Liver transplantation in the era of obesity: A metabolic public health crisis meets a surgical frontier

Abstract

The global obesity epidemic has reshaped the landscape of liver transplantation (LT). Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the leading indications for LT in Western countries, while excess adiposity simultaneously complicates donor and recipient selection, surgical outcomes, and long-term graft survival. Although previous studies have examined obesity, MASLD, and LT separately, an integrative overview of their bidirectional relationship and its clinical implications is lacking. This mini-review addresses that gap by synthesizing current evidence on how obesity influences LT candidacy, perioperative risk, graft outcomes, and metabolic complications after transplantation. We further highlight emerging concepts of “metabolic fitness,” the role of prehabilitation, novel pharmacotherapies, and bariatric interventions, while underscoring the urgent need for transplant-specific metabolic guidelines. Without upstream prevention and coordinated system-level adaptation, transplant programs will face an unsustainable burden of obesity-related liver disease.

1. Introduction

Liver transplantation (LT) remains one of the most complex yet successful surgical interventions in modern medicine. According to data from the WHO–ONT Global Observatory, 41,111 liver transplants were reported worldwide in 2023, marking a 10 % increase from 2022, notably, 25 % involved living donors [1]. More specifically, in the United States, a record of 10,660 liver transplants was carried out in 2023, marking the first time the annual figure surpassed 10,000. Alcohol-associated liver disease (ALD) remains the predominant indication, with 34.6 % for cirrhosis and 6.5 % for acute hepatitis, followed by MASH (metabolic dysfunction-associated steatohepatitis) at 20.3 % [2]. In the U.S., MASH prevalence among LT recipients surged from approximately 9 % in 2000 to nearly 28 % by 2022, while in Europe, it rose from about 5 % to 12 %, with ALD similarly emerging as the leading indication [3].

Over the past three decades, significant advancements in surgical techniques, perioperative and postoperative care, immunosuppression, and overall patient management have markedly improved survival rates and graft longevity. At the same time, the growing prevalence of obesity and metabolic syndrome has introduced a new layer of complexity, reshaping both the indications for and outcomes of LT. Historically, end-stage liver disease was primarily driven by viral hepatitis or alcohol-related liver damage. Nowadays, it is increasingly rooted in metabolic dysfunction. Over the past two decades, the global burden of metabolic dysfunction-associated steatotic liver disease (MASLD) has risen sharply, with a prevalence in the adult population climbing from approximately 25 %–32 % [4]. This trend now affects nearly two billion people worldwide and closely parallels the escalating rates of obesity and type 2 diabetes [5].

Despite the rapidly growing body of research on obesity, MASLD and liver transplantation, current reviews have largely addressed these domains separately. Prior work has focused on the epidemiology of MASLD and its rising prevalence [6,7], on transplant outcomes in patients with obesity or MASH [[8], [9], [10]], or on advances in pharmacologic therapies for metabolic liver disease [[11], [12], [13], [14], [15], [16], [17], [18]]. However, a comprehensive synthesis that integrates the bidirectional impact of obesity on liver transplantation, i.e., from donor and recipient selection, perioperative risk, graft function, and recurrence of disease to the emerging roles of metabolic pharmacotherapies, bariatric surgery, and multidisciplinary care model remains limited. In particular, there is a paucity of reviews that bridge public health implications of the obesity/MASLD epidemic with the surgical and metabolic challenges faced in the transplant setting. Therefore, the aim of this mini-review is to critically summarize current evidence on the complex interplay between obesity, MASLD, and liver transplantation. Specifically, we seek to: (i) describe how obesity shapes transplant candidacy, perioperative risk, and post-transplant outcomes; (ii) review novel strategies for optimizing metabolic fitness, including prehabilitation, pharmacologic therapies and bariatric interventions; and (iii) highlight future directions and multidisciplinary approaches required to address this growing metabolic and surgical frontier.

