Metabolic syndrome after liver transplantation: A silent threat to long-term success

Abstract

Liver transplantation (LT) has significantly improved survival for patients with end-stage liver disease, but post-transplant metabolic syndrome (MetS) has emerged as a major challenge, affecting graft function and long-term outcomes. Characterized by obesity, dyslipidemia, hypertension, and insulin resistance, MetS increases the risk of cardiovascular disease, recurrent liver disease, and reduced graft survival. We systematically examine current literature on the diagnosis, risk stratification, and management of MetS in LT recipients, with a focus on lifestyle interventions, pharmacologic strategies, and potential modifications in immunosuppressive regimens. Additionally, we discuss the role of emerging therapies, including GLP-1 receptor agonists, PCSK-9 inhibitors, and bariatric interventions, in mitigating metabolic risk in this population. With cardiovascular complications being the leading cause of post-LT mortality, proactive management of MetS is crucial. A multidisciplinary approach integrating hepatology, endocrinology, and cardiology is essential to optimize patient outcomes. Future research should focus on personalized metabolic interventions and long-term strategies to enhance post-transplant survival and quality of life.

Key Words: Liver transplantation; Metabolic syndrome; Post-transplant diabetes mellitus; Immunosuppression; Cardiovascular disease; Metabolic dysfunction associated steatohepatitis

Core Tip: Metabolic syndrome (MetS) is increasingly recognized as a major contributor to morbidity and mortality after liver transplantation. This review highlights the pathophysiology, epidemiology, and clinical impact of post-transplant MetS. We also outline current strategies for screening, prevention, pharmacological treatment and surgical management.

INTRODUCTION

Liver transplantation (LT) has significantly improved survival for patients with acute and chronic end-stage liver disease (ESLD). LT restores normal health and extends lifespan by an average of 15 years or more[1]. Reported overall survival rates for LT recipients range from 81% to 97% at one year, 56% to 81% at five years, and 52% to 72% at ten years post-transplant[2]. Improvements in surgical techniques, expansion of the organ donation pool, and greater emphasis on the quality of life for both recipients and donors have contributed to these increased survival rates[3].

One of the most significant emerging challenges in the post-transplant population is the development of metabolic syndrome (MetS). Characterized by central obesity, dyslipidemia, hypertension, and insulin resistance, MetS has become increasingly prevalent following LT (Table 1)[4]. In the United States, the prevalence of MetS has shown a significant upward trend, increasing from 37.6% [95% confidence interval (CI): 34.0%–41.4%] in 2011–2012 to 41.8% (95%CI: 38.1%–45.7%) in 2017–2018, according to data from the National Health and Nutrition Examination Survey[5]. MetS has several clinical implications in LT recipients, including an increased risk of cardiovascular disease, recurrent liver disease, renal dysfunction, and reduced overall survival.

Table 1 Definitions of components of metabolic syndrome.

Component	Definition	Criteria (example: ATP III)
Central obesity	Excess fat accumulation around the abdomen	Waist circumference ≥ 102 cm (men), ≥ 88 cm (women)
Hypertriglyceridemia	Elevated triglyceride levels	Triglycerides ≥ 150 mg/dL (1.7 mmol/L)
Low HDL cholesterol	Reduced high-density lipoprotein cholesterol	< 40 mg/dL (men), < 50 mg/dL (women)
Hypertension	Elevated blood pressure	≥ 130/85 mmHg or on antihypertensive treatment
Impaired fasting glucose	Elevated fasting blood glucose indicating insulin resistance or diabetes	Fasting glucose ≥ 100 mg/dL (5.6 mmol/L) or diabetes diagnosis

ATP: Adult treatment panel; HDL: High-density lipoprotein.

This review explores the prevalence, pathophysiology, and clinical implications of MetS after LT, differentiating the impact of immunosuppressive therapy, pre-existing metabolic risk factors, and post-transplant metabolic shifts. In addition, management of MetS in LT recipients, from pharmacologic treatment, modifications in immunosuppressive regimens and surgical interventions were also discussed.

