Mechanisms and treatment of metabolic dysfunction-associated fatty liver disease after liver transplantation

Abstract

Metabolism dysfunction-associated fatty liver disease (MAFLD) has emerged as a frequent complication for liver transplant (LT) recipients. In view of the high incidence of MAFLD after LT, research on MAFLD is of considerable clinical significance. Key research areas include the mechanisms responsible for the development of MAFLD following LT, therapeutic strategies, and the optimization of immunosuppressive regimens to achieve a balance between graft protection and metabolic protection. Most existing studies relating to MAFLD following LT are clinical observational studies, and the majority of investigations into pharmacological aspects are based on non-transplantation populations, thus highlighting significant gaps in research. In this review, we propose that the development of MAFLD after LT is primarily driven by the use of immunosuppressive agents and comprehensively synthesize the existing evidence regarding pathogenesis, immunosuppressive optimization strategies, and therapeutic approaches. Specifically, we focus on mechanistic analyses centered on insulin resistance pathways to elucidate immunosuppression-related mechanisms underlying the development and progression of MAFLD following LT. Based on the evaluation of current immunosuppressive optimization strategies and therapeutic agents, we propose several important directions for future research: Optimizing immunosuppressive regimens, conducting transplant recipient-specific pharmacological studies, and exploring strategies to balance metabolic protection with graft preservation.

Key Words: Metabolism dysfunction-associated fatty liver disease; Diabetes; Hypertension; Hyperlipidemia; Immunosuppressants

Core Tip: Metabolism dysfunction-associated fatty liver disease has become a prevalent complication following liver transplantation, appearing as either de novo or recurrent disease. The long-term use of immunosuppressants, specifically glucocorticoids, calcineurin inhibitors, and mammalian target of rapamycin inhibitors, serves as a primary driver of metabolic syndrome by disrupting glucose and lipid homeostasis. In this review, we delineate the synergistic mechanisms of drug-induced insulin resistance, hypertension, and dyslipidemia that promote hepatic steatosis. Management requires a multi-faceted strategy integrating lifestyle modifications, targeted metabolic pharmacotherapy and the optimization of immunosuppressive regimens to balance graft protection with metabolic health.

INTRODUCTION

Metabolism dysfunction-associated fatty liver disease (MAFLD), previously referred to as non-alcoholic fatty liver disease, represents the hepatic manifestation of metabolic dysfunction and encompasses a spectrum of metabolic abnormalities in terms of etiology, clinical presentation, severity, and prognosis[1,2]. Liver transplantation (LT) remains the definitive treatment for end-stage liver disease, hepatocellular carcinoma, and fulminant hepatitis[3]. At present, metabolic dysfunction after LT manifests in the liver as MAFLD, posing a new challenge for the management of post-transplant health and the improvement of clinical outcomes[4]. The incidence of de novo MAFLD is 7%-37% in patients following LT while the incidence of recurrent MAFLD is 8.2%-32.9%; these conditions are associated with poor post-LT outcomes, graft steatosis, progression to fibrosis, overall survival, and cardiovascular issues[5]. However, the specific mechanisms underlying the development of MAFLD following LT have yet to be fully elucidated.

Immunosuppressive therapy is a major contributing factor to metabolic syndrome (MS) following LT[6]. The postoperative use of immunosuppressive agents, particularly glucocorticoids (GCs), calcineurin inhibitors (CNIs), and mammalian target of rapamycin (mTOR) inhibitors, can lead to substantial changes in glucose and lipid metabolism, predisposing recipients to MS following transplantation[7]. Pre-transplant viral infections may contribute to baseline steatotic or inflammatory changes, yet immunosuppressant-driven metabolic injury remains the dominant driver for MAFLD after LT[8]. In this review, we propose that the core pathogenic mechanism of MAFLD following LT is an immunosuppression-mediated metabolic pathway centered on insulin resistance, which subsequently leads to lipid metabolism dysregulation and abnormal hepatic lipid accumulation, ultimately resulting in the development of MAFLD.

In this narrative review, we summarize current evidence relating to the epidemiology, pathogenesis, and management of MAFLD after LT, with a specific focus on the metabolic effects of immunosuppressive regimens and their mechanistic underpinnings. We also outline current therapeutic strategies and highlight research priorities for improving metabolic outcomes in LT recipients; achieving a balance between graft protection and metabolic protection remains essential.

