor policies that mandate specific durations of abstinence or documentation of rehabilitation prior to waitlisting.¹³ Marked disparities emerge from these practices (Table 1). Individuals of female sex, Black race, or those with limited English proficiency are less likely to be referred or waitlisted for LT or to successfully undergo transplant.^14-16 Non-Hispanic white patients comprise 75% of patients waitlist for LT with ALD, a higher-than-expected proportion after accounting for population-level burden of ALD.¹⁶ The highest burden of ALD continues to be within white Hispanic males.¹⁷ Based on a survey data, less than 40% of transplant centers have defined metrics for success in LT for AH, and less than 50% have protocols for managing alcohol relapse after transplant.

Co-existing mental health diseases, including major depression, anxiety, and bipolar disorder, occur in a substantial proportion of LT patients with AUD limiting treatment engagement and access to the waitlist.¹⁸ Patients with ALD and AH who require LT are frequently declined or excluded from “early” LT protocols for psychosocial factors.^19,20 In a study of patients referred for LT at safety net hospitals, psychiatric illness was the reason for denial for LT in 14.8% of cases.²¹

Opportunity: Improve fairness and consistency in transplant referral, evaluation, and listing practices across centers

Amongst the core ethical principles outlined by the Organ Procurement and Transplantation Network (OPTN) is “justice,” which refers to fair and equitable practices for evaluation, selection, and organ distribution.²² Within the context of LT for ALD, achieving justice will require improving transparency in selection criteria, generating consensus on accepted indications for LT, and eliminating medically unsound policies and processes that add undue or excessive burden on patients. Published expert guidance for candidacy for LT in AH already exists but continued re-assessment and refinement will be key.²³

Other potential interventions may include outreach and education for community providers, implicit bias training for transplant teams, and quality metrics for transplant referral. Community hepatology or GI providers will need to be counselled to start helping their ALD patients engage with alcohol cessation treatment protocols and increase their confidence in making earlier referral for LT for ALD. Importantly, LT centers will also benefit from support to hire addiction specialists, not only to ensure patients undergo thorough, objective pre-transplant evaluations, but also to provide access to the expertise required for treating active mental health disease and substance use before and after LT.

Opportunity: Favorable payor policies can increase access to LT in ALD

The transplant community plays an integral role in advocating for policy reform. Recent evidence shows Medicaid expansion, implemented in 2014 under the Affordable Care Act, was associated with increased access to the LT waitlist. The observed increase was greater among Black, Hispanic, and Asian patients and was notable for patients with ALD.²⁴

Challenge #2: Disparities persist in the access to AUD management and transplant

Data from the Substance Abuse and Mental Health Services Administration from 2022 show that amongst individuals in the general population aged 18 or older with AUD, only 7.6% received treatment.²⁵ In the subset of patients with ALD, receipt of appropriate AUD treatment is even lower.²⁶ Data from the National Epidemiologic Survey on Alcohol and Related Conditions showed that patients who identified as racial and ethnic minorities had half the odds of receiving alcohol intervention (OR 0.48, 95% CI 0.28-0.81) compared with white patients after adjusting for sex, age, education, income, health insurance, drinking severity, and prior alcohol treatment.²⁷ In transplant recipients, evidence regarding AUD therapy, including pharmacologic treatment is sparse, and prior trials have been difficult to complete.²⁸ Nonetheless, AUD treatment in LT recipients has been associated with lower rates of relapse.²⁹

Major barriers to treatment of AUD in the context of ALD are inadequate quantification of alcohol use, poor insight into the addiction and need for treatment, and lack of available resources in the post-transplant setting ^30-32. These challenges pervade multiple levels of the healthcare system. Appropriate treatment of addiction often requires medications and toxicology testing, weekly individual psychotherapy, regular group participation and family therapy. Lack of these coordinated multi-modal treatment programs delivered in a patient-centered way contributes to the lack of treatment engagement. The resulting disparities are well-documented (Table 1).

