Challenges in the management of MetALD after liver transplantation
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0Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are among the leading indications for liver transplantation (LT). The definition of metabolic dysfunction- and alcohol-associated liver disease (MetALD) identifies individuals with MASLD who consume moderate levels of alcohol, representing a severe phenotype within the steatotic liver disease (SLD) spectrum. Patients with MetALD face higher risks of post-LT complications, including metabolic syndrome, graft steatosis, and fibrosis. Despite the rising prevalence of MetALD due to increasing obesity and alcohol consumption, data on its recurrence or de novo development post-LT remain limited. The management of MetALD post-LT is particularly challenging due to the interplay of metabolic factors and potential alcohol relapse. Current evidence suggests that recurrent or de novo MetALD often progresses more rapidly to advanced fibrosis than in native livers, underscoring the importance of early detection and management. Integrated approaches addressing both metabolic syndrome and alcohol-related risks are essential for optimal management. Non-invasive diagnostic modalities, such as transient elastography and specific biomarkers like phosphatidylethanol (Peth), are promising in assessing graft health and alcohol relapse, respectively. Emerging therapies, including glucagon-like peptide-1 receptor agonists (GLP1-RAs) and fibroblast growth factor-21 (FGF21) analogs, offer potential dual-action benefits targeting metabolic dysfunction and alcohol consumption. These innovations, coupled with lifestyle interventions and tailored immunosuppressive regimens, may improve patient outcomes and reduce graft failure. This review highlights the need for multidisciplinary strategies and further research to optimize the management of MetALD post-LT, aiming to improve survival and quality of life in this high-risk population.
Keywords
INTRODUCTION
Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD) are among the leading causes of chronic liver disease and primary indications for liver transplantation (LT)[1,2]. The recently introduced classification “MetALD” identifies individuals with MASLD who had moderate alcohol consumption (up to 20-50 g/day for females, 30-60 g/day for males), refining our understanding of the overlapping spectrum of these conditions. MetALD represents a more severe phenotype within the spectrum of steatotic liver disease (SLD), associated with higher all-cause mortality and poorer clinical outcomes compared to MASLD or ALD alone[3].
The global rise in obesity and alcohol consumption has led to an increasing prevalence of MetALD among LT candidates. These patients experience elevated risks of waitlist mortality, graft failure, and post-LT complications[4]. Risk factors, including alcohol relapse, metabolic syndrome, obesity, and diabetes, may persist or newly develop post-LT, leading to recurrent or de novo SLD.
Limited data exist on recurrent or de novo MetALD, though emerging evidence suggests that MetALD patients were at high risk of post-LT metabolic syndrome and increased liver graft injury driven more by metabolic features than by alcohol relapse. High BMI at the time of LT and post-LT weight gain have been identified as independent risk factors for recurrent SLD, while severe alcohol relapse remains the predominant cause of graft cirrhosis[5,6].
Effective management of pre- and post-LT metabolic syndrome, particularly obesity, is crucial for MetALD patients. Multidisciplinary approaches targeting metabolic and alcohol-related factors may prevent SLD progression and improve outcomes. Historically, MASLD and ALD have been managed as distinct conditions, focusing on metabolic syndrome and alcohol relapse, respectively. However, MetALD underscores the need for integrating pre- and post-LT strategies addressing both metabolic and alcohol-related factors. Promising therapies, such as glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the fibroblast growth factor-21 (FGF21), offer the potential to concurrently target these overlapping risks. This review examines the diagnostic and therapeutic challenges of MetALD in the post-LT setting, emphasizing the importance of integrated strategies to optimize patient outcomes and guide future research in this evolving field.
THE MAGNITUDE OF THE PROBLEM
Over the past two decades, the prevalence of obesity, type 2 diabetes, and other components of metabolic syndrome has risen significantly, reaching 25%-30% in the general population and 40%-60% in LT recipients[7]. ALD remains the leading indication for LT in Europe, but MASLD has emerged as a prominent indication in the past decade[8,9]. MetALD is also increasingly recognized as it accounts for 10%-20% of LT indications and is associated with worse outcomes compared to ALD or MASLD alone[6]. Post-LT, all three conditions can recur in the graft (recurrent disease) or develop as de novo disease.
The impact of SLD of the graft has been extensively characterized, though definitions of MASLD/metabolic dysfunction-associated steatohepatitis (MASH) vary significantly across studies, complicating accurate data interpretation. Recurrence of MASLD has been reported to range from 24.8% to 88.2% and recurrence of MASH occurs in 30%-40% of LT patients[10]. Importantly, the progression to advanced fibrosis or cirrhosis of the graft occurs in one-quarter of these patients and happens more rapidly than in the native liver, usually within 5-10 years[11]. De novo MASLD is also significant, with a prevalence ranging from 26% to 56% of LT recipients for non-MASLD causes[10,12]. De novo MASH has a prevalence of 2%-10%, suggesting that it seems to be less frequent than recurrent MASH. Similarly, the rates of advanced fibrosis in de novo MASLD seem to be lower as compared to recurrent MASLD (0%-17.7% vs. 20%-71%)[13,14].