2. MASLD: the metabolic age of liver transplantation

MASLD is nowadays the liver transplant indication with the greatest rate of growth in Western nations [5,11]. This increase is indicative of a larger epidemiological shift toward chronic illnesses linked to insulin resistance, sedentary lifestyles, and high calorie intake. Commonly associated with obesity, type 2 diabetes mellitus (T2DM), hypertension, and dyslipidemia, MASLD is the hepatic expression of systemic metabolic dysfunction and frequently falls within the metabolic syndrome [19,20].

According to recent data from the US and Europe, MASLD is currently one of the top three indications for LT, and during the next ten years, its incidence is predicted to overtake all other causes [7,21]. More importantly, many patients arrive at advanced stages, frequently with concurrent hepatocellular carcinoma (HCC), which can develop in non-cirrhotic livers, being more common in MASLD than in other etiologies [22,23]. Limited treatment windows and delayed referrals are caused by the underdiagnosis and silent development of MASLD.

3. Obesity: more than just BMI

According to standard definitions, up to 40 % of liver transplant candidates in North America are obese, with a body mass index (BMI) of ≥30 kg/m² [9]. However, in this cohort, BMI is not a sufficient indicator of metabolic risk on its own. Compared to subcutaneous fat or weight alone, visceral adiposity, sarcopenic obesity, and ectopic fat distribution (especially hepatic, pancreatic, and epicardial fat) are more predictive of perioperative problems and metabolic sequelae [10,11].

Patients with obesity face higher rates of perioperative complications, including wound infections, hepatic artery thrombosis, prolonged ventilation, and extended ICU stays [20]. Moreover, obesity is independently associated with higher rates of early allograft dysfunction, likely due to altered hemodynamics and increased susceptibility to hepatic ischemia-reperfusion injury [21]. Importantly, metabolic syndrome, regardless of body mass index (BMI), has been shown to adversely affect both patient and graft survival following liver transplantation [22].

4. The post-transplant metabolic burden

Although LT may effectively resolve hepatic decompensation, it does not address the underlying metabolic derangements. Indeed, insulin resistance, dyslipidemia, and hypertension may be exacerbated by the post-transplant milieu, which is characterized by the use of corticosteroids, calcineurin inhibitors (CNIs), and mammalian target of rapamycin (mTOR) inhibitors [23]. According to studies, de novo metabolic syndrome may occur in as many as 50–60 % of LT patients within the first year following transplantation [24]. Furthermore, MASLD recurrence in the allograft is frequent, especially in patients who already have metabolic risk factors, and it may progress to fibrosis or even cirrhosis [25,26].

Post-transplant diabetes mellitus (PTDM) is another significant concern, with a prevalence exceeding 30 %, influenced by immunosuppressive regimens and baseline insulin sensitivity [27]. PTDM has been linked to adverse long-term graft outcomes, increased cardiovascular mortality, and renal impairment. Moreover, increased appetite, reduced physical activity, and corticosteroid use contribute to both de novo and recurrent obesity after transplantation [28].

5. Metabolic fitness: a new paradigm in transplant candidacy

Traditional criteria for transplant candidacy have emphasized MELD (Model for End-Stage Liver Disease) score and liver-specific metrics. However, in the metabolic era, there is growing recognition that transplant fitness must incorporate cardiometabolic status. Tools such as cardiopulmonary exercise testing (CPET), sarcopenia assessment via cross-sectional imaging, and frailty indices are increasingly utilized to predict operative risk and post-transplant recovery [[29], [30], [31]]. Additionally, non-invasive determinations of insulin resistance, hepatic steatosis and body composition have been increasingly incorporated into the evaluation of liver transplant candidates [31].

Prehabilitation, defined as the enhancement of functional capacity prior to surgery, has gained attention as a means to improve outcomes in metabolically compromised patients. Targeted interventions include supervised exercise regimens, dietary optimization, and pharmacologic agents aimed at improving insulin sensitivity and reducing hepatic steatosis [32].

