In MetALD, the coexistence of alcohol consumption and metabolic dysfunction creates a pattern of liver injury that outpaces what either factor would cause independently^[21]. Both conditions share key mechanisms, including lipid dysregulation, oxidative stress, and disrupted gut-liver signaling^[21]. Their combined effect becomes clinically relevant once advanced chronic liver disease (aCLD) is established. At that stage, alcohol is not a static etiologic label but an ongoing contributor to disease trajectory. This ongoing contribution is relevant for transplant candidates, where alcohol exposure continues to influence outcomes after the diagnosis of aCLD. Intake of ≥ 280 g per week has been independently associated with higher mortality (HR 1.98) and hepatic decompensation (HR 1.62)^[22], suggesting that ongoing drinking directly worsens outcomes in the short and medium term. Notably, the prognostic impact extends beyond the liver; a systematic review of over 50,000 individuals with ALD found a 2.4-fold higher risk of cardiovascular death [relative risk (RR) 2.4, 95%CI: 1.6-3.8] and 8.2 higher risk of extrahepatic cancer (RR 8.2, 95%CI: 4.7-14.3) compared to controls, with the highest rates in those with cirrhosis and decompensated disease^[23]. For MetALD candidates, alcohol use carries prognostic weight that extends beyond disease classification. This shapes referral timing and whether transplant evaluation is pressing.

The underlying metabolic dysfunction also lowers the threshold at which alcohol becomes harmful. Population-based studies suggest that individuals with metabolic risk are more vulnerable to alcohol-related liver injury than those without it. In a long-term cohort of individuals with hepatic steatosis, the combination of metabolic syndrome and excessive alcohol consumption was associated with a significantly increased risk of all-cause mortality (HR 3.35), suggesting that metabolic dysfunction lowers the alcohol-related risk curve toward lower levels of consumption^[24,25]. While these data come from largely non-cirrhotic populations, they are still relevant to pre-LT evaluation, even moderate alcohol intake may have greater risk when metabolic dysfunction is already present.

Beyond cumulative volume, the pattern of alcohol intake also appears to influence disease severity. For instance, persistent binge drinking independently increases the risk of advanced fibrosis [adjusted odds ratio (aOR) 2.23] and all-cause mortality (aHR 1.48), even when controlling for average daily intake^[26]. As such, the pre-LT evaluation of patients with MetALD must evolve beyond simple alcohol quantification to encompass a more nuanced, multidimensional characterization of exposure, including intensity, temporal patterns, prior hazardous use, and duration of abstinence. This approach is aligned with the expert recommendation of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) expert consensus, which advocates evaluating drinking topography rather than relying exclusively on weekly averages^[27].

Moreover, among patients with aCLD and decompensated cirrhosis, alcohol exposure may also reduce the probability of clinical recovery. In a single-center cohort of patients with decompensated cirrhosis, those with MetALD achieved a 12-month recompensation rate of only 3.4%, compared to 18.5% in the ALD group^[28]. Although these findings require external validation, they suggest that the metabolic component of MetALD may limit hepatic recovery even when alcohol consumption is addressed. The latter interpretation is also consistent with national registry data showing that MetALD candidates face a higher risk of waitlist removal due to death or clinical deterioration than ALD candidates^[10]. This contrast becomes even more striking in light of recent multicenter data showing that sustained abstinence enables recompensation in approximately one-third of patients with decompensated ALD cirrhosis, with early abstinence (within the first month of index decompensation) more than doubling the probability of achieving recompensation, and with none of the recompensated patients who maintained abstinence dying from liver-related causes^[29]. The fact that MetALD shows lower recompensation rates than ALD, despite the shared alcohol-related component, points to the metabolic burden as an independent constraint on hepatic reserve.

This evidence has practical consequences for pre-LT evaluation. In established aCLD, alcohol does not simply define the diagnosis; it continues to influence outcomes, and how much a patient is drinking at any given point should inform how closely they are monitored, when to escalate intervention, and whether transplantation evaluation is pressing.

Because alcohol exposure after the onset of aCLD is frequently underreported and continues to impact clinical trajectory, objective alcohol-use assessment becomes essential during transplant evaluation. Self-reported alcohol intake is vulnerable to underestimation in this setting, where stigma and concern about candidacy may limit disclosure. For this reason, objective biomarkers serve a critical role in suspected MetALD, in whom accurate alcohol phenotyping has direct implications for diagnosis and for risk stratification and management.