We conducted a narrative review using a structured literature search strategy. Databases including PubMed, EMBASE, and Scopus were searched for articles published between January 2000 and May 2025. The search was not limited by language or country of origin. Search terms included “metabolic syndrome”, “liver transplantation”, “post-transplant diabetes”, “dyslipidemia”, “obesity”, “hypertension”, and “cardiovascular risk”. We prioritized randomized controlled trials, original studies, meta-analyses, and major clinical guidelines. Reference lists of key articles were also manually reviewed to ensure comprehensive coverage. In addition, we specifically included studies evaluating emerging pharmacologic and surgical interventions to provide updated perspectives on post-transplant MetS management. Findings were synthesized qualitatively based on clinical significance, recency, and overall quality of evidence.

UNDERSTANDING METS IN THE POST-TRANSPLANT SETTING

Several organizations have proposed criteria for diagnosing MetS. The National Cholesterol Education Program Adult Treatment Panel III defines MetS as the presence of at least three of the five criteria (Table 1)[6]. The International Diabetes Federation definition requires central obesity (based on ethnicity-specific waist circumference cutoffs) plus any two of the following: Raised triglycerides, low high-density lipoprotein (HDL) cholesterol, elevated blood pressure, or raised fasting plasma glucose[7].

The incidence of metabolic abnormalities in LT recipients is high: Hypertension occurs in approximately 85% of LT recipients, dyslipidemia in 66%, obesity in 40%, and hyperglycemia in 51%[4]. These metabolic derangements often arise early after transplantation and may persist long-term, significantly impacting both graft function and overall patient outcomes.

Central obesity

In MetS, central obesity is a more significant indicator of metabolic risk than general obesity, which is defined by a body mass index (BMI) of ≥ 30 kg/m²[7]. While BMI is commonly used, waist circumference provides a more accurate assessment of central obesity, (Table 1 for diagnostic criteria)[7]. Unlike BMI, central obesity reflects visceral fat burden and better predicts adverse outcomes such as major adverse cardiovascular events (MACE), mortality, and metabolic complications.

Post-LT, many patients experience notable weight gain, typically within the first year, with studies reporting an average increase of 2 kg to 9 kg[8]. Obesity after LT results from a complex interplay between immunosuppressive therapy [especially corticosteroids and calcineurin inhibitors (CNIs)], metabolic alterations, and lifestyle changes that promote weight gain and insulin resistance. These factors contribute to increased visceral adiposity and a pro-inflammatory state, which may predispose to post-LT MetS and recurrent or de novo metabolic dysfunction-associated steatotic liver disease (MASLD). Approximately one-third of patients who are normal weight at the time of transplantation become obese afterward. This increase in weight often includes a disproportionate accumulation of abdominal fat, a key component of MetS. One study found that LT recipients with higher abdominal visceral fat had poorer survival, especially those with lower trunk muscle mass[8]. This highlights the clinical relevance of central obesity, not just as part of the MetS profile, but also as a factor associated with overall post-transplant prognosis, with an incidence of up to 30% and prevalence of up to 60% in the first 1 year after LT[8,9].

Hypertension

Hypertension is one of the most common metabolic complications following LT, with studies estimating a prevalence as high as 85% among LT recipients[4]. The early onset of hypertension is primarily attributed to immunosuppressive therapies, particularly CNIs such as tacrolimus and cyclosporine, which promote renal arteriolar vasoconstriction and sodium retention, thereby elevating blood pressure. Steroids and mammalian target of rapamycin (mTOR) inhibitors may also contribute to hypertension, although to a lesser degree[10].

The diagnostic thresholds for hypertension in LT recipients generally mirror those used in the general population (Table 1). However, due to the high prevalence of coexisting cardiovascular risk factors such as diabetes, obesity, and renal insufficiency, some transplant centers adopt more stringent blood pressure targets, aiming for levels below 130/80 mmHg to mitigate long-term complications[11]. Uncontrolled hypertension increases the risk of major cardiovascular events, making blood pressure control essential for optimizing long-term outcomes[11].