6. Pharmacologic interventions: a new era of metabolic modulation

Recent developments in metabolic pharmacotherapy provide hope in pre- and post-transplant management. GLP-1 receptor agonists (semaglutide, liraglutide) have been shown to significantly improve hepatic steatosis, fibrosis scores, and cardiovascular risk [33]. SGLT2 inhibitors and dual incretin agonists (tirzepatide) are also being investigated for their effects on hepatic fat, weight loss, and insulin sensitivity in patients with advanced liver disease [34,35]. Initial trials suggest that these agents may be both safe and effective in some pre-LT cohorts, while there are limited data in decompensated cirrhosis [36]. Finally, thyroid hormones and their receptors, particularly through the action of thyroid hormone receptor (TR) agonists, have emerged as promising tools for enhancing metabolic function and reducing hepatic inflammation [37]. Among these, resmetiron, a hepatocyte-targeted, orally administered selective TR agonist, gained approval from the U.S. Food and Drug Administration (FDA) in March 2024 for treating moderate to severe fibrosis in non-cirrhotic individuals with metabolic dysfunction-associated steatohepatitis (MASH). This approval was based on significant findings from the MAESTRO clinical program [38]. While the authorization of resmetirom marks a significant advancement in the therapeutic landscape of MASLD and MASH, uncertainties remain concerning its sustained efficacy and influence on broader clinical outcomes. Continued investigation, especially through ongoing MAESTRO studies, is expected to shed further light on the long-term role of resmetirom and related agents in managing MASLD [38]. Resmetirom, in combination with diet and exercise, is approved for adults with noncirrhotic MASH and F2–F3 fibrosis. In MAESTRO-NASH, Week 52 co-primary endpoints were MASH resolution without fibrosis worsening or ≥1-stage fibrosis improvement without MASH worsening, validated surrogates predictive of liver-related outcomes [39,40]. The continuation of resmetirom is advised for patients with significant fibrosis improvement, while discontinuation should be considered if disease progression is evident at 12 months (e.g., rising ALT or Non-Invasive Liver Disease Assessment (NILDA)-confirmed fibrosis progression). For patients without clear improvement or worsening, continuation should be guided by a comprehensive assessment, considering baseline fibrosis stage, potential benefit of disease stabilization, comorbidities, adherence and response to lifestyle measures, biochemical and NILDA trends, and treatment tolerability [41].

Metabolic pharmacotherapies, such as GLP-1 receptor agonists, SGLT2 inhibitors, dual incretin agonists, and thyroid hormone receptor agonists such as resmetirom, usually offer potential to reduce hepatic steatosis, attenuate fibrosis progression, and improve cardiometabolic risk profiles. Evidence in patients with advanced liver disease and post-liver transplantation remains limited, with safety concerns particularly in decompensated cirrhosis. Integration into transplant protocols requires judicious patient selection, rigorous monitoring, and individualized evaluation of therapeutic response. While these agents may complement lifestyle modification, metabolic or bariatric surgery currently provides more reliable and durable improvements in weight and metabolic outcomes in high-risk populations. Finally, it is worth noting that the limited data available comparing drug therapy and metabolic surgery for MASH and its complications strongly favor surgery as a treatment option, although data on newer and potentially more effective drugs, such as tirzepatide, remain insufficient [42].

7. Bariatric surgery: a selective strategy

Bariatric surgery, most commonly sleeve gastrectomy, is increasingly used to optimize metabolic risk in selected LT candidates. Bariatric surgery has been performed prior to, at the time of, or after LT with the hope of decreasing obesity-related complications and improving long-term outcomes. While bariatric surgery performed before liver transplantation offers the greatest metabolic benefits, it is often not feasible for patients with decompensated liver disease due to associated risks [37]. Simultaneous LT and sleeve gastrectomy has shown encouraging results in highly specialized centers, showing durable weight loss, improvements in metabolic syndrome and reductions in allograft steatosis; yet it remains technically demanding and is best reserved for carefully selected patients [[43], [44], [45], [46]]. Post-LT bariatric surgery is possible but currently supported by limited data. Collectively, these strategies underscore the need for robust, multidisciplinary selection pathways that balance surgical complexity against long-term metabolic gains [[45], [46], [47]].