Among currently available alcohol biomarkers, phosphatidylethanol (PEth) offers the most specific readout of recent alcohol exposure, covering the previous 2-4 weeks with interpretative cutoffs that facilitate the detection of harmful drinking^[30]. In SLD, PEth-based exposure assessment has also been associated with prognostic discrimination for hepatic decompensation and death^[31,32], highlighting its relevance not only as a confirmatory biomarker but also as a measure of ongoing risk.

PEth may also refine disease classification. In a large PEth cohort, about one in five individuals labeled as MASLD had PEth levels consistent with MetALD, with an additional subset meeting ALD-range exposure^[33]. This high rate of reclassification highlights the limitations of relying solely on self-reporting, which often masks significant alcohol intake and leads to phenotyping errors. This problem is also reflected in real-world clinical cohorts. In a Swedish national registry of 15,107 patients initially coded as MASLD, 12% had a pre-existing diagnosis of ALD or alcohol use disorder (AUD), with a further 5.2% identified during the follow-up^[34]. Such misclassification is a critical concern during pre-LT evaluation, as it potentially delays both addiction-focused interventions and accurate candidacy assessment.

In addition, a prospective cohort of suspected MetALD cases combining cardiometabolic criteria with either self-reported alcohol consumption within the MetALD range or a PEth level ≥ 25 ng/mL found that the majority of cases were identified through PEth testing, and a subsequent diagnostic pathway of Fibrosis-4 index (FIB-4) followed by VCTE demonstrated a low false-negative rate of detecting significant fibrosis in this population^[35]. Together, these data support the incorporation of PEth into pre-LT algorithms for patients in whom alcohol consumption is uncertain, minimized, or clinically discordant with the apparent phenotype.

From an implementation standpoint, PEth also appears attractive in the waitlist setting. A cost-effectiveness analysis demonstrates that monthly serum PEth testing is the most accurate and cost-effective strategy for detecting alcohol use in LT candidates with ALD compared with other alcohol biomarkers^[36]. Although more data are needed for MetALD candidates, the relatively low cost of PEth in the context of LT makes it a reasonable strategy to extend to all patients being evaluated for transplantation [Figure 1]. Objective monitoring is also relevant because abstinence cannot be assumed once a patient is listed. In a multicenter cohort of ALD-listed patients, documented alcohol consumption during waitlisting was documented in 9.6% of patients at a median of 6.2 months after listing. Furthermore, alcohol use on the waiting list was strongly associated with post-LT alcohol use [odds ratio (OR) 6.36] despite no observed difference in 5-year post-LT survival^[37].

Yet, there are important considerations when using PEth. Because the biomarker reflects cumulative exposure over the previous two to four weeks, an isolated binge may yield variable or low concentrations depending on the timing and amount consumed, reducing sensitivity for sporadic heavy drinking. Results can also be falsely negative with low-level intake or falsely positive following exposure to non-beverage ethanol. Accurate interpretation depends on established cut-offs, approximately 25 ng/mL for recent exposure and near 210 ng/mL for sustained ALD-range intake, and requires high-quality assays, with whole-blood liquid chromatography-tandem mass spectrometry (LC-MS/MS) remaining the standard over current serum-based enzyme-linked immunosorbent assays (ELISAs)^[30].

Routine monitoring is typically recommended monthly during waitlisting and every three to six months after transplantation, individualized to baseline risk; however, implementation is frequently constrained by regional costs and assay availability. Critically, a positive or rising PEth value should be a signal to initiate intensified, non-stigmatizing multidisciplinary addiction support rather than as a punitive mechanism for waitlist removal.

At the same time, biomarker results should not be interpreted in isolation. Because alcohol use may precipitate or exacerbate components of metabolic dysfunction, such as hypertension or hypertriglyceridemia, current clinical recommendations suggest re-evaluating metabolic criteria after an 8-12-week period of abstinence^[38]. Liver injury should only be classified as “metabolic” if it persists beyond this window, thereby preventing phenotypic mischaracterization of the metabolic axis in candidates with recent alcohol intake^[38]. With that in mind, PEth is viewed as a complement to careful clinical history, longitudinal assessment and multidisciplinary addiction care integrated from the earliest stages^[39].

Summarizing the evidence, the use of biomarkers, especially PEth, is clinically useful for detecting alcohol use in LT candidates with suspected MetALD. Its value lies not only in identifying recent alcohol use, but also in improving phenotypic classification, supporting risk assessment, and enabling more reliable surveillance during the waitlist period. In this context, objective biomarker-based monitoring should be incorporated into LT evaluation frameworks while remaining embedded within a non-stigmatizing, multidisciplinary approach.