The etiopathogenesis of post-LT MASLD is probably multifactorial. Several studies point out the presence of metabolic risk factors before LT that persist post-LT as possible key drivers[7,15,16]. In addition, immunosuppressive regimens, including corticosteroids (CSs) and calcineurin inhibitors (CNIs), further exacerbate post-LT metabolic syndrome by promoting insulin resistance[17]. Donor factors also seem to play a role in post-LT outcomes, particularly for patients with MASH. The prevalence of donor type 2 diabetes has increased over the past two decades, contributing to lower patient and graft survival due to hepatic steatosis in donor livers, which primes recipients for hepatic and non-hepatic metabolic complications[14,18]. According to the hypothesis regarding the genetic mechanisms of MASLD recurrence following LT, several studies have investigated potential genetic factors contributing to the recurrence of MALSD post-LT in both donors and recipients. The patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409-G variant, or PNPLA3 I148M polymorphism, has emerged as a significant genetic determinant of graft steatosis. This allele, whether present in heterozygosity or homozygosity, increases the risk of post-LT steatosis in a dose-dependent manner, whether inherited from the donor or present in the recipient. When both donor and recipient carry this variant, the risk is significantly amplified, with an odds ratio of up to 29-fold for early post-LT steatosis. Another important genetic factor is the transmembrane 6 superfamily member 2 (TM6SF2) rs58542926-A allele, which is associated with more severe steatosis, inflammation, and fibrosis. Its effects are modulated by recipient adiposity and may interact additively with the PNPLA3 I148M polymorphism. Contrarily, some genetic variants may confer protective effects. The superoxide dismutase-2 (SOD2) rs4880-A variant in recipients and the HSD17B13 rs6834314 variant in donors have been linked to a reduced risk of MASLD recurrence [Figure 1]. The multifactorial nature of post-LT steatosis recurrence underscores the interplay between genetic predisposition and metabolic factors such as recipient obesity and diabetes, highlighting the necessity for personalized management strategies in LT patients[19-21]. The impact of post-LT MASLD on survival remains unclear. While overall survival does not appear significantly affected, higher morbidity has been reported, particularly cardiovascular (CV) events[15,22]. CV events have been found in 15.3% and 30.3% of LT recipients at 3 and 8 years, respectively, especially in recurrent MASLD[23]. Higher rates of extrahepatic cancers, particularly skin (non-melanoma), urological, colorectal, and lung cancers, have also been described[14,15].
Figure 1. Genetic predisposition for SLD between donor and recipients. SLD: Steatotic liver disease; LT: liver transplantation.
Relapse of alcohol use post-LT is another critical concern, with rates of 26.3% to 50.0% depending on alcohol relapse definition, follow-up, and psychosocial support[24]. Relapse increases the risk of graft MASLD, alcoholic hepatitis, advanced fibrosis/cirrhosis, and 10-year mortality three times in relapsed compared to non-relapsed patients[24]. The development of a severe alcohol use disorder (AUD) post-LT is particularly detrimental, with a significant impact on clinical outcomes[25].
A significant challenge in interpreting data on MetALD post-LT arises from variability in diagnostic criteria across studies. The definition of MetALD is relatively recent, and prospective cohort studies specifically designed to investigate its natural history and outcomes post-LT are currently lacking. Instead, most available data come from retrospective analyses that reclassify patients based on prior definitions of alcohol-related and metabolic liver disease, which may not fully capture the unique clinical trajectory of MetALD. A key issue is the distinction between MASLD, MetALD, and ALD. MASLD is defined by the presence of hepatic steatosis in individuals with at least one metabolic risk factor (e.g., obesity, diabetes, dyslipidemia) and minimal alcohol consumption, below 20 g/day for women and 30 g/day for men. MetALD, in contrast, is characterized by both metabolic dysfunction and an average daily alcohol consumption ranging from
HOW TO DETECT METALD POST-LT?
The diagnosis of MetALD hinges on two main aspects: detecting graft steatosis, with a particular emphasis on quantifying fibrosis to provide prognostic insights, and conducting an anamnestic evaluation, complemented by biochemical markers, to assess potentially harmful alcohol consumption in patients with metabolic risk factors.
Liver biopsy is the gold standard for diagnosing steatosis and mostly fibrosis in the post-LT setting and has a pivotal role in ruling out other allograft issues[27]. Despite being generally safe and associated with a low complication rate, liver biopsy is likely not cost-effective given the increasing burden of post-LT steatosis. Consequently, there is a compelling need for effective and reliable non-invasive tests (NITs) in this context. Table 1 summarizes the results of the available studies using NITs in the post-LT era.