Fig. 1 summarizes key obesity-related considerations across the LT continuum, i.e., from pre-LT assessment (cardiometabolic risk, sarcopenia/frailty, steatosis burden), through intraoperative challenges (airway/ventilation, wound, vascular/technical difficulty), to post-LT complications (PTDM, recurrent MASLD, graft steatosis/fibrosis) and highlights intervention points (prehabilitation, pharmacotherapy, and staged or simultaneous bariatric surgery). This framework clarifies where integrated metabolic care can most effectively improve outcomes.

Fig. 1.

Legend. Obesity-related considerations across the liver transplantation continuum. Schematic depiction of (A) Pre-LT factors (obesity class, visceral adiposity, sarcopenia/frailty, cardiopulmonary reserve, steatosis burden, metabolic syndrome); (B) Intraoperative challenges (airway and ventilation management, wound complications, technical difficulty, vascular thrombosis risk); (C) Post-LT complications (post-transplant diabetes mellitus, recurrent/de novo MASLD, hypertension/dyslipidemia, allograft steatosis/fibrosis); and (D) Intervention levers (prehabilitation, pharmacotherapy: GLP-1RA/SGLT2i/TR-agonist where appropriate, and timing options for bariatric surgery: pre-LT, simultaneous, post-LT). Abbreviation's list: LT: liver transplantation; MASLD: metabolic dysfunction-associated steatotic liver disease; PTDM: post-transplant diabetes mellitus.

A number of important studies have examined the complex relationship between obesity, MASLD and LT, spanning outcomes, surgical strategies, and metabolic complications. Table 1 summarizes these investigations, arranged chronologically, highlighting the evolution of evidence from early registry analyses to contemporary data on combined transplantation and bariatric surgery. While these studies collectively underscore the detrimental impact of obesity on graft and patient outcomes, they also reveal critical gaps, particularly the paucity of large prospective cohorts and the underrepresentation of diverse ethnic populations.

Table 1.

Key studies on obesity, MASLD and liver transplantation.