Dyslipidemia

Dyslipidemia refers to an imbalance in the lipid profile, typically characterized by elevated levels of pro-atherogenic lipoproteins such as low-density lipoprotein (LDL) cholesterol, triglycerides, and apolipoprotein B, along with reduced levels of HDL cholesterol[12]. High blood lipid levels are uncommon in patients with ESLD due to impaired hepatic synthetic function prior to LT. In contrast, post-LT dyslipidemia is a common metabolic complication, with prevalence rates reported as high as 85% among LT recipients[4,13]. Hyperlipidemia during immunosuppression arises from the metabolic effects of agents like corticosteroids, CNI (e.g., cyclosporine), and mTOR inhibitors, which impair lipid metabolism by increasing hepatic lipogenesis, reducing LDL receptor activity, and inhibiting lipoprotein lipase (LPL). These alterations lead to elevated levels of LDL, triglycerides, and total cholesterol, contributing to heightened cardiovascular risk post-LT[6].

Insulin resistance and post-transplant diabetes mellitus

Insulin resistance is a central feature of MetS and plays a key role in the development of post-transplant diabetes mellitus (PTDM), a common complication following LT[14]. Compared to the general population, LT recipients have a higher prevalence of PTDM, with reported rates ranging from 12% to 45%[14]. Most cases develop within the first year after LT; a retrospective study found that approximately 50% of cases occur within the first six months, and 75% by twelve months[15]. This elevated risk is multifactorial, but immunosuppressive therapy is recognized as a major contributing factor. In addition to immunosuppressive medications, the development of PTDM is also influenced by a combination of recipient, donor, and transplant-related factors. These include demographic variables, pre-existing metabolic abnormalities, and perioperative complications[6].

Together, the core components of MetS, central obesity, insulin resistance, hypertension, and dyslipidemia, often present concurrently in LT recipients and interact in complex ways. In contrast to the general population, these metabolic abnormalities in transplant patients arise within the unique context of immunosuppression, pre-existing comorbidities, and rapid postoperative metabolic shifts. As a result, MetS after transplantation carries a distinct clinical burden, contributing to cardiovascular disease, graft dysfunction, and renal impairment[13].

PATHOPHYSIOLOGY OF POST-TRANSPLANT MetS AND RISK FACTORS

Pre-existing risk factors

There are several demographic, clinical, and biochemical predictors present pre- and perioperatively that may predispose to MetS for LT recipients. Advanced recipient age has consistently been associated with an increased risk of developing MetS after LT[16]. In addition, Hispanic and Asian populations appear to have higher predisposition to insulin resistance and central adiposity[17]. Male sex is associated with higher risk of MetS after LT. PNPLA3, TM6SF2 and MBOAT7 variants have been shown to impact risks for lipid dysregulation and hepatic fat accumulation[18]. Pre-transplant diabetes and obesity are among the most significant clinical risk factors. A meta-analysis reported a pooled odds ratio (OR) of 2.44 for obesity (based on four studies) and 4.03 for pre-transplant diabetes (based on seven studies)[16].

MASLD encompasses a clinical spectrum ranging from simple steatosis without inflammation to metabolic associated steatohepatitis (MASH) cirrhosis, which involves both fat accumulation and hepatic inflammation, and can progress to cirrhosis, ESLD, or hepatocellular carcinoma[19]. In the United States, MASH is now the leading indication for LT among females and patients over age 65 years[20].

Patients transplanted for MASLD, particularly those with MASH, represent one of the highest-risk groups for developing post-transplant MetS. This is largely attributable to their high burden of pre-transplant metabolic comorbidities; estimates suggest that 64%–71% of patients with MASLD already meet the diagnostic criteria for MetS[21]. Consequently, these individuals are at significantly higher risk for developing MetS post-transplant compared to those undergoing transplantation for other reasons. The overall prevalence of MetS among LT recipients ranges from 43% to 59%. However, it has been reported to reach as high as 90% among those transplanted for MASH-related or cryptogenic cirrhosis[21].