Opportunity: Reduce barriers to diagnosis and management of AUD from pre- to posttransplant phase

Increasing awareness and education of AUD among primary care providers, gastroenterologists, and hepatologists is crucial to mitigate the reported suboptimal rates of referral for behavioral therapy and provision of AUD pharmacotherapy.³³ Few transplant centers have structured programs to manage addiction, leaving patients to seek these resources independently.¹² After transplant, the minority of patients who return to alcohol use require additional clinical attention from nurse coordinators and social workers who may not be equipped with the resources or bandwidth to counsel patients and initiate appropriate interventions. There is opportunity for stakeholders (e.g., insurance companies, national organizations) to provide a “Center of Excellence” designation to programs that successfully implement integrated pathways of care for AUD, which include embedded addiction specialists as well as connections to community-based mental health services.³⁴ In communities where a significant proportion of residents speak languages other than English, transplant programs should prioritize investing in robust language services or hiring healthcare providers fluent in the native languages. This will ensure optimal diagnosis and effectively motivate patients for treatment.

Challenge 3: Variable definitions, and associated stigma contributes to lack of treatment

The stigmatization of AUD dates back to early 1950s, framing it as personality disorder or personal failing.³⁵ Advances in neuroscience support that AUD is a chronic brain disease, that can be relapsing and remitting, resulting from neurobiological, genetic, and environmental factors.^36,37 Older terminology like “alcoholism,” “alcoholic,” “alcohol dependence,” “alcohol abuse” and “addict” imply patient intent and invite punishment thereby demoralizing patients. Stigmatization occurs using aforementioned patient-blaming language and hinders AUD treatment,^38,39 with only 7.6% of patients with AUD receiving help in 2019, potentially due to societal bias.⁴⁰ Efforts to destigmatize and promote accurate terminology are crucial for supporting recovery, particularly in medical settings such as LT. In 2019, the American Society of Addiction Medicine redefined addiction to reduce stigma: Addiction is a treatable, chronic medical disease involving complex interactions among brain circuits, genetics, the environment, and an individual’s life experiences.⁴¹

Table 2 shows the diagnostic criteria for AUD, dependence, and patterns of alcohol use as described by the most recent edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), the International Classification of Diseases, 11th edition (ICD-11), the World Health Organization (WHO), and the National Institute of Alcohol Abuse and Alcoholism (NIAAA).^42-45 Published studies on LT recipients use definitions provided by the NIAAA, which vary according to patient sex.^46,47

Table 2.

Diagnostic Criteria for Alcohol Use Disorder, Alcohol Dependence, and Patterns of Alcohol Use

DSM-5 Criteria for Alcohol Use Disorder*	ICD-11 Criteria for Alcohol Dependence#	NIAAA Patterns of Alcohol Use
Impaired Control Alcohol often taken in larger amounts or over longer period than was intended Persistent desire to cut down on alcohol use or unsuccessful efforts to cut down or control alcohol use Great deal of time spent in activities necessary to obtain alcohol, use alcohol, or recover from alcohol use Strong desire or urge to use alcohol	Impaired control of alcohol use	Moderate Use Male: ≤ 2 drinks/day Female: ≤ 1 inks/day
Social Impairment Recurrent alcohol use negatively affecting major role obligations at work, school, or home Continued alcohol use despite having persistent or recurrent social or interpersonal problems or exacerbated by the effects of alcohol Important social, occupational, or recreational activities are given up or reduced because of alcohol	Social dysfunction due to alcohol use	Heavy Drinking Male (under age 65): 4+ drinks/day or 14+ drinks/week Female (or anyone age 65 or greater): 3+ drinks/day or 7+ drinks/week
Risky Use Recurrent alcohol use in situations in which it is physically hazardous Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been cause or exacerbated by alcohol	Physiological symptoms related to alcohol use: tolerance and withdrawal	Binge Drinking Male: 5+ drinks within 2 hours Female: 4+ drinks within 2 hours
Pharmacological Effects Tolerance defined by either: A need for markedly increased amounts of alcohol to achieve intoxication or desired effect, OR A markedly diminished effect with continued use of same amount of alcohol Withdrawal or taking alcohol to relieve withdrawal	Additional Patterns of Alcohol Use “Harmful”: Repetitive alcohol use causing harm to physical or mental health “Hazardous”: Pattern of alcohol use that increases the risk of harmful physical or mental health consequences

^*At least 2 symptoms in the past year: mild 2-3 symptoms; moderate 4-5; severe disorder 6 or more

^#Requires 2 of the 3 above criteria; DSM- Diagnostic and Statistical Manual of Mental Disorders, ICD- International Classification of Diseases; NIAAA National Institute on Alcohol Abuse and Alcoholism.