CURRENT STATUS OF MAFLD FOLLOWING LT

MAFLD has been re-defined internationally as a distinct disease entity with diagnostic criteria encompassing risk factors associated with metabolic disorder[1]. The incidence of MAFLD following LT has increased substantially over recent years, with both de novo and recurrent forms being frequently reported in clinical studies. According to a pathological study of MAFLD after LT in 2022, recurrent MAFLD is becoming generally more unavoidable and may be associated with less favorable outcomes, although the histological features of this condition largely resemble those of de novo MAFLD[9]. Up to 78% of hepatitis C virus (HCV)-positive recipients exhibit concurrent HCV recurrence and de novo MAFLD. Immunosuppressive regimens do not differ significantly when compared between de novo MAFLD and recurrent MAFLD after LT. Larger long-term studies are still required to define the natural history of MAFLD following LT, clarify the relative contribution of immunosuppressants and host metabolic factors, and improve risk stratification in this specific population. To achieve more accurate and generalizable conclusions, it is necessary to investigate a larger number of cases and extend follow-up periods.

IMMUNOSUPPRESSANT-RELATED RISK FACTORS FOR MAFLD AFTER LT

Multi-factor metabolic pathway categorization

Immunosuppressive therapy is a principal driver of post-transplantation metabolic dysfunction and a major contributor to MAFLD in LT recipients. GCs, CNIs, and mTOR inhibitors are known to disrupt carbohydrate, lipid, and vascular regulatory pathways, generating inter-dependent abnormalities, including obesity, insulin resistance, diabetes, hypertension, and hyperlipidemia; these are all factors that can promote hepatic steatosis[10-13].

GCs, a class of steroid hormones, are routinely used after LT for immunosuppression and to reduce immune rejection[14]. However, when used after LT, GCs may lead to post-transplantation MAFLD through multiple mechanisms, thus representing a key component of MS[15,16]. GCs may also lead to post-transplantation diabetes mellitus through various mechanisms, including the induction and exacerbation of insulin resistance and the enhancement of hepatic gluconeogenesis[15,16]. GCs induce lipid metabolism disorders and adipocyte differentiation in adipose tissue and can also modulate hepatic carbohydrate and lipid metabolism, upregulate key gluconeogenic enzymes, and interact with antigen-presenting cells, exerting both immunosuppressive and anti-inflammatory effects[17,18].

CNIs are known to induce apoptosis in pancreatic β-cells, thus reducing insulin secretion[19]. Tacrolimus and cyclosporine are strongly associated with post-transplantation diabetes mellitus due to their inhibitory effects on insulin signaling[20]. Hyperlipidemia is also a common complication of CNIs, leading to the dysregulation of lipid metabolism. Tacrolimus leads to hyperlipidemia by causing a reduction in the synthesis of lipoprotein lipase (LPL) or a reduction in LPL activity[21].

Sirolimus (an mTOR inhibitor) is known to increase the risk of hyperlipidemia, thus representing a common risk factor for disorders of lipid metabolism; furthermore, mTOR inhibitors can interact with CNIs to increase the risk of hypertension[22]. Immunosuppression is a major factor responsible for HCV infection; these factors can also interact with each other to induce the accelerated recurrence and compressed natural history of MAFLD[23]. HCV remains a particularly relevant contributor in recipients of LT for HCV-related cirrhosis resulting from metabolic repercussions, including impaired insulin signaling, exacerbated insulin resistance, and altered hepatic lipid processing[24,25].

Immunosuppressant-related insulin resistance

GCs directly interfere with insulin signaling and increase the hepatic supply of triglycerides, which are major contributors to hepatic insulin resistance[26]. At therapeutic doses, GCs can significantly reduce hepatic insulin sensitivity. A potential glucocorticoid receptor target gene involved in the inhibition of insulin action is phosphoinositide-3-kinase regulatory subunit 1[27,28]. In the liver, GCs promote endogenous glucose production by activating numerous genes involved in carbohydrate metabolism, including phosphoenolpyruvate carboxy kinase and glucose-6-phosphatase, thereby inducing gluconeogenesis. However, prolonged exposure to GCs also induces lipolysis and muscle protein catabolism, thus providing substrates for gluconeogenesis. Furthermore, GCs promote the differentiation of pre-adipocytes into mature adipocytes, increase the accumulation of visceral fat by selectively enhancing the affinity of LPL for visceral adipose tissue, and stimulate lipolysis, thus leading to the release of non-esterified fatty acids that are not suppressed by insulin. The actions of various adipokines, including the increased levels of leptin and resistin associated with expanded white adipose tissue, further contribute to insulin resistance, resulting in β-cell dysfunction and the exacerbation of hepatic lipid metabolic dysregulation[29].