Studies that have analyzed the use of NITs in post-LT settings
| Author | Study design | Study population/Etiology | N | Endpoint | Method of detection | Cutoff for selected endpoints | Accuracy | Limitations |
| Carrión et al., 2006[80] | Prospective study | LT recipients with HCV | 124 | Fibrosis CSPH | TE TE | ≥ F2: 8.5 kPa CSPH: 8.74 kPa | Se: 90%, Sp: 81% Se. 90%, Sp: 81% | Only HCV patients |
| Toniutto et al., 2007[81] | Prospective study | HCV-infected LT recipients | 51 | Fibrosis HCV recurrence | APRI | > F2: 1.4 | Se: 76%, Sp: 77% | Single-center Only HCV patients |
| Kamphues et al., 2010[82] | Prospective study | LT recipients for HCV or alcoholic disease | 135 | Fibrosis | TE APRI FIB-4 | ≥ F2 8.5 kPa = F4 10.5 kPa ≥ F2 0.48 = F4 0.48 ≥ F2 2.8 = F4 4.44 | Se: 72%, Sp: 83% Se: 100%, Sp: 65% Se: 70%, Sp: 63% Se: 89%, Sp: 44% Se: 44%, Sp: 87% Se: 44%, Sp: 84% | Possibility of diagnostic failures in the examination of the liver biopsy, resulting in wrong estimation of non-invasive measurements of liver fibrosis |
| Rigamonti et al., 2012[83] | Prospective study | LT recipients | 69 | Graft disease | TE | Cutoff for exclusion: ≤ 5.3 kPa Cutoff for inclusion: ≥ 7.4 kPa | Se: 100%, Sp: 54% Se: 54%, Sp: 100% | |
| Barrault et al., 2013[84] | Prospective study | LT recipients | 43 | Fibrosis | TE | ≥ F2: 7 kPa | Se: 88%, Sp: 68% | |
| Lutz et al., 2015[85] | Prospective study | LT recipients | 48 | Fibrosis | HVRI TE | ≥ F2: HVRI < 1.05 ≥ F2: TE 8.35 kPa | Se: 100%, Sp: 91% Se: 85%, Sp: 91% | Small sample size; the points of measuring the respective values in Doppler ultrasound evaluation; Doppler ultrasound is influenced by stage of respiration and cardiac reflux. |
| Mikołajczyk-Korniak et al., 2016[86] | Comparative study | LT recipients for HCV cirrhosis | 36 | Fibrosis | TE | ≥ F2: 4.7 kPa | Se: 93%, Sp: 57% | Small size sample |
| Crespo et al., 2016[87] | Prospective study | LT recipients who developed biopsy-proven ACR during a 30-month period | 27 | ACR | TE | Moderate/severe ACR (RAI ≥ 5) vs. Mild ACR: TE cutoff 8.5 kPa | Se: 84%, Sp: 100% | Small sample size; patients with post-transplant HCV excluded |
| Della-Guardia et al., 2017[38] | Prospective study | LT recipients for all etiologies LT recipients with HCV | 267 | Fibrosis in all etiologies Fibrosis in HCV-positive | TE TE | ≥ F1: 8.1 kPa ≥ F2: 12.3 kPa ≥ F3: 15.1 kPa = F4: 16.7 kPa ≥ F1: 8.1 kPa ≥ F2: 12.3 kPa ≥ F3: 16.5 kPa = F4: 17.6 kPA | Se: 51%, Sp: 90% Se: 43%, Sp. 91% Se: 59%, Sp: 90% Se: 100%, Sp: 90% Se: 53%, Sp: 94% Se: 49%, Sp: 91% Se: 55%, Sp: 90% Se: 100%, Sp: 91% | Reduced number of cases with fibrosis F3-4 |
| Siddiqui et al., 2022[31] | Prospective study | LT recipients | 99 | Steatosis | CAP | 0 dB/m vs. 1-3: 270 dB/m 0-1 dB/m vs. 2-3: 295 dB/m 0-2 dB/m vs. 3: 295 dB/m | Se: 74%, Sp: 87% Se: 100%, Sp: 89% Se: 100%, Sp: 84% | Limited number of patients |
| Siddiqui et al., 2023[35] | Prospective study | LT recipients | 132 | Fibrosis | TE APRI AAR FIB-4 NFS | 0 kPa vs. 1-4: 7 kPa 0-1 vs. 2-4: 10.50 kPa 0-2 vs. 3-4: 12.2 kPa 0 kPa vs. 1-4: 0.69 kPa 0-1 kPa vs. 2-4: 0.75 kPa 0-2 kPa vs. 3-4: 0.75 kPa 0 kPa vs. 1-4: 0.89 kPa 0-1 kPa vs. 2-4: 0.89 kPa 0-2 kPa vs. 3-4: 0.89 kPa 0 kPa vs. 1-4: 3.40 kPa 0-1 kPa vs. 2-4: 1.73 kPa 0-2 kPa vs. 3-4: 2.52 kPa 0 kPa vs. 1-4: 0.77 kPa 0-1 kPa vs. 2-4: 0.57 kPa 0-2 kPa vs. 3-4: 0.57 kPa | Se: 81%, Sp: 69% Se: 81%, Sp: 82 Se: 86%, Sp: 89% Se: 42%, Sp: 80% Se: 35%, Sp: 74% Se: 41%, Sp: 73% Se: 67%, Sp: 54% Se: 85%, Sp: 51% Se: 86%, Sp: 50% Se: 33%, Sp: 88% Se: 81%, Sp: 43% Se: 59%, Sp: 66% Se: 40%, Sp: 86% Se: 62%, Sp: 73% Se: 59%, Sp: 71% | Single-center |
| Arshad et al., 2023[88] | Prospective study | LT recipients with histological fibrosis assessment | 132 | Fibrosis | TE FIB-4 | 0 kPa vs.1-4: 7 kPa 0-1 kPa vs. 2-4: 10.50 kPa 0-2 kPa vs. 3-4: 12.2 kPa 0 kPa vs. 1-4: 3.40 kPa 0-1 kPa vs. 2-4: 1.73 kPa 0-2 kPa vs. 3-4: 2.52 kPa | Se: 81%, Sp: 69% Se: 81%, Sp: 82% Se: 86%, Sp: 89% Se: 33%, Sp: 88% Se: 81%, Sp: 43% Se: 59%, Sp: 66% |
In terms of detecting steatosis, ultrasound (US) remains the most commonly used technique, primarily because it is routinely employed, at least annually, for standard surveillance in LT recipients[28]. Steatosis is typically suspected on B-mode imaging when the liver exhibits higher echogenicity compared to the kidney, a difference quantifiable through the hepatorenal index (HRI), which measures the ratio of the echo intensities between the liver parenchyma and renal cortex. Additional indicators include posterior attenuation of the US beam, vessel blurring, difficulty visualizing the diaphragm, and areas of focal sparing[29]. The primary limitation of US in detecting steatosis lies in its poor longitudinal reproducibility. Therefore, quantitative methods are more suitable for longitudinal monitoring. Few studies have investigated the use of CAP in the post-LT period, proposing a cutoff value between 252 dB/m and