Author et al. Year	Design/Population	Obesity-related focus in LT	Main findings	Clinical implications
Larson et al., 2025 [38]	Multicenter retrospective cohort; Simultaneous LT + sleeve gastrectomy; [n ~ 150; US/Europe; middle-aged adults; ∼60 % male] with ESLD due to MASLD and obesity. Two groups population (both groups transplanted): - Simultaneous liver transplant + sleeve gastrectomy (LTSG): 72 patients. - LT alone: 185 patients with BMI >30.	Simultaneous LT + sleeve gastrectomy	Durable weight loss, improved metabolic syndrome Diabetes: Significantly lower prevalence in LTSG group after 8 years (p < 0.05). Steatosis: Significantly lower incidence in LTSG group (p = 0.004). LTSG group: sustained weight loss >9 years post-transplant (p < 0.001). LT-alone group: no significant BMI change.	- Supports combined LT and SG as feasible in specialized centers with long-term benefits - Long-term efficacy in managing both end-stage liver disease and obesity - Metabolic benefit: LTSG provides long-term improvements in diabetes, hypertension, weight control, and reduces recurrent allograft steatosis—key concerns in MASLD patients. - Fibrosis: Trend toward reduced fibrosis progression suggests improved graft protection.
Ghanem et al., 2024 [39]	Patients with end-stage organ disease and obesity being evaluated for or having undergone SOT.		Pretransplant MBS Feasible in well-compensated cirrhosis Hypoabsorptive procedures risk long-term malnutrition- (SG) preferred. Posttransplant MBS Effective for long-term weight loss and improved graft outcomes (less steatosis, fibrosis).	Nutritional optimization pre- and postoperatively (micronutrient screening, supplementation) is critical for graft survival and patient outcomes. SG is the procedure of choice in transplant patients because it: avoids bowel anastomosis, preserves biliary access, has less effect on immunosuppressant pharmacokinetics, provides adequate weight/metabolic benefits.
Whang et al., 2023 [40]	Adults with obesity undergoing bariatric surgery (BS). Comparison with obese controls who did not undergo BS. 16.8 million BS patients and 10.6 million controls. Large, diverse, multicenter cohorts from population-based and observational studies.		Bariatric surgery significantly reduced risk (HR = 0.33, 95 % CI 0.31–0.34). Nonalcoholic cirrhosis: Strong protective effect (HR = 0.07, 95 % CI 0.06–0.08). Liver transplantation, failure, and liver-related mortality: Global reduction included	Bariatric surgery reduces long-term risk of cirrhosis (nonalcoholic) and liver cancer in obese patients. Bariatric surgery may serve as a strategy to mitigate MASLD progression to cirrhosis, transplantation, and liver-related death.
de Barros et al., 2021 [27]	Systematic review; 28 studies; heterogeneous LT populations; 144 patients had both procedures: 27 (18.8 %) before, 42 (29.1 %) simultaneously and 75 (52.1 %) after; SG in 84 % cases and Roux-en-Y gastric bypass in 13.9 % cases	Timing of bariatric surgery relative to LT	Best outcomes when bariatric surgery performed before LT; feasible at or after LT in select centers	Timing should be individualized; pre-LT surgery yields strongest benefits when feasible
Zamora-Valdés et al., 2018 [41]	Cohort; LT + sleeve gastrectomy; n = 36; US; mean age 52 ± 9; 55 % male	Concomitant LT + SG	Durable weight loss, lower allograft steatosis - LT-only: initial weight loss not sustained (29.4 % maintained at 3 years). - LT + SG: durable weight loss (100 % maintained >10 % loss; ∼35 % TBW loss). - LT + SG patients had lower hypertension, insulin resistance, and steatosis with fewer medications.	Combined procedure feasible and metabolically beneficial in specialized centers - LT + SG ensures lasting weight loss and better metabolic outcomes. - Pre-LT weight loss alone often fails long-term. - Simultaneous LT + SG is safe and effective for severe obesity. - Bariatric surgery should be considered in selected high-BMI LT candidates.
Thoefner et al., 2018 [37]	Systematic review & meta-analysis; 3539 patients n > 2500 L T recipients across 20 studies	Metabolic syndrome after LT	- High post-LT prevalence of metabolic syndrome; obesity a key driver - pre-transplant diabetes (OR:3.54, 95 % CI: 2.51–4.98) and pre-transplant obesity (OR: 2.44, 95 % CI: 1.48–4.03)	Emphasizes structured metabolic follow-up after LT
Conzen et al., 2015 [31]	Single-center retrospective cohort; n = 785 L T recipients; mean age 54 ± 11; 62 % male	Morbid obesity at LT	Morbid obesity independently associated with worse graft and patient survival. BMI influences pretransplant characteristics, etiology of liver disease, waiting time, post-transplant survival, graft outcomes, and complication patterns. Focus on outcomes in severely obese (BMI >35–40 kg/m2) and morbidly obese (>40 kg/m2) patients.	Obesity severity impacts outcomes; should inform risk counseling. Morbid obesity (BMI >40 kg/m2) not contraindicated for LT but linked to poorer long-term survival. MASH common in obese recipients Closer long-term follow-up needed to improve graft and patient outcomes.