Beyond accurate phenotyping and biomarker-based monitoring, successful LT candidacy in MetALD depends on addressing behavioral and psychosocial barriers that limit access to transplantation^[40]. Among candidates with presumed MASLD, the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) was associated with a lower probability of being listed for transplant (OR 0.82 per 5-point increment, with a threshold of ≥ 12 providing optimal discrimination)^[41]. If psychosocial barriers already reduce the likelihood of listing in candidates with metabolic disease, the negative effect may be even more critical in MetALD, where alcohol-related stigma and the dual burden of addiction and metabolic risk compound the psychosocial complexity. Therefore, psychosocial assessment must be specifically calibrated for MetALD candidates. Emerging data from integrated multidisciplinary ALD clinics suggest that combining hepatology and addiction care can yield significant improvement in liver function with a median Model for End-stage Liver Disease (MELD) reduction from 16 to 12, alcohol exposure (median PEth from 263 to 0 ng/mL), and remission of severe AUD (from 85% to 52%), along with reduced emergency department admission^[42]. Patients who declined referral to the integrated clinic had higher social vulnerability indices and more advanced cirrhosis, reinforcing that the populations in need of multidisciplinary intervention are also those facing the greatest barriers to accessing it.

Based on these observations, a MetALD-specific evaluation framework should move beyond single-etiology protocols to simultaneously address three domains: cardiometabolic risk, alcohol use profile, and psychosocial complexity. While integrated hepatology-addiction care models offer a promising delivery platform for this approach^[42], the field still lacks a validated prognostic tool that synthesizes these dimensions into a unified, patient-level risk estimate. Development of such a tool, potentially incorporating PEth-based alcohol characterization, metabolic phenotyping, and recompensation predictors into a composite score, would represent a tangible advance toward individualized pre-LT decision-making in MetALD, particularly given the absence of cardiometabolic risk calculators specifically designed for the SLD spectrum. Until then, the convergence of limited recompensation capacity, competing extrahepatic mortality, and psychosocial barriers in this population argues for a lower threshold for early transplant referral. Importantly, these same vulnerabilities also shape post-LT trajectories, as discussed in the following section.

Because the MetALD definition was formally defined in the 2023 SLD nomenclature, most existing transplant registries lack explicit diagnostic labeling for this entity. As a result, the available evidence on post-LT outcomes derives largely from retrospective reclassification using alcohol intake threshold and cardiometabolic criteria, an approach that introduces misclassification bias and likely underestimates the true burden of MetALD among LT recipients. Despite these limitations, early registry-level data already indicate that MetALD carries a distinct post-LT risk profile compared with ALD alone.

In a retrospective cohort study using UNOS patient-level data, LT recipients reclassified as MetALD exhibited a 13% higher risk of all-cause mortality and 12% higher risk of graft failure when compared to those transplanted for ALD^[4]. While these findings establish that MetALD carries a distinct post-LT risk profile, they do not identify which component of metabolic dysfunction leads to these outcomes. A single-center analysis of patients with decompensated cirrhosis referred for LT evaluation provides more insight, when MetALD was decomposed into its individual metabolic components, hypertension (HR 0.38, 95%CI: 0.16-0.89) and increasing BMI (HR 0.91 per unit, 95%CI: 0.84-0.99), rather than diabetes or dyslipidemia, emerged as independent predictors of failed recompensation^[28]. Of note, patients with MetALD in this cohort also had significantly higher baseline prevalence of CKD than those with ALD (31.6% vs. 17.0%, P = 0.025), a finding with direct implications for post-LT immunosuppression management given the nephrotoxic potential of calcineurin inhibitors (CNIs). The latter evidence suggests that post-LT care in MetALD should not rely on generic metabolic risk reduction but should instead prioritize blood pressure control, weight management, and renal-sparing immunosuppression strategies as the interventions most likely to influence long-term graft and patient survival.

Another important consideration is the temporal horizon over which post-LT risk unfolds. Long-term data from the UNOS registry (2002-2016) indicate that 5-year survival after LT for ALD is comparable to non-ALD indications (79% vs. 80%), but 10-year survival diverges significantly (63% vs. 68%, P = 0.006) with malignancy and infections as the leading etiologies of late mortality^[43]. Given this trend in ALD, MetALD recipients, who carry the additional burden of metabolic alterations, may face an even greater long-term risk. Although prospective validation is required, these findings suggest that post-LT surveillance should extend beyond the conventional 5-year window and support an extended follow-up protocol for this population.