Several serum biomarkers, such as the aspartate aminotransferase to platelet ratio index (APRI) and the Fibrosis-4 score (FIB-4), have been investigated for their potential utility in this setting. Additionally, imaging modalities such as transient elastography (TE) and magnetic resonance elastography (MRE) offer promising alternatives. However, the application of these methods remains limited in post-LT patients due to inadequate validation and the paucity of robust studies specifically addressing this population[33]. TE has shown strong diagnostic accuracy in detecting fibrosis in LT recipients in several studies[32,34-39] and outperforms traditional indices like the APRI and FIB-4, which are less reliable in this setting due to persistent thrombocytopenia - a common finding even after resolution of portal hypertension - that diminishes the accuracy of these tests[27]. In multiple prospective studies, TE has demonstrated high sensitivity and specificity for detecting significant fibrosis (≥ F2), with AUROC values ranging from 0.746 to 0.962, with sensitivities and specificities ranging from 51% to 100% and 54% to 100%, respectively, depending on the fibrosis stage and study population [Table 1]. The method appears highly effective in distinguishing early fibrosis from advanced fibrosis. However, its performance may be influenced by factors such as graft stiffness due to inflammation, biliary complications, or early rejection, which can lead to overestimation of fibrosis. Despite these limitations, TE remains the most validated and widely used non-invasive tool for fibrosis assessment in LT recipients, offering a practical alternative to liver biopsy in routine follow-up. MRE is particularly valuable for assessing post-LT fibrosis, providing insights into both liver parenchyma and the biliary tree when integrated with MRI studies[40,41]. A pooled analysis by
Accurate detection of alcohol use is pivotal for diagnosing alcohol-related liver damage in MetALD, particularly in the post-LT setting, where clinical outcomes rely on sustained abstinence. The initial step involves a detailed history, often complemented by rapid screening tools like AUDIT-C[43], which alone may be sufficient to detect problematic alcohol use. However, given the sensitivity of the post-LT context, where individuals are acutely aware of the harm caused by alcohol, the use of additional markers can provide valuable support. Biomarkers of alcohol use are broadly classified into indirect and direct markers. Indirect markers, such as gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), carbohydrate-deficient transferrin (CDT), and mean corpuscular volume (MCV), reflect the physiological effects of chronic alcohol consumption. However, their reliability post-LT is reduced by confounding factors, including pre-existing graft dysfunction, the iatrogenic effect of immunosuppression, and systemic conditions like bone marrow suppression or vitamin deficiencies. Direct markers, including ethyl glucuronide (EtG) and phosphatidylethanol (PEth), measure alcohol metabolites directly and offer higher specificity. EtG, detectable in urine, blood, and hair, provides insights into recent alcohol use, with hair EtG distinguishing between abstinence, moderate use, and heavy drinking. However, external ethanol exposure (e.g., from hygiene products or medications) can lead to false positives[44-47]. PEth, a phospholipid marker with a detection window of up to 28 days in blood, is both highly sensitive and specific and is not influenced by age, sex, or liver function[48,49]. Lim et al. demonstrated PEth’s superiority in detecting alcohol use pre- and post-LT, with a significant increase in relapse detection rates[50]. De La Torre et al.’s study further highlighted PEth’s role in improving surveillance for alcohol relapse in LT recipients[51]. Extensive evidence confirms that PEth is not endogenously formed without ethanol exposure, underscoring its reliability[52]. Studies reporting these biomarkers in the post-LT setting are reported in Table 2.