Wong et al., 2014 [43]	Retrospective cohort study from the United Network for Organ Sharing Registry; US HCC LT candidates; n > 12,000; diverse ethnicity; ∼65 % male	NASH/obesity as LT indication in HCC	NASH most rapidly growing indication for LT among HCC patients HCC-related LT increased markedly after MELD implementation HCV remained the leading HCC etiology (43–50 % of HCC-related LT). NASH-related HCC rose significantly (8.3 % in 2002 → 13.5 % in 2012). NASH-HCC LT cases increased ∼4-fold, compared to a 2-fold increase for HCV-HCC	Highlights rising metabolic burden in LT Highlights the need for early identification, prevention, and management of metabolic risk factors to curb NASH and HCC incidence. LT programs should anticipate rising NASH-related transplant demand.
VanWagner et al., 2014 [44]	Consensus/critical review; multidisciplinary expert panel	Cardiac & pulmonary risk in LT (obesity-related)	Recommends structured cardiopulmonary risk assessment Cirrhotic cardiomyopathy affects up to 30 % of LT candidates, with increased resting cardiac output and blunted stress response. Intraoperative hemodynamic stress can unmask latent cardiac disease. Pulmonary vascular disease, including portopulmonary hypertension, further complicates perioperative management. Knowledge gaps in screening, risk stratification, and perioperative management strategies.	Incorporate multidisciplinary metabolic and cardiopulmonary screening Optimization of obesity-related metabolic and cardiovascular conditions (e.g., diabetes, hypertension, dyslipidemia) may improve outcomes. Future research should target improved diagnostic tools and risk prediction models for this high-risk population.
Heimbach et al., 2013 [26]	Case series; n = 7 L T + gastric sleeve; US; middle-aged; mixed gender	Combined LT + SG	Feasibility demonstrated; early metabolic benefits - LT alone group (n = 37): Weight regains common in 21/34 had BMI >35 post-LT. Post-LT diabetes in 12/34; steatosis in 7/34. 3 deaths and 3 graft losses. - LT + SG group (n = 7): No deaths or graft losses. 1 gastric leak, 1 excess weight loss. No post-LT diabetes or steatosis. Sustained weight loss (mean BMI = 29).	First report supporting simultaneous bariatric surgery in LT Combined LT + SG appears safe and effective for selected obese patients, promoting durable weight loss and preventing metabolic complications. Multidisciplinary management (hepatology, bariatric surgery, nutrition, endocrinology) is key. Long-term follow-up is essential to assess metabolic, nutritional, and graft outcomes.
Malik et al., 2009 [32]	Cohort; LT for NASH cirrhosis; n = 98; mean age 56 ± 10; ∼60 % male	Recurrent NASH post-LT	High recurrence with progression to fibrosis Recurrent fatty liver disease occurred in 70 % of NASH recipients. Recurrent NASH (histologic inflammation and ballooning) in 25 %. Fibrosis ≥ stage II in 18 % at mean 18 months post-LT. No graft failures or retransplants over 3 years of follow-up. No donor or recipient baseline factors predicted recurrence. One-third of recurrent NASH cases had normal liver enzymes at detection.	Reinforces need for post-LT metabolic control Recurrent fatty liver disease is common after LT for NASH, but short-term graft survival remains good. Metabolic risk factors (obesity, diabetes, dyslipidemia) drive recurrence Normal liver enzymes do not exclude recurrence, which highlights the need for biopsy-based or imaging surveillance. Long-term monitoring for progressive fibrosis and metabolic syndrome management is crucial to prevent late graft injury.
Nair et al., 2002 [36]	Registry analysis; US OLT recipients; 18,172 patients; broad demographics	Obesity and post-LT survival	Obesity associated with reduced survival after LT - Morbidly obese (BMI 40–50) had: Higher primary graft nonfunction. Higher 30-day, 1-year, and 2-year mortality (P < 0.05). Significantly lower 5-year survival, with deaths primarily due to cardiovascular events. - Severely obese (BMI 35–40) also had higher 5-year mortality. - Morbid obesity was an independent predictor of mortality in multivariate analysis. - Obese recipients had higher rates of diabetes, cryptogenic cirrhosis, and female sex	Early evidence that obesity adversely impacts LT outcomes; underscores risk modification - Morbid obesity (BMI >40) is associated with higher perioperative and long-term mortality, largely from cardiovascular causes. Weight reduction prior to LT should be strongly encouraged, particularly for BMI >35. Highlights need for metabolic optimization and cardiovascular risk management pre- and post-transplant. Supports the development of weight loss interventions and eligibility criteria to improve long-term outcomes in obese LT candidates.