Opportunity: Foster Patient-Centered Language and Including Patient Perspectives in the management of AUD

Using patient-centered terminology reduces stigma and facilitates treatment by shifting the focus from labelling and blaming individuals by their condition to considering the individual’s full biopsychosocial history,^38,48 Instead of the terms “alcoholics” or “addicts,” individuals can be referred to as patients with AUD (Table 3). Despite these efforts, a systematic review of AUD-related articles indexed in PubMed published between May 2018 to April 2020 reported that only 20.1% of publications adhered to patient-centered language.⁴⁹ The 2019 Dallas consensus conference and AASLD suggest best practices for destigmatizing language.^23,50 Motivational enhancement therapy for AUD uses patient-centered language as part of increasing patient insight into problem drinking. Table 3 offers concrete language clinicians should use to facilitate patient-centered language and should be referred to as an effort to reduce frequently utilized stigmatizing terms within liver transplant setting.

Table 3 -.

Patient-centered Language for Alcohol Use Disorder and Alcohol-related Liver Disease

Stigmatizing Terminology	Preferred Terminology
Abuse	Use/Misuse
Alcoholism/alcohol abuse	Alcohol use disorder
Alcoholic	Person with alcohol use disorder
Alcoholic liver disease	Alcohol-related/associated liver disease
Alcoholic hepatitis	Alcohol-related/associated hepatitis
Alcoholic cirrhosis	Alcohol-related/associated cirrhosis
Clean	Testing negative/Being in remission or recovery
Dirty	Testing positive/Person actively using substances
Recidivism	Relapse (or return or recurrence) to alcohol use

Challenge #4: Post-LT relapse pose demands on transplant team.

Post-LT relapse rates and risk factors:

It is difficult to precisely estimate rates of AUD relapse after LT, due to significant study variation in definitions of relapse, methods for assessing alcohol use (e.g., biomarkers vs. self/collateral report), and follow-up duration. Across studies, relapse rates vary from 13-46% for any drinking and 8-24% for harmful drinking,^51-57 with a systematic review and meta-analysis of 86 studies with over 8,000 patients over a mean follow-up of 48 ± 24 months generating a pooled relapse rate of 22% and 14% for any and harmful drinking, respectively.⁵⁸

For patients transplanted for AH with short sobriety, studies are conflicting regarding whether the relinquishment of the 6-month rule has led to an increase in observed relapse rates. In early trials of LT for severe AH, relapse rates ranged from 11-33% for any drinking and 11-22% for harmful/sustained drinking.^19,46,59-62 However, a recent prospective multicenter study at 19 French and Belgian hospitals demonstrated 2-year relapse rates of 34% in LT recipients with early LT for AH compared to 25% with ALD and >6 months of abstinence.⁶² Another single-center retrospective U.S.-based study showed a significantly higher return to harmful drinking at 3 years in the early LT for AH cohort compared to ALD controls (33.2% vs 14.6%, p=0.05).⁶³

A variety of other factors have been associated with relapse, albeit with inconsistent results across multiple studies. A systematic review of 92 studies found that psychiatric comorbidities (OR 3.46, 95%CI: 1.87-6.39), pre-transplant abstinence of less than 6 months (OR 2.76, 95%CI: 2.10-3.61), unmarried status (OR 1.84, 95%CI: 1.39-2.43), and smoking (OR 1.72, 95%CI: 1.21-2.46) were associated with alcohol relapse after LT.⁵⁸ In another retrospective single-center study, 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 drinking in patients with short pre-LT sobriety.⁶³

There are multiple pre-LT risk scores that predict post-LT relapse (Table 4), including the high-risk alcohol relapse score (HRAR), harmful alcohol use post-LT (HALT) score, sustained alcohol use post-LT (SALT) score, the Stanford Integrated Psychosocial Assessment for Transplant (SIPAT), and the alcohol relapse risk assessment (ARRA).^57,64-70 However, these scores are not generally externally validated, and while cut-off scores on some have a high negative predictive values (e.g., SALT), it lacks sensitivity.⁷¹ Motor impulsivity may also predict post-LT alcohol use.⁷²

Table 4.