Studies using Peth or EtG to detect alcohol use in the setting of post-LT
| Author | Study design | Study population / Etiology | N | Follow-up (median) | Endpoint | Method of detection | Cutoff for selected endpoints | Accuracy | Limitations |
| Staufer et al., 2011[45] | Prospective study | ALD LT- recipients | 141 | 9 months | Alcohol relapse | DRI-EtG-enzyme immunoassay, confirmed by LC-MS-MS DRI-EtG-enzyme immunoassay, confirmed by LC-MS-MS | ≥ 0,5 mg/L ≥ 1 mg/L | Se: 89.3%, Sp: 98.9% Se: 75%, Sp: 99.3% | FU less than 1 year |
| Piano et al., 2014[89] | Prospective study | ALD LT- recipients | 23 | Over 1 year | Alcohol relapse | DRI-Etg enzyme immunoassay | ≥ 0,5 mg/L | Se: 89,2%, Sp: 98,8% | Lack of confirmation by LC-MS; small population size |
| Fleming et al.[48] | Prospective study | ALD LT-recipients | 151 | 1 year | Alcohol relapse | DBS-Peth extraction, followed by LC-MS-MS | ≥ 8 ng/mL | AR (using Peth):29% vs. AR* (self-reported): 8,6% P-value: 0.007 | Se/Sp not evaluated; FU of 1 year; 13 ALD-LT-recipients were also transplanted because of LF by HCV |
| Andersen-Streichert et al., 2017[90] | Prospective study | ALD LT- recipients | 61 | 1 year | Alcohol relapse | Etg hair LC-MS-MS DBS- Peth extraction, followed by LC-MS-MS DRI-Etg enzyme immunoassay, confirmed by LC-MS-MS | ≥ 7 pg/mL ≥ 20 ng/mL ≥ 0.5 mg/L | Se: 84%, Sp: 92% Se: 100%, Sp:96% Se: 71%, Sp: 98% | FU 1 year, small population size |
| De La Torre et al., 2024[51] | Single-center retrospective study | ALD LT-recipients before and after using Peth | 263 | 3 years | Alcohol relapse | DBS- Peth extraction, followed by LC-MS-MS | ≥ 20 ng/mL | AR (using Peth):17% vs. AR (before using Peth): 7% P-value: 0,012 | Alcohol screening was applied only in case of high clinical suspicion |
The integration of these biomarkers, alongside clinical assessments and NITs, provides a comprehensive approach to screening MetALD in post-LT recipients, while liver biopsy remains the gold standard. Future research should focus on refining biomarker thresholds, understanding their limitations in this unique population, and leveraging point-of-care testing technologies to improve real-time monitoring.
THERAPEUTIC APPROACH
Classical approach to MASLD post-LT
The prevention and management of MASLD post-LT focuses on addressing traditional cardiometabolic risk factors (both pre-existing and de novo post-transplant), such as obesity, diabetes, hypertension, and dyslipidemia. Strategies must be adapted to the unique post-LT setting, balancing metabolic health with immunosuppressive therapy requirements. Reducing CS use, lowering CNI doses, and incorporating alternative immunosuppressors such as antimetabolites or mammalian target of rapamycin (mTOR) inhibitors can mitigate metabolic complications while preserving graft function. Thus, the primary approach to managing MASLD after LT remains focused on addressing the individual components of metabolic syndrome[53] [Figure 2].
Figure 2. Management workflow of comorbidities in post-LT setting[17,70,91-95]. BMI: Body mass index; GLP1-RAs: glucagon-like peptide-1 receptor agonists; LT: liver transplantation; eGFR: estimated glomerular filtration rate; SGLT2: sodium-glucose cotransporter-2; CCBs: calcium channel blockers; ACE-I: angiotensin converting enzyme-inhibitor; ARBs: angiotensin receptor blockers; mTOR: mammalian target of rapamycin; EtG: ethyl glucuronide; PEth: phosphatidylethanol; AUD: alcohol use disorder.
Obesity
Obesity post-LT contributes to adverse outcomes such as graft steatosis, fibrosis, CV events, and de novo SLD. CSs are a well-documented contributor to weight gain, emphasizing the importance of their early tapering. Among CNIs, tacrolimus is associated with less weight gain than cyclosporine in the first year post-transplant. Recent data suggest that everolimus with reduced tacrolimus exposure minimizes weight gain at one and two years post-LT[53,54]. Obesity management begins with supervised physical activity and personalized weight-loss programs tailored to prevent sarcopenia, supported by nutritional assessments[55]. When lifestyle measures are insufficient, pharmacological treatments, like GLP1-RAs, or bariatric surgery, such as sleeve gastrectomy, may be considered, balancing metabolic benefits with potential immunosuppressive drug interactions, although more research is needed to establish their safety post-LT[56]. In the diabetic population, trials evaluating the effects of metformin on weight loss revealed 2.1% weight loss over the first 2 years of therapy[57]. A randomized control trial (RCT) following kidney transplant showed a trend toward less weight gain in the metformin group[58]. Some drawbacks include drug malabsorption related to post-LT bariatric surgery and the need to stabilize transplant outcomes for a congruent time.