Abbreviations: ESLD: end-stage-liver disease; HCC: hepatocellular carcinoma; LT: liver transplantation; LTSG: liver transplantation sleeve gastrectomy; MASLD: metabolic dysfunction-associated steatotic liver disease; MBS: metabolic and bariatric surgery; NASH: nonalcoholic steatohepatitis; OLT: orthotopic liver transplantation; SG: sleeve gastrectomy; SOT: solid organ transplantation; US: United States.

Taken together, these findings emphasize both the risks that obesity poses across the transplant continuum and the promise of innovative metabolic and surgical interventions. However, most available studies are limited by small sample sizes, retrospective designs, or single-center experience, underscoring the need for multicenter prospective trials.

8. Multidisciplinary models and future directions

Managing the metabolically complex transplant patient requires a truly multidisciplinary approach. Transplant hepatologists need to work collaboratively with endocrinologists, nutritionists, cardiologists, bariatric surgeons, and physiatrists to provide integrated care to the patient. In addition to the multidisciplinary approach, there is also an urgent need for transplant-specific metabolic guidelines and consensus statements for standardizing care across centers at the system level. From a research perspective, numerous future directions are essential to continue to advance our understanding and management of MASLD in the context of LT [8,11]. Longitudinal research is needed to better understand the natural history of MASLD recurrence and its progression to graft fibrosis after LT, as this area is poorly defined. Additionally, randomized clinical trial studies are needed to address the safety and efficacy of metabolic-targeted pharmacotherapies, including GLP-1 receptor agonists, SGLT2-inhibitors, and farnesoid X receptor (FXR)-agonists - in patients with cirrhosis and those who had undergone liver transplant [24]. At a mechanistic level, molecular studies examining adipokine signaling, mitochondrial dysfunction, and immunometabolic pathways could help provide insight in determining the pathophysiological mechanisms in independent pre- and post-transplant metabolic liver disease. Finally, addressing systemic disparities in transplant access for individuals with obesity and related metabolic conditions requires targeted policy interventions. Such efforts are essential to ensure fair and sustained treatment outcomes for this expanding patient population [28].

The integration of artificial intelligence (AI) and predictive analytics is transforming clinical decision-making in liver transplantation (LT) for metabolic liver disease. Recent studies show that machine- and deep-learning models using pre-transplant clinical, imaging, and laboratory data can outperform traditional risk scores in predicting post-transplant outcomes. A large multitask deep-learning framework analyzing over 160,000 L T records improved prediction of multiple post-transplant risks while reducing bias [48]. Similarly, a systematic review highlighted the growing application of AI in LT-related cardiovascular risk prediction and machine-learning models have shown strong accuracy in identifying MASLD risk from baseline features [49]. For clinicians, these tools enable individualized risk stratification for graft fibrosis, cardiovascular events, and metabolic complications, guiding prehabilitation and targeted monitoring [49]. Integrating AI models into electronic health records and transplant registries supports real-time decision-making and long-term follow-up, though ongoing clinician oversight and validation remain critical to ensure fairness and reliability across centers [49,50].

Key knowledge gaps persist regarding MASLD recurrence and graft fibrosis after liver transplantation. Standardized longitudinal studies are needed to clarify its natural history. The safety and efficacy of metabolic therapies like GLP-1 receptor agonists, SGLT2 inhibitors, and FXR agonists also require evaluation in advanced liver disease and post-transplant settings. Mechanistic insights into adipokine signaling, mitochondrial dysfunction, and immunometabolic pathways may guide targeted therapies. Finally, addressing inequities in transplant access for patients with obesity and metabolic comorbidities remains a critical priority.

Overall, the increasing demand for liver transplantation due to MASLD poses a challenge in terms of surgical resources, perioperative risk, and long-term outcomes. Patients with MASLD have greater surgical complexity and higher costs compared to viral etiologies. Preoperative risk stratification with noninvasive assessment of fibrosis (FIB-4, transient elastography) may optimize surgical candidacy. Policy and surgical planning should incorporate obesity management, targeted monitoring of high-risk patients, and multidisciplinary perioperative care to reduce complications and improve transplant outcomes.