Immunosuppressive agents and their metabolic effects

Immunosuppressive agents are essential for preventing graft rejection and improving both short- and long-term outcomes following LT. However, their use has been associated with an increased incidence of metabolic complications such as dyslipidemia, diabetes, and hypertension, all of which contribute to the development and progression of MetS in LT recipients[22].

Corticosteroids

Corticosteroids stimulate appetite, often leading to increased consumption of calorie-dense, high-fat, and high-sugar foods. They also induce insulin resistance in a dose-dependent manner by decreasing insulin secretion, reducing peripheral insulin sensitivity, and increasing hepatic gluconeogenesis[22], thereby elevating the risk of PTDM. In addition, corticosteroids contribute to hypertension through mineralocorticoid-mediated sodium and water retention and may promote hyperlipidemia with prolonged use. However, because corticosteroids are typically tapered and discontinued over time, their long-term metabolic impact is generally less pronounced than that of other immunosuppressive agents[22].

CNIs

CNI use has been associated with several metabolic disturbances that contribute to the development of MetS. Both tacrolimus and cyclosporine are linked to new-onset diabetes mellitus after transplantation, primarily due to reduced insulin secretion from pancreatic β-cells. Notably, tacrolimus carries a higher risk of de novo insulin-requiring diabetes mellitus compared to cyclosporine. A Cochrane review of 16 randomized trials reported a significantly increased incidence in the tacrolimus group [relative risk (RR) = 1.38; 95%CI: 1.01–1.86][20]. CNIs have also been associated with dyslipidemia, with cyclosporine exerting a stronger effect on elevating cholesterol levels[22,23]. Additionally, CNIs promote renal arteriolar vasoconstriction and sodium retention, thereby contributing to the development of post-transplant hypertension.

Beyond these metabolic effects, CNIs are known to cause both acute and chronic nephrotoxicity. While acute toxicity is often reversible, chronic exposure can result in progressive, irreversible structural damage. Among LT recipients, the cumulative incidence of chronic kidney disease (CKD) stage ≥ 3 ranges from 36% to 57%, while stage ≥ 4 CKD occurs in approximately 5% to 12% of patients post-transplant[24]. These kidney impairments significantly affect long-term patient outcomes and survival.

mTOR inhibitors

mTOR inhibitors, including sirolimus and everolimus, are associated with both dyslipidemia and insulin resistance. Sirolimus has been linked to elevated levels of triglycerides and LDL cholesterol. Clinical studies in organ transplant recipients have reported hypertriglyceridemia in approximately 51% of patients and hypercholesterolemia in about 44%, with these rates exceeding those observed with other immunosuppressive agents[25]. These lipid abnormalities may be further exacerbated when mTOR inhibitors are used in combination with other immunosuppressive agents[22]. The underlying mechanism is thought to involve the inhibition of LPL activity and reduced catabolism of apolipoproteins B100 and CIII[12].

PREVALENCE AND CLINICAL IMPACT

MetS emerges as a common complication following LT[6,12]. A pooled incidence of de novo MetS of 24.7% (95%CI: 18.0%–32.9%) across 15 studies involving 2683 recipients over a mean followup of 15.3 months; rates were particularly elevated in those transplanted for MASLD at 60.0% (95%CI: 52.0%–67.5%) compared with other etiologies[26]. Established risk factors for posttransplant MetS include advanced recipient age, obesity, and preexisting type II diabetes mellitus[27]. The onset of MetS can be early (within the first year, often linked to immunosuppressive regimens and rapid metabolic shifts) or late (driven by lifestyle factors and chronic immunosuppression).