Diabetes
Diabetes management post-LT includes addressing both pre-existing diabetes and new-onset diabetes after transplantation (NODAT), which significantly increases morbidity, CV risk, and graft loss. CSs and CNIs, particularly tacrolimus, are primary contributors due to their diabetogenic effects. Definitive diagnosis, based on HbA1c or oral glucose tolerance testing, should occur after three months post-LT, as perioperative hyperglycemia often resolves. Glycemic targets are individualized, aiming for HbA1c levels
Hypertension
Post-LT hypertension arises from systemic changes, CNI-induced vasoconstriction, and CS use. CNIs promote sodium retention and increase sympathetic activity, while CSs activate the renin-angiotensin-aldosterone system (RAAS). Management strategies include lifestyle changes such as sodium restriction, weight loss, smoking cessation, and exercise, alongside pharmacological interventions. Calcium channel blockers (CCBs), particularly amlodipine, are the preferred first-line agents due to their efficacy in counteracting CNI-induced vasoconstriction. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are recommended for patients with proteinuria or diabetes, as they may also provide renal protection and mitigate fibrosis. If edema or rhythm problems are present, diuretics and beta-blockers may be considered, as well as alpha-blockers if arterial pressure is not controlled with a single agent[18,53-55,59].
Dyslipidemia
Multiple factors contribute to dyslipidemia post-LT, including weight gain, poor glycemic control, renal dysfunction, and genetic predisposition. Immunosuppressive medications play a pivotal role: cyclosporine is more commonly associated with hyperlipidemia and hypertriglyceridemia than tacrolimus, due to its inhibition of bile salt synthesis, and mTOR inhibitors promote hypertriglyceridemia by altering insulin signaling and increasing triglyceride production. Combining mTOR inhibitors with tacrolimus or switching to antimetabolites, however, appears to mitigate these effects. Elevated LDL and triglyceride levels contribute to CV morbidity. Management aligns with guidelines for high- or very-high CV risk patients, with statins as the first-line therapy, and pravastatin, rosuvastatin, and fluvastatin preferred due to minimal interaction with CNIs. Ezetimibe may be added when the desired LDL target is not reached with statin monotherapy. Omega-3 fatty acids can be considered for isolated hypertriglyceridemia. Reducing exposure to dyslipidemia-inducing agents such as mTOR inhibitors may also improve outcomes[53-56,60]. Data about the use of proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors and bempedoic acid in this group of patients are lacking.
In terms of MASH-specific therapy, lifestyle interventions, including dietary modifications like the Mediterranean diet and structured physical activity, form the foundation of MASLD management[18,27]. As known, many drugs are currently under investigation for the treatment of MASH, showing efficacy in fibrosis regression and MASH resolution in non-transplanted populations, but have yet to be extensively studied in the post-LT context. Among the most advanced agents, resmetirom is an oral, selective thyroid hormone receptor-β agonist developed to target MASH. In March 2024, resmetirom received accelerated approval from the FDA for use in combination with diet and exercise for the treatment of adults with noncirrhotic MASH and moderate (F2) to advanced (F3) liver fibrosis, though its use in cirrhosis remains under evaluation in ongoing phase 3 trials. Resmetirom is also under regulatory review in the European Union for the treatment of MASH[61]. Other agents in phase 3 trials have demonstrated varying degrees of efficacy in fibrosis regression and MASH resolution; these agents include the GLP1-RA semaglutide, the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor co-agonist tirzepatide, the pan-PPAR agonist lanifibranor, the FGF21 analogs efruxifermin and pegozafermin, the fatty acid synthase inhibitor denifanstat, and the dual glucagon and GLP-1 receptor agonist survodutide[62-68].
Classical approach to ALD post-LT
In the post-LT population, patients with metabolic risk factors require heightened awareness regarding alcohol consumption, even at low-to-moderate levels. While the management of AUD is a well-recognized priority, it is equally important to consider the potential for disease progression associated with non-harmful but regular alcohol use in this population. Alcohol consumption, even lower than 20-50 g/day for females and 30-60 g/day for males, can act as an additive risk factor, potentially contributing to hepatic steatosis, graft dysfunction, and CV complications. Therefore, tailored counseling after LT should include education on the potential implications of alcohol intake in the context of their metabolic profile and graft health, to highlight that even non-harmful alcohol consumption might represent incremental risks. By addressing both AUD and the risks of moderate alcohol consumption, we can implement a comprehensive preventative strategy aimed at optimizing long-term outcomes and minimizing the risk of disease progression. The management of AUD and relapse prevention in patients following LT for ALD involves a multidisciplinary approach that combines behavioral, psychosocial, and pharmacological strategies to mitigate the risks of alcohol relapse, graft loss, and associated complications [Figure 2].