9. Conclusion

Addressing the upstream determinants of MASLD is an urgent imperative for the public health community, requiring concerted efforts in prevention and early intervention. The increasing prevalence of obesity, insulin resistance, and associated metabolic dysfunctions has emerged as a significant public health crisis, contributing directly to the growing demand for liver transplantation [47,48]. If these modifiable risk factors remain unaddressed at the population level, transplant centers will continue to bear an unsustainable burden, with rising numbers of patients presenting with preventable metabolic liver diseases, such as MASLD [[49], [50], [51]].

Preventive measures should be initiated through comprehensive public health campaigns that emphasize lifestyle modification, including improved dietary habits, increased physical activity, and the promotion of early screening for metabolic disorders [45]. These strategies have the potential to prevent or delay the onset of MASLD and other related liver comorbidities, thereby reducing the need for costly and complex interventions, such as liver transplantation [[45], [46], [47]]. Furthermore, healthcare systems must adopt more rigorous metabolic assessments as part of routine care to facilitate the early detection of liver dysfunction in high-risk populations [45,[48], [49], [50], [51], [52]]. Investing in research to clarify the molecular mechanisms linking obesity and metabolic syndrome to liver disease is equally important. Translational research that bridges basic science and clinical practice is essential for the development of targeted therapies that may alter the trajectory of MASLD before it progresses to end-stage liver disease. Such efforts will not only enhance patient outcomes but will also alleviate the pressure on transplant programs [[49], [50], [51], [52], [53]].

Finally, the challenge lies in reducing the prevalence of metabolic liver disease while simultaneously strengthening transplant programs to meet this evolving burden [49,[51], [52], [53], [54]]. A comprehensive approach, which combines public health efforts, advanced research, innovative clinical practices and equitable access to care, is essential to tackling the underlying drivers of MASLD. Through such an integrated strategy, we may aim to lessen the need for liver transplantation and achieve substantially better outcomes for patients [54].

CRediT authorship contribution statement

Sofia Rozani: Conceptualization, Data curation, Investigation, Methodology, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. Maria Dalamaga: Conceptualization, Data curation, Investigation, Methodology, Supervision, Visualization, Writing – review & editing. Georg Weber: Conceptualization, Data curation, Supervision, Writing – original draft, Writing – review & editing. Robert Grützmann: Conceptualization, Data curation, Supervision, Writing – original draft, Writing – review & editing.

Funding

This study received no external funding.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Given her role as co-Editor-in-chief, Prof Maria Dalamaga had no involvement in the peer review of this article and had no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to another journal editor. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

List of Abbreviations:

ALT: alanine aminotransferase; BMI: body mass index; CNI: calcineurin inhibitor; CPET: cardiopulmonary exercise testing; FDA: U.S. Food and Drug Administration; FXR: farnesoid X receptor; GLP-1RA: glucagon-like peptide-1 receptor agonist; HCC: hepatocellular carcinoma; ICU: intensive care unit; LT: liver transplantation; MAFLD: metabolic (dysfunction)-associated fatty liver disease; MASLD: metabolic dysfunction-associated steatotic liver disease; MASH: metabolic dysfunction-associated steatohepatitis; MELD: Model for End-Stage Liver Disease; mTOR: mammalian target of rapamycin; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; NILDA: non-invasive liver disease assessment; OLT: orthotopic liver transplantation; OR: odds ratio; PTDM: post-transplant diabetes mellitus; SG: sleeve gastrectomy; SGLT2i: sodium–glucose cotransporter-2 inhibitor; T2DM: type 2 diabetes mellitus; TR: thyroid hormone receptor; US: United States; ESLD: end-stage- liver diseases; LTSG: liver transplant sleeve gastrectomy; SOT: solid organ transplantation; MBS: metabolic and bariatric surgery.