Post-transplant Alcohol Relapse Risk Scores

Risk Score	Author	Study Design, Population	Outcome	Score Components	AUC*
ARRA	Rodrigue et al., 201364	Single-center, retrospective, chronic ALD	Any alcohol use	Absence of HCC, tobacco dependence, continued alcohol use after liver disease diagnosis, low motivation for alcohol treatment, poor stress management skills, no rehabilitation relationship, limited social support, lack of nonmedical behavioral consequences, and continued engagement in social activities with alcohol present.	0.89
BIS-11 SF	Umman et al., 202372	Single-center, retrospective Alcohol-associated liver failure	Any alcohol use	Questions that assess motor impulsiveness	0.83
HALT	Satapathy et al., 202069	Single-center, retrospective, chronic ALD and AH	Harmful alcohol use (> 3 drinks per week or medical/social harm)	Older age at LT, non-alcohol-related criminal history, pre-LT abstinence period < 6 months, > 10 drinks per day.	0.79
HRAR	DiMartini et al., 200068	Single-center, retrospective, chronic ALD	Any alcohol use	daily alcohol consumption, drinking duration, previous alcohol treatment history	Not predictive
Penn Psychosocial Model	Deutsch-Link, et al., 202057	Single-center, retrospective, chronic ALD	Any alcohol use	Failure to engage in an IOP despite clinician recommendation, history of relapse after initial attempt at sobriety, did not stop alcohol consumption when diagnosed with liver disease	0.77
SALT	Lee et al., 201870	Multi-center, retrospective	Sustained alcohol use with > 100 days of use	>10 drinks per day at initial hospitalization, multiple prior rehabilitation attempts, prior alcohol-related legal issues, and prior illicit substance use	0.76
SIPAT	Deutsch-Link, et al., 202057	Single-center, retrospective, chronic ALD	Any alcohol use	SIPAT score ≥21	0.71

Abbreviations: AH, alcohol-associated hepatitis; ALD, alcohol-associated liver disease; ARRA, Alcohol Relapse Risk Assessment Scale; BIS-11 SF, Barratt Impulsiveness Scale-11 Short Form, HALT - HCC – hepatocellular carcinoma, IOP – intensive outpatient program, HRAR - High-Risk Alcoholism Relapse, SALT - Sustained Alcohol Use Post-Liver Transplant, SIPAT-Stanford Integrated Psychosocial Assessment for Transplant

^*95% CI was not uniformly provided in the reviewed publications and has not been reported.

Consequences of post-LT alcohol relapse:

Severe post-transplant alcohol relapse is associated with medication non-adherence, allograft rejection, pancreatitis, steatosis, steatohepatitis, graft fibrosis, and cirrhosis. Early onset trajectories of post-LT alcohol use have been found to be associated with higher risk of steatohepatitis (23% vs. 9%), biopsy-proven acute allograft rejection (41% vs. 18%), and graft failure (73% vs. 37%).⁷³ Multiple studies showed that any post-LT relapse was associated with allograft rejection, medication nonadherence, allograft fibrosis, and allograft loss.^53,74-79