CNIs can downregulate the expression of insulin receptor substrate-2 messenger RNA or upregulate the cleavage activity of caspase-3, induce apoptosis in pancreatic β-cells, thus reducing insulin secretion, and ultimately causing diabetes mellitus[19]. Male recipients appear to be particularly vulnerable to the CNI-associated disruption of insulin sensitivity. In addition to glucose dysregulation, there are also vascular effects[30]. Insulin resistance and disorders in carbohydrate metabolism lead to the occurrence of MAFLD; the occurrence of MAFLD can exert a reverse effect on insulin resistance, thus exacerbating the degree of insulin resistance[31,32] (Figure 1).

Figure 1 Mechanistic interplay between immunosuppression and post-transplant metabolic dysfunction-associated fatty liver disease. This schematic illustrates how immunosuppressive agents drive metabolic dysfunction-associated fatty liver disease following transplantation. Glucocorticoids stimulate hepatic gluconeogenesis, calcineurin inhibitors impair insulin signaling, and mammalian target of rapamycin inhibitors often exacerbate adiposity. These pathways converge to induce insulin resistance (IR), characterized by systemic hyperglycemia and defective hepatic glucose metabolism. Central to this pathology, IR triggers adipose tissue lipolysis, increasing free fatty acid flux to the liver. This influx, coupled with dysfunctional insulin signaling, promotes de novo lipogenesis while suppressing lipid clearance. Concurrently, immunosuppressant-induced oxidative stress and inflammatory signaling amplify hepatocellular injury. These interconnected mechanisms form a pro-steatotic feedback loop, positioning IR as the primary hub linking clinical therapy to metabolic dysfunction-associated fatty liver disease progression and identifying IR as a critical target for metabolic intervention. GCs: Glucocorticoids; CNIs: Calcineurin inhibitors; mTOR: Mammalian target of rapamycin; FFA: Free fatty acid; MAFLD: Metabolic dysfunction-associated fatty liver disease.

Mechanisms of insulin resistance-induced lipid overload

Under conditions of insulin resistance, the insulin-mediated suppression of gluconeogenesis is impaired, yet hepatic lipogenesis remains significantly increased. Studies have shown that blockade of the insulin/insulin receptor substrate/protein kinase B signaling pathway reduces hepatic lipid accumulation in insulin-resistant states, thus suggesting that insulin can promote lipogenesis in the liver in a manner that is independent of its effects on glucose metabolism. Moreover, due to peripheral insulin resistance, other tissues may also contribute to disturbances in lipid metabolism[33]. Most tissue cells in the body take up glucose through glucose transporter 4 (GLUT4); insulin resistance induces GLUT4 to be taken up by the cell membrane, thus reducing the ability of the cell to take up glucose[34]. Liver cells predominantly take up and transport glucose through GLUT2; insulin resistance does not directly affect the ability of the liver to take up glucose[35]. However, hyperglycemia directly leads to a high glucose uptake by liver cells and inhibits glycogen synthase kinase 3β, which subsequently inhibits the ability of glycogen synthase to initiate glycogen synthesis[36]. Hyperglycemia subsequently enhances hepatic de novo lipogenesis and suppresses the activity of glycogen synthase, thereby facilitating the accumulation of triglyceride within hepatocytes, thus resulting in MAFLD[37] (Figure 1).

Risk factor-induced direct hepatic lipid overload

GCs modulate hepatic lipid metabolism, upregulate the circulating levels of free fatty acids, and stimulate the differentiation of adipocytes and deposition of lipids[18]. GCs also promote the synthesis of fatty acids, resulting in increased very low density lipoprotein cholesterol (VLDL-C) synthesis in the liver, while causing insulin resistance, which in turn leads to hyper-insulinemia. This process inhibits adrenocorticotropic hormone, resulting in the upregulation of VLDL-C synthesis and downregulation of the LDL receptor, thus causing the levels of free fatty acids to increase and promote the accumulation of lipids in both hepatic tissue and skeletal muscle[38-40].