The development of MetS in LT recipients portends a markedly increased cardiovascular burden: Cardiovascular disease has become the predominant cause of nongraft–related mortality in this population[28]. Recipients with MetS exhibit a more than twofold higher risk of cardiovascular events [hazard ratio (HR) = 2.42; 95%CI: 1.54–3.81; P < 0.01][29]. Furthermore, the presence of MetS at one year postLT was also found correlate with a significant, timedependent rise in cumulative risk of major cardiovascular events (P < 0.001)[29]. MASH etiology of liver disease, pre-existing major cardiovascular events, and development of de novo malignancy were independent predictors of all-cause mortality in liver recipients.

Beyond cardiovascular sequelae, MetS also contributes to recurrent liver disease, particularly MASLD and MASH[30-32]. A recent meta-analysis reported that the post-LT hepatic steatosis prevalence was 39.76% (95%CI: 34.06-45.46), with an 11.1% increase per decade and higher prevalence in the Americas vs Europe and Asia[30]. In multicenter cohort study, graft steatosis developed in 31% of patients and steatohepatitis in 3.8% by 3.3 years postLT[33]. Another systematic review and meta-analysis indicated a weighted prevalence of 26% (95%CI: 20%–31%) for graft steatosis and 2% (95%CI: 0%–3%) for graft steatohepatitis[34]. These incidence rates were varied depending on the different follow-up periods, but de novo graft steatosis was overall very common in post-transplant patients.

Renal dysfunction is another key sequela of MetS after LT[35]. CNIs can result in chronic nephrotoxicity, and when combined with hypertension, dyslipidemia, and hyperglycemia, they accelerate glomerulosclerosis. MetS was significantly associated with an increased risk of developing CKD (OR = 1.42; 95%CI: 1.28-1.57), albuminuria or proteinuria (OR = 1.43; 95%CI: 1.10-1.86), and rapid decline in kidney function (OR = 1.25; 95%CI: 1.07-1.47)[36]. PostLT patients with MetS experience faster declines in glomerular filtration rate and higher rates of endstage renal disease compared with metabolically healthier peers[37]. Post-LT acute kidney injury, while often reversible, can significantly increase the risk of subsequent CKD development[38]. Since renal failure further compromises survival, MetS thus acts as a multiplier of risk across multiple organ systems. CKD after LT significantly reduces long-term survival, with stage 3 or higher CKD linked to a 2–3-fold increased risk of mortality due to cardiovascular events, infections, and progression to ESRD. Risk is amplified by factors such as pre-transplant renal dysfunction and CNIs use, highlighting the importance of early nephrology involvement and renal-sparing strategies post-transplant[39].

Comparative analyses of de novo MetS by transplant indication reveal variability in incidence. Recipients transplanted for MASLD exhibit the highest rate (60.0%; 95%CI: 52.0%-67.5%), followed closely by those with alcoholassociated liver disease (56.5%; 95%CI: 48.1%-64.5%), hepatitis B virus (40.2%; 95%CI: 30.1%-51.3%), hepatitis C virus (36.4%; 95%CI: 23.8%-51.2%), and autoimmune liver disease (33.2%; 95%CI: 16.8%-55.1%)[26].

DIAGNOSIS AND SCREENING STRATEGIES

Early identification of MetS after LT is critical to mitigating long-term complications. Most transplant centers implement structured surveillance of MetS components including BMI, fasting glucose or hemoglobin A1C, blood pressure, and lipid panel. In practice, weight, BMI, and blood pressure are recorded at every clinic visit; fasting glucose or A1C is measured biannually, and a full fasting lipid profile is obtained once each year[12,40].