The cumulative risk of developing recurrent cirrhosis with severe relapse is documented as 16% at 5 years, 35% at 10 years, and 51% at 15 years post LT.⁸⁰ The effect of recurrent alcohol use on post-LT patient survival depends on the pattern of use and the duration of follow-up. Two year survival is similar despite higher rates of heavy alcohol use in LT for AH compared to ALD and >6 months of abstinence (HR 0.87, 95% CI 0.33 – 2.26).⁶² In a U.S study of LT for AH, 3- and 5-year survival were significantly lower only in those with early patterns of any recurrent alcohol use (both non-heavy and heavy).⁸¹ A French study of patients with ALD cirrhosis from 1990 to 2007 showed that recurrent cirrhosis, present in 32% of those with severe alcohol relapse, was associated with lower 5-year (49.7% vs. 69.9%) and 10-year survival (21% vs. 41.1%) compared to no relapse.⁸⁰ A meta-analysis of 7 studies showed that return to alcohol use was associated with increased odds of death at 10 years (OR 3.67, 95% CI 1.42 – 9.50), with the most common causes of death being recurrent cirrhosis, extrahepatic malignancy, and cardiovascular events.⁷⁶

Opportunity: Effective Pre and Post LT Monitoring, Behavioral, and Pharmacologic Approaches to manage post-transplant relapse

A multi-dimensional approach that involves validated measures such as the Alcohol Use Disorder Identification Test-Concise (AUDIT-C) or Alcohol Timeline Follow-Back paired with regular measurement of biomarkers (e.g., urine ethyl glucuronide or blood phosphatidyl ethanol [PEth]) can increase detection of relapse post-LT.

Biochemical Monitoring:

Several biomarkers are currently in clinical use, but only a few are direct biomarkers of ethanol molecules (Table 5). Urine ethyl glucuronide (uEtG) can detect recent alcohol use within 3-5 days but has some potential for false positives.⁸² PEth is the most sensitive direct biomarker for alcohol intake and has been studied in pre- and post LT populations.⁸² PEth is a lipid species formed by phospholipase D on the surface of red blood cells and has a detection window of 2 to 4 weeks with up to 100% specificity for alcohol ingestion.^83-86 Concerns for false positives with blood transfusions have been raised; low-positive PEth results in patients who have received blood transfusions and had no access to alcohol should be carefully considered within the clinical perspective as it could represent a false positive, especially when uEtG is negative.⁸⁷

Table 5 -. Direct Biomarkers for Alcohol Use.

Biomarker	Detection Window	Test Performance	Utility
Urine Ethanol	5-8 hours	Sensitivity: 100% Specificity: 100%	If encephalopathic, useful to estimate risk of alcohol withdrawal
Urine Ethyl Glucuronide (EtG)	5 days	Sensitivity: 76% Specificity: 93%	Can be 100% sensitive within 2-3 days
Blood Phosphatidyl Ethanol (PEth)	Low use: 12 days Moderate use: 2-3 weeks Heavy use: 3-4 weeks	Sensitivity: 97-99% Specificity: 100%	Can estimate quantity of use based on last daily drink

PEth test validity extends to chronic liver disease and can distinguish between various levels of alcohol use: <20 ng/mL (little or no drinking), 20-200 ng/mL (moderate consumption), and >200 ng/mL (heavy consumption), making it possible to estimate the degree of daily alcohol intake within the detection window.^86,88,89 In a recent single-center report, widespread adoption of PEth (74%) led to a substantial positivity rate (22%, ranging from 10 ng/mL to 2000 ng/mL) with high rates of discordance with patient self-report.⁹⁰ This discordance requires clear and effective communication, utilizing non-stigmatizing language, to maintain a strong patient-provider relationship. Strategies for compassionate and effective communication can be taught and adapted for specialty clinics (See Table 3 for basic updated patient-centered terminology).⁸⁷

Medical and Psychosocial Therapy, Nutrition, and Exercise Management:

Figure 1 shows the general principles of specific management, including risk stratification, biochemical monitoring, use of medications, and other psychological interventions. The management of AUD after LT is a comprehensive and multidisciplinary approach based on the type of AUD encompassing pharmacological, psychosocial, exercise, and nutritional components.⁹¹ The initial and most important step is increasing insight and motivation for treatment.³²

Figure 1:

General Principles of Post-transplant ALD Management

Medications for AUD (MAUD):

While no medication has been tested for safety and/or efficacy in the post-LT population, naltrexone, acamprosate, and disulfiram are FDA-approved for AUD, whereas the use of baclofen, topiramate, and gabapentin is off-label (Table 6). In a meta-analysis of 122 randomized controlled trials with at least 12 weeks duration in the outpatient setting in general population, naltrexone and acamprosate were associated with marked reduction in return to drinking with the number needed to treat of 20 and 12, respectively.⁹² Moderate quality evidence supports an association with improvement in some consumption outcomes for nalmefene and topiramate.⁹²

Table 6 -.