CNIs increase the activity of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG-CoA reductase); this reduces the activity of LPL, and reduces VLDL-C and chylomicrons, resulting in the limited clearance of triglycerides in the plasma, thus causing the levels of triglyceride to increase in the blood[21-41]. HCV can activate sterol regulatory element-binding protein-1/2, reduce the activity of microsomal triglyceride transfer protein, and inhibit peroxisome proliferators-activated receptors signaling, thereby impairing VLDL assembly and promoting the intracellular accumulation of triglyceride and free fatty acids[8] (Figure 1).

MAFLD development under lipid overload

Previous research suggested that MAFLD is more likely to occur under conditions of lipid overload[42]. Increased levels of triglyceride and free fatty acids cause the excessive growth of adipose tissue while insulin resistance in adipose tissue leads to the breakdown of local fat, increasing de novo lipid synthesis and the accumulation of fatty acids in the liver[43]. The liver stores these free fatty acids in lipid droplets in the form of triglycerides. This leads to an increase in the production of triglyceride-rich VLDL, further exacerbating hyperlipidemia[42]. This increased flow of triglycerides has been shown to lead to an increase in mitochondrial free fatty acid-β oxidation in the liver and an increased circulation of lipid droplets through lysosomes, a process known as fat phagocytosis[42]. This process increases the risk of MAFLD-related liver steatosis. Collectively, these changes can induce an increase in free fatty acids and the accumulation of ectopic fat. Excess lipids are stored in liver cells in the form of triglycerides, thus resulting in simple hepatic steatosis[44] (Figure 1).

Inflammation and oxidative stress

MAFLD is closely related to inflammation and oxidative stress[45]. At the stage of simple steatosis, untreated or uncontrolled obesity may progress to non-alcoholic steatohepatitis and advanced MAFLD[46,47]. In this environment, Kupffer cells, dendritic cells, and hepatic stellate cells become activated, amplifying inflammatory and fibrogenic pathways that can aggravate hepatic injury[48] (Figure 1).

Immunosuppressants interact with antigen-presenting cells, regulate the transcription of interleukin-1 (IL-1), inhibit IL-1-dependent lymphocyte activity, and reduce the number of circulating cluster of differentiation 4⁺ T cells, thereby exerting both immunosuppressive and anti-inflammatory effects[17].

ASSESSMENT TOOLS

Controlled attenuation parameter measurement has demonstrated strong potential for the early diagnosis and assessment of hepatic steatosis, including MAFLD, due to its high efficiency, reliability, and non-invasive operation[49]. Lifestyle patterns change after transplantation. For example, patients exhibit reduced physical activity and can develop unhealthy dietary habits, thus aggravating weight gain and metabolic instability, ultimately increasing the deposition of fat in the liver[50]. Recent analyses of recurrent fatty livers following LT suggest that genetic predisposition interacts with environmental and behavioral factors, amplifying individual susceptibility to steatosis[51,52].

TREATMENT METHODS FOR MAFLD AFTER LT

The management of MAFLD following LT requires a multi-faceted strategy that incorporates lifestyle modification, metabolic pharmacotherapy, cardiovascular risk control, and individualized adjustment of immunosuppressive regimens.

Optimized immunosuppressive regimens

The primary objective of optimal post-transplantation immunosuppression is to maintain stable allograft function using the minimum effective systemic dosage. This type of optimization aims to maximize therapeutic efficacy while mitigating adverse effects, thereby reducing metabolic injury, reducing the incidence of MAFLD following LT and improving the long-term survival of recipients[17].

A 2023 study reported that tapering postoperative corticosteroid dosages was associated with a reduced incidence of various metabolic complications. Notably, the optimal dosage and duration of corticosteroid therapy following LT are subject to significant inter-individual variability and must be meticulously determined by clinicians[53]. Recent evidence from a 2024 study suggested that the early reduction or withdrawal of corticosteroids following LT may mitigate prevalent steroid-related adverse effects, including dyslipidemia, the recurrence of viral hepatitis, and MAFLD. Crucially, early steroid withdrawal has not been significantly associated with adverse outcomes, such as biopsy-proven acute rejection, graft failure, or increased patient mortality. Consequently, the rapid discontinuation of corticosteroids within two weeks post-LT appears to be a safe strategy for LT recipients that does not elevate the risk of acute rejection[54].