In this context, the primary drivers of late mortality following transplantation are predominantly non-hepatic. A population-based cohort of 10,213 recipients indicates that while cardiovascular death accounts for only 1.4% of first-year mortality, major adverse cardiovascular events (MACE) occur in 2.6% of patients in this period^[44]. Nevertheless, non-fatal MACE during the first year independently correlated with diminished long-term survival (HR 1.37; 95%CI: 1.05-1.79). Beyond the first year, cardiovascular and infection-related mortality rates are substantially higher in patients with early MACE (16.7% and 23.3%) compared to those without (7.9% and 13.3%). Competing models identify older age, diabetes, and comorbidity burden as independent predictors of MACE, features inherent to the MetALD phenotype. Furthermore, recipients transplanted for ALD-related cirrhosis exhibit higher MACE rates than those with other indications (32.1% vs. 24.8%). While these data lack specific MetALD stratification, they provide a quantitative framework suggesting that MetALD recipients, burdened by both alcohol-related vascular injury and metabolic risk, represent a high-risk subgroup within the post-LT cardiovascular landscape. These observations carry two implications: follow-up of MetALD recipients should address biomarker-based alcohol surveillance after LT, and active monitoring for cardiometabolic complications.

Alcohol relapse following LT occurs in 15%-50% of recipients, varying by definition and follow-up duration; notably, heavy relapse is consistently linked to graft injury, allograft loss, and increased mortality^[45]. A clinically relevant stratification divides post-LT consumption into three cohorts: occasional slips, continuous drinking within recommended limits, and sustained heavy use. Of these, only sustained heavy use has been consistently associated with significant graft and patient mortality, whereas isolated slips do not appear to compromise outcomes^[46]. This distinction is central in MetALD, where the metabolic substrate may lower the threshold for alcohol-induced damage. This combined effect, already documented in pre-cirrhotic populations^[24], likely persists as immunosuppression-related metabolic derangements exacerbate pre-existing risk factors.

Mortality following LT for ALD is rarely driven by recurrent cirrhosis. Large-scale cohorts show that recurrent ALD accounts for only 1%-3% of deaths; aerodigestive malignancies and cardiovascular disease emerge as the principal causes^[47,48]. In the MetALD population, this change in mortality has clinical relevance since even moderate post-LT consumption may act alongside the metabolic substrate to amplify both oncologic and cardiovascular risk rather than producing overt hepatic decompensation. Waiting for liver-related signs before intervening would therefore miss the primary mechanism through which alcohol harms this population after transplantation.

Current surveillance practices are poorly equipped to detect relapse in time. A national survey of transplant providers found that while 84% of programs endorse abstinence as the default post-LT goal, verbal screening frequency ranged from every clinic visit to symptom-triggered discussion only, with variable assignment of responsibility for addressing craving and alcohol use^[49]. This heterogeneity creates gaps in detection that biomarkers-based monitoring can narrow. In a single-center study using PEth among LT recipients with ALD, approximately 17% had detectable alcohol consumption within 3 years, and 74% of these relapses were identified by PEth alone rather than by self-report^[50]. The cost-effectiveness of monthly PEth testing has been demonstrated in LT candidates with ALD^[36], and its adoption in the post-LT setting is a logical extension, particularly for MetALD recipients in whom the clinical consequences of undetected drinking may be worsened by concurrent metabolic disease. On this basis, systematic PEth monitoring is recommended from the first year after LT for all MetALD recipients, with the frequency tailored to the individual risk profile assessed during pre-LT evaluation [Figure 1].

A positive result is only useful if the response to it is defined in advance. The same scheme applies on the waitlist and after transplantation. A low or isolated value, just above 25 ng/mL, warrants a non-judgmental discussion with the patient, a repeat test in two to four weeks, and referral to addiction support. A sustained or rising value, particularly in the ALD range around 210 ng/mL, calls for formal addiction-medicine review, pharmacotherapy and behavioral treatment, and discussion of the case by the multidisciplinary team. These cut-offs are a practical protocol that still needs prospective validation before being established as a standard recommendation.

Detection alone, however, is insufficient without a treatment infrastructure capable of responding to positive results. The integration of addiction medicine in the transplant programs has shown measurable benefit. In a single-center observational study, post-LT relapse decreased from 35.1% to 16.4% after addiction specialists were incorporated into the transplant teams^[51]. Preliminary evidence from integrated care models combining hepatology and addiction medicine has shown early improvement in alcohol use, liver function, and healthcare utilization in populations that include post-LT recipients^[42]. An additional consideration is that pharmacotherapy for AUD is feasible in this population.