Medications for Alcohol Use Disorder (MAUD)

Drug Name	Mechanism	Liver Safety116	Efficacy	Common Side Effects
Disulfiram 250-500mg QD (FDA approved for AUD)	Irreversible inhibitor of Aldehyde Dehydrogenase Causes a disulfiram-ethanol reaction which is aversive with alcohol use. Best practice is to include family in dose monitoring	Hepatic metabolism, cannot start if baseline LFTs are >2x UNL or Tbili > 3mg/dl LiverTox Grade: A (known cause of apparent liver injury)	Meta-analysis (Skinner, 2014)117 22 RCTs (N=2414) Effect Size = 0.82 (to prevent return to drinking) Requires cessation of alcohol to start	Drowsiness Tiredness Headache
Naltrexone 50mg QD 380mg SC QM (FDA approved for AUD)	Mu and Kappa-opioid receptor antagonist Reduces cravings and enhances sedative effects of alcohol. Best practice to start SC depot if nonadherence	Hepatic metabolism, Obtain LFTs at baseline and every 6 months LiverTox Grade: E (unproven but suspected cause of liver injury)	Meta-analysis (Jonas, 2014)92 53 RCTs (N=9140) NNT=12 (to prevent heavy drinking) Can be started while patient drinking heavily	Nausea/vomiting Fatigue Dizziness
Acamprosate 333-666 mg TID (FDA approved for AUD)	GABA agonist and partial NMDAR antagonist Tempers cravings and improves insomnia after alcohol cessation.	No hepatic metabolism but needs renal adjustment. LiverTox Grade: E (unproven but suspected cause of liver injury)	Meta-analysis (Jonas, 2014)92 27 RCTs (N=7519) NNT = 12 (to prevent return to drinking) Best practice to start one week after cessation	Diarrhea Nausea/vomiting
Baclofen 10-20 mg TID (off label)	GABA B receptor agonist Inhibits alcohol-induced dopamine release to temper cravings. Also treats muscle tension	Minimal hepatic metabolism but needs renal adjustment. LiverTox Grade: D (Possible, rare, cause of apparent liver injury)	Meta-analysis (Pierce, 2018)118 8 RCTs (N=1244) OR = 1.93 (to prevent return to drinking)	Sedation Dizziness
Gabapentin 200-600 mg TID (off label)	GABA analog Treats alcohol withdrawal and possible anxiety related to alcohol craving. Also treats neuropathy	No hepatic metabolism but needs renal adjustment LiverTox Grade: C (Probable cause of apparent liver injury)	Meta-analysis (Kranzler, 2019)119 7 RCTs (N=730) Effect Size = 0.69 (to reduce heavy drinking days)	Sedation Dizziness
Topiramate 75-400 mg QD (off label)	GABA/glutamate modulator Inhibits alcohol-induced dopamine release to temper cravings. Also used for impulsivity and binge eating.	Hepatic metabolism CYP 3A4 LiverTox Grade: C (Probable cause of apparent liver injury)	Meta-analysis (Blodgett, 2014)120 7RCTs (N=1125) Effect Size = 0.47 (to prevent return to drinking)	Parasthesias Weight loss Dizziness Cognitive slowing

Despite its efficacy, fewer than 10% of patients ever receive MAUD.⁹³ In a single center study, patients with AUD and cirrhosis treated with MAUD had 63% lower adjusted odds of developing ALD and 65% lower odds of hepatic decompensation compared to no MAUD. When stratified by types of MAUD, receipt of naltrexone, gabapentin, topiramate, or baclofen in particular were associated with decreased odds of developing ALD while receipt of naltrexone and gabapentin were associated with decreased odds of developing hepatic decompensation.⁹⁴ Concern for the safety of naltrexone with liver disease has been raised without a strong evidence base; accordingly, the black box warning for liver injury was removed in 2013.^95-98 The Drug Induced Liver Disease Network, evaluating 899 cases of drug-induced liver injury between 2004 and 2013, did not attribute any cases to naltrexone or other opioid antagonists.⁹⁹