Behavioral and psychosocial interventions
The cornerstone of post-LT care for AUD is ongoing psychosocial and behavioral therapy, emphasizing the critical need for long-term monitoring and support. Pre-LT interventions, such as structured psychoeducational and addiction treatment programs, have been shown to reduce the risk of post-LT relapse significantly. Integrating addiction specialists into transplant care teams ensures consistent post-LT engagement, enabling early identification and treatment of high-risk behaviors. Collaborative care models that align addiction specialists, hepatologists, and mental health professionals have demonstrated reduced rates of harmful post-LT alcohol use[69,70]. Socioeconomic factors, such as limited access to healthcare resources, financial constraints, and instability in social support networks, often hamper patients’ ability to fully engage in behavioral and psychosocial therapies. These challenges can limit consistent participation in follow-up care, therapy sessions, or lifestyle modifications that are essential to recovery.
Pharmacological therapies
Data on the treatment of AUD in post-LT patients are extremely limited, particularly regarding pharmacologic therapies. The post-LT population has unique characteristics, such as interactions with immunosuppressive drugs, variability in liver and renal function, and a lack of specific clinical studies, which complicates the application of standard pharmacological treatments. As a result, the safety and efficacy of AUD medications in this population remain unclear, making it difficult to formulate definitive recommendations. This underscores the urgent need for more research to clarify these issues and develop evidence-based strategies specifically designed for post-LT patients. Pharmacotherapy plays an adjunctive role in managing AUD in post-LT settings. Despite limited evidence specific to post-LT populations, several agents used in the general management of AUD are being explored. Further research is necessary to elucidate the effects of both on-label medications (e.g., naltrexone and acamprosate) and off-label options (e.g., gabapentin, baclofen, and topiramate) on alcohol consumption following LT. Baclofen, a gamma-aminobutyric acid (GABA)-B receptor agonist, has shown promise in reducing alcohol cravings and consumption among patients with cirrhosis, including pre-LT populations; its use in post-LT care requires caution due to renal and hepatic adjustments. Naltrexone, an opioid receptor antagonist, is another promising agent, though its use requires careful monitoring for potential interactions with immunosuppressants. Acamprosate, which modulates glutamatergic activity, has also demonstrated effectiveness in AUD but requires further evidence in LT recipients. Importantly, these agents have not shown significant adverse interactions with immunosuppressive therapies when used under careful supervision[70-72].
Comprehensive multidisciplinary models
Optimal post-LT outcomes for ALD patients depend on a seamless integration of interventions addressing AUD within the broader transplant care pathway. Establishing centers of excellence in transplant care, equipped with dedicated addiction management teams, has been advocated. These centers could implement standardized protocols for relapse prevention, provide consistent access to behavioral and pharmacological therapies, and integrate digital tools for remote monitoring and telehealth interventions. Future research should aim to refine definitions of relapse and establish evidence-based guidelines for the management of AUD in LT recipients[70,71].
Dual approach: what is on the horizon? Therapies valid for MetALD as an entity
Post-LT management of MetALD requires addressing metabolic dysfunction and the risk of alcohol relapse[73]. Emerging therapeutic agents, notably GLP-1-RAs and FGF21, offer significant potential by targeting both the metabolic and behavioral aspects of the disease[74].
GLP1-RAs, originally developed for type 2 diabetes and obesity, have shown potential for dual-action benefits in MASLD and in reducing alcohol relapse. Preclinical studies have shown that GLP1-RAs modulate alcohol-induced dopamine release in key brain regions, such as the nucleus accumbens (NAc), while concurrently improving metabolic parameters, including weight reduction and enhanced insulin sensitivity. Semaglutide, a long-acting GLP1-RA, in a phase 2 trial in MASH patients with compensated cirrhosis, did not significantly improve fibrosis or achieve higher rates of MASH resolution compared to placebo. However, semaglutide was associated with significant reductions in liver fat, ALT levels, and metabolic parameters such as weight and glycemic control[62]. On the other hand, semaglutide has exhibited dose-dependent reductions in binge-like and dependence-induced alcohol intake in animal models[75]. The mechanisms underlying the reduction in alcohol consumption observed with semaglutide likely involve a combination of central pathways, including modulation of the dopamine reward system, and peripheral effects, such as delayed gastric emptying and enhanced satiation. Furthermore, the capacity of GLP1-RAs to attenuate the rewarding effects of alcohol while improving cardiometabolic health underscores their potential as dual-action therapies for MetALD[75-77]. In a phase 2 trial, tirzepatide, a dual GLP-1 and GIP receptor agonist, demonstrated significant efficacy, with up to 62% of patients achieving MASH resolution without fibrosis worsening and 55% showing fibrosis improvement[63]. In people with obesity, tirzepatide has been shown to reduce the intake of alcohol; these synergistic benefits warrant further investigation[76,77]. FGF21, a hepatokine induced by ethanol exposure, complements GLP1-RAs by acting through both hepatic and central pathways. It mitigates ethanol-induced toxicity and addresses hepatic injury through its actions on metabolic regulation and systemic inflammation. FGF21 directly activates noradrenergic neurons in the locus coeruleus (LC), facilitating recovery from ethanol-induced sedation without altering ethanol metabolism. Two FGF21 analogs, pegozafermin and efruxifermin, have been evaluated in clinical phase 2 trials for patients with MASH. Pegozafermin significantly improved fibrosis (up to 27%) and achieved MASH resolution (up to 37%) compared to placebo[66]. Similarly, efruxifermin led to fibrosis improvement in up to 41% of patients and MASH resolution in 33%-36%[65]. In addition, both agents have been shown to reduce metabolic abnormalities, such as elevated triglycerides and LDL cholesterol. These effects establish FGF21 as another therapeutic candidate for MetALD[78,79].