Additionally, acamprosate, gabapentin, and baclofen have no relevant interaction with CNI, mechanistic target of rapamycin (mTOR) inhibitors, or antimetabolites; naltrexone can be considered after LT with liver enzyme monitoring given its favorable once-daily compliance profile^[45]. The availability of these agents, combined with behavioral therapies such as cognitive-behavioral therapy and motivational enhancement, supports a multimodal approach in routine post-LT follow-up from the outset.

The metabolic consequences of LT do not resolve with transplantation, they intensify. Post-LT metabolic syndrome affects more than half of all recipients regardless of etiology^[52], and its components: diabetes, hypertension, dyslipidemia, obesity, and CKD, are exacerbated by CNI-based immunosuppression, corticosteroid exposure, and the sedentary recovery period that follows surgery.

New-onset diabetes mellitus after liver transplantation (NODALT) illustrates the trajectory of metabolic risk inherent to LT. Data from a Brazilian LT cohort showed that NODALT developed in 35.5% of recipients and was independently associated with high BMI, older age, longer follow-up, and post-LT MASLD. In fact, post-LT MASLD itself occurred in 26% of recipients and was linked to both NODALT (OR 2.00, 95%CI: 1.13-7.92) and hypertriglyceridemia (OR 2.80, 95%CI: 1.22-6.43), with the greatest weight gain concentrated in the first three years after transplantation^[53]. This evidence, derived from a Latin American population with high baseline metabolic burden, reveals a self-reinforcing cycle: graft steatosis promotes insulin resistance, which promotes diabetes, which in turn worsens steatosis and cardiovascular risk. In addition, dual-etiology post-LT cohorts have demonstrated higher rates of metabolic syndrome and fatty liver graft disease compared with ALD alone^[54], reinforcing that, in MetALD recipients, the metabolic axis does not attenuate after transplantation but is instead transferred to the graft.

Therefore, cardiovascular risk in this population requires a structured approach. Existing multidisciplinary practice-based recommendations for cardiac disease management in LT recipients provide a concrete framework: screening for diabetes, hypertension and dyslipidemia in all recipients; sodium/glucose cotransporter 2 (SGLT2) inhibitors or glucagon-like peptide-1 (GLP-1) agonists as first-line antidiabetic agents in those with established cardiac disease; blood pressure target below 130/80 mmHg for recipients with multiple cardiac risk factors; and echocardiographic surveillance at defined intervals for those with pre-existing cardiac dysfunction^[52]. At a Spanish transplant center, introducing a post-LT multidisciplinary team (hepatologist, endocrinologist, and advanced-practice nurses) reduced cardiovascular events from 14% to 6%^[55]. Although these data derive from MASLD and general LT cohorts rather than MetALD, they establish proof of concept that structured cardiometabolic care after LT translates into measurable outcome improvement.

Immunosuppression choice also influences metabolic risk. CNIs increase blood pressure through renal vasoconstriction, worsen insulin resistance (especially tacrolimus over cyclosporine), and accelerate CKD, while corticosteroids add weight gain, glucose intolerance, and dyslipidemia in the early months, when metabolic vulnerability is highest. For obese, hypertensive MetALD recipients, this argues for early steroid withdrawal, minimal CNI exposure, and consideration of an mTOR inhibitor such as everolimus, which causes less weight gain and spares renal function, although it can cause dyslipidemia and proteinuria, which must be monitored and treated. None of these strategies has been tested in a MetALD-defined population; the evidence is extrapolated from ALD, MASLD, and general transplant cohorts. Where no single regimen fits, the decision should be made on a case-by-case basis^[52,56]. Finally, Table 1 summarizes the principal clinical challenges identified in each phase of transplant evaluation, alongside the supporting evidence and proposed strategies to address each challenge.

Accordingly, we suggest that all MetALD recipients undergo formal cardiometabolic stratification within the first three months after LT, including specific NODALT screening, adherence to the current recommendations for oral glucose tolerance test at 3 and 12 months, blood pressure optimization, lipid management according to individual atherosclerotic cardiovascular risk and structured weight management including consideration of GLP-1 receptor agonist or bariatric referral when appropriate [Figure 2]. These interventions should run in parallel with the alcohol surveillance strategies outlined above and be managed through an integrated care model that bridges hepatology, addiction medicine, endocrinology and cardiology. Yet, delivering this level of coordinated care remains limited by allocation systems that were designed before the growing recognition of patients with MetALD.