Psychological and peer support Interventions:

Several evidence-based psychological interventions are effective in treating AUD.^75,100-105 These include cognitive behavioral therapy (CBT), motivational enhancement therapy (MET), 12-Step Facilitation, contingency management (CM), family therapy, mindfulness, and acceptance therapy.^101,106 Peer support resources may complement evidence-based treatments.¹⁰⁷ The addition of evidence-based behavioral therapies to medication treatments may improve outcomes. One meta-analysis of 30 randomized trials of CBT delivered along with pharmacological treatment for AUD or substance use disorders indicated that the combination of CBT with medications was associated with reductions in alcohol use compared with usual care plus pharmacotherapy.¹⁰⁸ No single psychological treatment modality is superior to others and recommendations are based on patient preference and local availability.¹⁰⁹

Evidence supporting interventions related to nutrition and exercise is emerging.^110-112 Patients with AUD are at risk of vitamin and mineral deficiencies, malnutrition, obesity, neurologic disease, and metabolic syndrome.^113,114 Engagement in exercise may reduce alcohol cravings, enhance mood, improve sleep, and coping.^111,112

Opportunity: Centers of Excellence for Post-LT AUD care.

The management of post-LT relapse is resource intensive and poses high demands on the transplant team. Many transplant centers outsource post-LT AUD therapy to the community due to lack of resources and to reduce travel time for patients. A potential solution is creation of ‘Centers of Excellence’ via a Hub and Spokes model, where the transplant center serves as the hub, networking with community-based addiction and mental health centers with addiction specialists (psychiatrists, psychologists, therapists and social workers) as spokes to provide integrated treatment before and after LT. Another model can include co-located services integrating medical, surgical, psychological, and addiction care within the transplant program. Telemedicine can serve an important role in delivering specialized AUD care over greater distances. The Centers for Medicare and Medicaid Services has instituted indefinite provisions for delivery of mental or behavioral services to patients at home and via video or audio,¹¹⁵ however interstate licensure restrictions may still hamper telemedicine delivery.

Areas for Future Research and Policy Development:

With the increasing prevalence of early LT for ALD and AH, areas for further implementation and research and are highlighted in Table 1. A strategic policy to enhance AUD care access for LT candidate and recipients involves establishing exclusive Centers of Excellence for transplant programs, offering comprehensive peri-transplant behavioral medical addiction services. Advocacy is crucial for ensuring insurance coverage of MAUD therapy and psychiatric and rehabilitation programs, either through transplant-bundled or standalone payments. Setting minimum standards for addiction, social work, psychology, psychiatry, and patient navigation services in ALD and AUD can empower transplant clinicians in resource advocacy. Medicaid expansion is essential for improving coverage and access to LT for vulnerable groups with ALD. The shortage of mental health and addiction specialists, often filled by other disciplines, highlights the need for enhanced clinician training, especially for hepatologists. Resource-intensive post-LT care for patients with relapse necessitates a shift to value-based models, with negotiated reimbursement for comprehensive services.

Further research is crucial for personalized behavioral treatments, multi-disciplinary care integration, and exploring digital health and telemedicine in the ALD/AUD care model. Structured screening linked to care can enhance the detection and management of recurrent alcohol use.

Abbreviations:

AH

Alcohol associated hepatitis

ALD

Alcohol associated liver disease

AUD

Alcohol use disorder

CI

Confidence Interval

HR

Hazard Ratio

MAUD

Medications for Alcohol use disorder

LT

Liver Transplantation

MASLD

Metabolic dysfunction associated steatotic liver disease

OR

Odds Ratio

PEth

Phosphatidyl ethanol

uEtG

Urine ethyl glucuronide