In conclusion, therapies like GLP1-RAs and FGF21 analogs offer innovative approaches to managing MetALD by addressing its metabolic, hepatic, and behavioral dimensions. Their dual efficacy highlights the potential for integrated treatments that improve post-LT outcomes and overall disease management.
Future research should focus on several key areas to optimize the management of MetALD in LT recipients. Early screening protocols for metabolic dysfunction and alcohol relapse, integrated with biomarker-based risk stratification, should be systematically implemented in the post-transplant follow-up phase. Initial interventions should focus on non-pharmacologic approaches, such as structured behavioral and nutritional programs, alongside pharmacotherapy [Figure 2]. A tailored, balanced diet, developed in collaboration with a nutritionist, is essential for preventing both nutritional deficiencies and excessive calorie intake, thereby avoiding weight gain and its associated complications. Regular physical activity and weight management programs are equally important to prevent obesity-related complications and support liver health. Smoking cessation, supported by both behavioral and pharmacological therapies, is critical, as smoking significantly increases the risk of post-transplant complications. Ensuring alcohol abstinence remains a cornerstone of recovery, and tools such as the AUDIT-C questionnaire should be regularly used for risk factor monitoring. This approach facilitates early identification of relapse, enabling timely interventions. In addition to these psychosocial assessments, biomarkers like PEth should be incorporated into the monitoring process to detect ongoing alcohol use. Therapeutic interventions, including cognitive-behavioral therapy and involvement in self-help groups, should be integrated into the care plan to support sustained sobriety and provide additional resources for relapse prevention. A multidisciplinary team, including hepatologists, addiction specialists, nutritionists, and psychologists, must be integrated to provide multidisciplinary care, addressing both physical and psychological aspects of recovery. This collaborative, comprehensive care pathway is essential for optimizing long-term outcomes. Additionally, randomized controlled trials (RCTs) investigating the efficacy of dual-target therapies, such as GLP1-RAs and FGF21 analogs, in LT recipients are crucial to establishing evidence-based treatment guidelines. These trials should assess not only hepatic endpoints (fibrosis regression and steatosis resolution) but also metabolic outcomes (glycemic control, lipid profile) and alcohol consumption patterns, and the long-term impact of GLP1-RAs and FGF21 therapies on graft survival and CV outcomes, as these agents have shown promise in reducing overall morbidity and mortality in metabolic liver disease populations. However, despite the promising therapeutic potential of these agents, there remain unresolved areas in the field of MetALD management in LT recipients. Future clinical trials should explore optimal treatment duration, potential drug-drug interactions with immunosuppressants, side effects, and the most effective combination therapies for addressing both metabolic dysfunction and alcohol-related relapse.
CONCLUSION
MetALD represents a significant and emerging challenge in the management of patients after LT, as it is associated with an accelerated progression of fibrosis and an increased risk of graft failure. This condition underscores the need for a paradigm shift in how post-transplant MASLD and ALD are approached. The hepatology community is beginning to recognize MetALD as a unique and unified clinical entity, rather than as two distinct pathologies requiring separate treatment strategies. This evolving perspective highlights the importance of adopting a more holistic and integrated approach to diagnosis and patient care. Furthermore, the development of new pharmacological therapies targeting both metabolic dysfunction and alcohol-related liver damage holds promise for improving outcomes in this complex and high-risk population. Tailored interventions addressing these overlapping pathophysiological mechanisms could play a pivotal role in preventing graft dysfunction and enhancing long-term LT outcomes. This requires collaboration among multiple specialists and an integrated approach to managing the patient’s complex caries, considering psychological, social, and clinical aspects. The hepatologist can serve as a central coordinator among these specialists and play a key role in promoting prospective studies to better define the role of emerging pharmacological agents in this unique setting.
DECLARATIONS
Authors’ contributions
Writing of the manuscript: Cucco M, Becchetti C, Scaravaglio M, Bolis F, Dispinzieri G, BiblPerricone G, Mazzarelli C, Airoldi A, Vangeli M, Belli LS
Bibliographic search and drafting tables and figures: Bagalà L, Strollo M, Orlando M
Revision for important intellectual content: Perricone G, Mazzarelli C, Airoldi A, Vangeli M, Viganò, Becchetti C
Availability of data and materials
Not applicable.
Financial support and sponsorship
None.
Conflicts of interest
All authors declared that there are no conflicts of interest.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2025.
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Cucco, M.; Becchetti, C.; Scaravaglio, M.; Dispinzieri, G.; Bolis, F.; Bagalà L.; Strollo, M.; Orlando, M.; Perricone, G.; Mazzarelli, C.; Airoldi, A.; Vangeli, M.; Viganò R.; Belli, L. S. Challenges in the management of MetALD after liver transplantation. Metab. Target. Organ. Damage. 2025, 5, 16. http://dx.doi.org/10.20517/mtod.2024.144
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