Non-invasive imaging modalities offer safe, reproducible assessment. Transient elastography, such as FibroScan and MR elastography quantify liver stiffness and fat accumulation, enabling early identification of steatosis or fibrosis before irreversible injury occurs[32]. FibroScan is a valuable non-invasive tool for monitoring liver graft fibrosis and steatosis in LT recipients, particularly effective in non-obese individuals and recurrent hepatitis C virus cases. However, obesity, inflammation, and technical factors may limit reliability-hence, results should be interpreted within a multimodal strategy that may include biopsy or magnetic resonance imaging elastography when appropriate[41]. Cardiovascular risk assessment relies on established calculators, such as the standardized atherosclerotic cardiovascular disease score, with selective use of coronary artery calcium scoring in patients who develop diabetes or severe dyslipidemia to guide prophylactic statin or antiplatelet therapy, although these risk calculators have not been classically applied to LT recipients[28,42].

Although these noninvasive methods have transformed post-transplant surveillance, liver biopsy remains the definitive test for unexplained graft dysfunction or suspected recurrent or de novo MASH. In practice, biopsy is reserved for patients whose imaging and serum markers are inconclusive[43,44]. In a Spanish prospective cohort of adults transplanted for MASH from 2010 to 2022 across three centers, liver stiffness measurements below 8 kPa after transplantation strongly predicted the absence of significant or advanced fibrosis[44]. By integrating routine clinical surveillance, targeted imaging and selective biopsy with histology assessment, this tiered approach facilitates early recognition and management of MetS after LT, thereby improving graft durability and patient survival.

MANAGEMENT STRATEGIES

Lifestyle interventions

Lifestyle modification remains the foundation of managing MetS after LT. Nutritional counseling should begin during the pretransplant evaluation and continue throughout outpatient followup, particularly critical for patients undergoing transplantation for MASH. A Mediterranean diet rich in monounsaturated fats, whole grains, fruits, vegetables, and fatty fish has been demonstrated to reduce hepatic steatosis, enhance insulin sensitivity, and lower cardiovascular risk even in the absence of weight loss[45]. Transplanttrained dietitians can customize meal plans to counteract immunosuppressionrelated appetite changes and prevent excessive weight gain. Equally important are structured exercise regimens and proactive weight management. Early posttransplant engagement in moderateintensity aerobic activity, in total at least 150 minutes per week, combined with resistance training twice weekly promotes weight stabilization and improves lipid profiles[46]. Compared with LT recipients who did not participate in the exercise program, those who did experienced lower 90day readmission rates (17.9% vs 20%) and shorter hospital stays (14 days vs 17 days)[46]. Physical therapists experienced in transplant care are ideally positioned to prescribe safe, tailored programs, and supervised cardiac rehabilitation may benefit recipients with established cardiovascular disease. Emerging data suggest telehealth delivery of cardioprotective lifestyle interventions is both practical and effective in this population. In an Australian randomized feasibility study, remote coaching led to significant reductions in MetS severity and improvements in mental health–related quality of life among LT recipients[47].

Pharmacologic management

Metformin is recommended as firstline therapy for PTDM in recipients with preserved renal function due to its well-established efficacy and safety profile[13,48]. When additional glycemic control is required or metformin is contraindicated, insulin can be used[49]. Insulin effectively regulates blood sugar without affecting immunosuppressant drugs, making it an ideal option immediately after transplantation. Also, sodium-glucose cotransporter-2 (SGLT2) inhibitors or glucagonlike peptide1 receptor agonists (GLP-1 RAs) have demonstrated potential benefits in the post-transplant population. SGLT2 inhibition has been associated with improvements in cardiovascular and renal outcomes, although careful dose adjustment and monitoring are necessary to mitigate risks of genitourinary infection and volume depletion[50-52]. GLP-1 RAs not only facilitate weight reduction and lower rates of cardiovascular events but also ameliorate hepatic steatosis, an effect that may be particularly advantageous in LT recipients[53,54]. Drug-interaction studies suggest minimal interference with CNIs for metformin and GLP-1 RAs, whereas the full interaction profile of SGLT2 inhibitors remains to be defined. Regardless of agent selection, rigorous surveillance of renal function and immunosuppressant levels is critical to optimize metabolic outcomes and preserve graft integrity.