To mitigate the metabolic toxicities associated with CNIs, alternative immunosuppressive regimens are increasingly being integrated into clinical practice[17]. These include corticosteroids, basiliximab, mycophenolate mofetil, and mTOR inhibitors, such as sirolimus and everolimus. While these agents generally exhibit lower immunosuppressive potency than CNIs, they are typically associated with a more favorable metabolic profile[55]. When utilized in combination with CNIs, they may provide a synergistic balance between immunosuppressive efficacy and metabolic safety.

However, the optimal therapeutic application of mTOR inhibitors requires further validation through large-scale, multi-center clinical trials. Such research is essential to identify superior immunosuppressive regimens that effectively reconcile metabolic protection with adequate immune suppression to improve clinical outcomes[56]. Ultimately, longitudinal immunosuppressive strategies should be tailored and adjusted based on specific diagnostic profiles and the clinical characteristics of individual LT recipients.

Sustaining a high quality of life following LT necessitates individualized immunosuppressive regimens tailored to the unique needs of each patient. Critical considerations include recipient age, comorbidities, indications for transplantation, allograft function, immunosuppression-related complications, and post-transplant physiological status[17]. The fundamental challenge is to achieve a precise equilibrium between the prevention of graft rejection and the minimization of long-term metabolic complications.

Dietary intervention

Nutritional patterns that promote the reduced intake of saturated fat, an increase in unsaturated fatty acids, and controlled caloric consumption, as exemplified by the Mediterranean diet, have been demonstrated to improve insulin sensitivity, reduce hepatic fat accumulation, and ameliorate the components of MS[57,58]. Ketogenic diets are worth investigating in future research[59].

Exercise

Exercise can increase calorific expenditure and is therefore an effective means of reducing triglyceride levels in the liver[60]. Both high-intensity/low-volume and low-intensity/high-volume aerobic exercise modalities have been associated with reductions in hepatic fat content and improvements in lipid profiles[61]. Exercise recommendations for LT recipients should therefore account for recovery status, muscle strength, comorbidities, and potential drug-induced myopathy to ensure safety and efficacy[62].

Anti-diabetic agents

Anti-diabetic agents mainly include glucagon-like peptide-1 (GLP-1) (an insulin receptor agonist), SGLT2i (a sodium-glucose coordinated transporter 2 inhibitor) and biguanide drugs[63]. GLP-1 can improve insulin levels, thereby inhibiting glucose production in the liver, reducing liver fat content, and alleviating MAFLD[64]. SGLT2i is often used to inhibit the transport of glucose; GLP-1 is often used in combination with SGLT2i. The use of SGLT2i and GLP-1 in LT recipients is increasing, although data remain sparse with regard to long-term safety, potential interactions with tacrolimus or cyclosporine, and potential effects on graft functionality[63,65,66]. Close monitoring of immunosuppressant levels is essential whenever glucose-lowering pharmacotherapy is initiated or adjusted in LT recipients.

Lipid-lowering treatment

Statins belong to the family of HMG-CoA reductase inhibitors and block the conversion of HMG-CoA to hydroxy methyl valeric acid to effectively reduce the hepatic synthesis of cholesterol and circulating lipids, with both lipophilic and hydrophilic agents achieving improvements in metabolic parameters[63-67]. Previous research has identified higher levels of lovastatin and simvastatin in the MAFLD liver[68].

Although transient elevations in transaminases may occur, statins are safe for most LT recipients, although it is important to carefully monitor potential drug-drug interactions, especially with cyclosporine. However, statins have been proven to be safe for the liver and can be used in patients with elevated levels of transaminases[69].

Angiotensin receptor blockers

Angiotensin receptor blockers (ARBs) are key components in the management of MAFLD as they can reduce the incidence of hepatic steatosis, suppress steatohepatitis and reduce lipid peroxidation in the liver[70]. Experimental models have demonstrated that ARB attenuates lipid peroxidation, suppresses transforming growth factor (TGF)-β-mediated fibrogenic pathways, and reduces the activation of hepatic stellate cells, thus resulting in improvements in both steatosis and inflammation[71]. ARB can induce vasodilation, increase the delivery and release of glucose and insulin to insulin-sensitive tissues, promote insulin secretion, enhance insulin-mediated regulation, and reduce both insulin resistance and MAFLD[72]. The predominant effect of ARB is to inhibit activated hepatic stellate cells[73,74]. ARB can also regulate lipid metabolism in cells, thereby playing a role in the treatment of MAFLD[75]. ARB, or rifaximin alone or in combination, can reduce the levels of α-smooth muscle actin, Toll-like receptor 4 and TGF-β in the liver and prevent the fibrosis associated with non-alcoholic liver disease[75].

Due to the limited number of published investigations of the responses of LT recipients to the anti-diabetic agents, lipid-lowering treatment and ARBs, most of the cited evidence regarding their specific effects is derived from studies conducted in the general (non-transplant) population. The lack of large-scale data derived from liver transplant recipients limits the strength and applicability of current findings. Therefore, careful consideration should be given to potential drug-drug interactions between immunosuppressive agents and these therapies, as well as to hepatic and renal burden and the risk of adverse events and unfavorable outcomes. This strategy will ensure individualized patient management following LT in clinical practice.

CONCLUSION

In summary, the risk factors for MAFLD after LT are closely associated with multiple mechanisms. Evidence suggests that obesity, diabetes mellitus, hypertension, and dyslipidemia, common consequences of long-term immunosuppressive therapy, all play a central role in post-transplantation steatosis and its progression. The current mechanisms underlying the development and progression of MAFLD after LT primarily revolve around the insulin resistance pathway. Widely used post-transplantation immunosuppressants, including corticosteroids and CNIs, all induce insulin resistance which can further lead to the dysregulation of glucose and lipid metabolism, resulting in lipid overload, abnormal hepatic lipid accumulation, and ultimately MAFLD. Furthermore, dysregulated lipid metabolism itself may induce and exacerbate insulin resistance, forming a vicious cycle[63]. In addition to this principal insulin resistance pathway, immunosuppressants and HCV infection can directly disrupt hepatic lipid metabolism, thereby contributing to MAFLD through the metabolic dysregulation of lipids. Furthermore, HCV and corticosteroids may also promote the development of MAFLD via inflammatory and oxidative stress pathways. The combined effects of these multiple factors contribute to the occurrence of MAFLD after LT. Therefore, the key to preventing and treating MAFLD after LT lies in minimizing the metabolic injury induced by immunosuppressive therapy. Future research should focus on selecting regimens with minimal impact on glucose and lipid metabolism, aiming to balance graft protection and metabolic safety. Given the substantial inter-individual variability in responses to immunosuppressants, as well as differences in the baseline conditions of patients before and after LT, immunosuppressive regimens should be individualized, using the lowest effective doses and agents with reduced metabolic toxicity. Although the use of immunosuppressants is strongly associated with insulin resistance, robust clinical and mechanistic evidence remains limited, and the underlying pathways have yet to be fully elucidated. Further clinical and experimental studies are now required to clarify this association. In addition, optimized immunosuppressive strategies and targeted therapies for MAFLD after LT are still lacking large-scale, systematic data in LT recipients. Current management predominantly relies on lifestyle modification and the pharmacological control of metabolic comorbidities, including anti-diabetic, lipid-lowering, and anti-hypertensive agents, while modulation of the gut microbiota is considered a potential adjunctive strategy. However, most therapeutic evidence is derived from studies in the general population, highlighting the need for larger-scale investigations and careful attention to individualized treatment and potential drug-drug interactions between immunosuppressants and metabolic therapies. Studies specifically addressing MAFLD in LT recipients remain limited, and the long-term natural history of this condition has yet to be fully defined. In conclusion, future work should focus on: (1) Further elucidating the mechanisms by which immunosuppressants induce insulin resistance and the dysregulation of glucose and lipid metabolism, thereby strengthening the body of causal evidence; (2) Optimizing immunosuppressive regimens to achieve a balance between metabolic protection and graft preservation; and (3) Systematically evaluating the effects of various therapeutic agents in LT recipients to generate robust and comprehensive data. To establish evidence-based preventive and therapeutic strategies, the development of immunosuppressive agents with lower metabolic risk, well-designed prospective studies, and extended follow-up will be essential. A deeper understanding of these mechanisms will contribute to improving the long-term outcomes of LT recipients.