Statins are the cornerstone of posttransplant dyslipidemia management and are safe with CNIs when monitored. In fact, statin therapy in LT recipients has been associated with a significantly reduction in mortality (HR = 0.10; 95%CI: 0.01-0.81; P = 0.03) and a lower rate of recurrent complications (HR = 0.43; 95%CI: 0.20-0.93; P = 0.032)[55]. Simvastatin and atorvastatin have the most robust data; rosuvastatin may be preferred for its potency but requires cautious titration. For refractory hypercholesterolemia, PCSK9 inhibitors offer a powerful, safe transplantcompatible option for lowering LDL cholesterol, as supported by several case series[56,57], though cost and injection frequency can be limiting factors.

In managing posttransplant hypertension, selection of antihypertensive agents should emphasize those with minimal metabolic impact and low potential for drug-drug interactions. Dihydropyridine calcium channel blockers are often favored as firstline therapy, given their least interaction with cytochrome P450 enzyme system, consequently, minimal risk of potential disruption of immunosuppressive drug levels[58]. In patients with resting tachycardia or elevated cardiac output, βblockers can also be appropriate initial agents. Although angiotensinconverting enzyme inhibitors and angiotensin receptor blockers are generally avoided in the immediate posttransplant period, their renalprotective properties render them valuable options in the later stages of recovery. Diuretics, such as furosemide and thiazide may be added to enhance blood pressure control and decrease the potassiumretaining effects of CNIs[59]. CNIs contribute to posttransplant hypertension through vasoconstriction, and strategies to reduce their hypertensive burden include switching to a longeracting agent or careful dose reduction under close monitoring.

Immunosuppressive therapy optimization

Glucocorticoids are a key contributor to MetS after LT, yet dosing protocols vary widely and are center-specific. High-dose mg 1000 intravenous methylprednisolone is commonly given for the first four days, followed by a rapid taper to achieve a prednisone maintenance dose of 5 mg per day by one month. With some exceptions (e.g. transplantation for patients with autoimmune hepatitis), we aim to discontinue steroids entirely by 3 months posttransplant to minimize longterm complication including impaired wound healing, hyperglycemia, hypertension, peptic ulcer disease, mood disturbances, visual changes, and osteopenia. A metaanalysis of 16 randomized trials including 1347 LT recipients showed that early glucocorticoid avoidance or withdrawal produced comparable outcomes to steroidcontaining regimens, with no significant differences in overall mortality (RR = 1.15; 95%CI: 0.93–1.44), graft loss (RR = 1.16; 95%CI: 0.91–1.48), or infection rates (RR = 0.88; 95%CI: 0.73–1.05). While steroidsparing protocols carried a higher risk of acute cellular rejection (RR = 1.33; 95%CI: 1.08–1.64), they also carried metabolic advantages, lowering the risk of newonset diabetes mellitus (RR = 0.81; 95%CI: 0.66–0.99) and hypertension (RR = 0.76; 95%CI: 0.65–0.90)[60].

Surgical and endoscopic interventions

For LT recipients who remain severely obese with persistent MetS despite optimal diet, exercise, and medications, bariatric surgery may be an option. Sleeve gastrectomy is preferred in this population because it preserves immunosuppressant absorption, maintains biliary tract access, and delivers durable weight loss. When performed posttransplant, sleeve gastrectomy has safely produced substantial weight reduction, remission of type 2 diabetes, and improved lipid profiles[13]. Most centers delay surgery until 12-18 months after transplantation to confirm stable graft function and immunosuppressant dosing, although some offer a combined LT and sleeve gastrectomy in a single operation[61]. Pretransplant bariatric procedures can also be employed for patients on the waiting list but require multidisciplinary coordination to avoid malnutrition or surgical complications that could delay transplantation.

Endoscopic sleeve gastroplasty (ESG) has emerged as a less invasive alternative to weight loss surgery. By suturing and reducing gastric volume endoscopically, ESG minimizes the risks of open surgery while still promoting significant weight loss[62,63]. Although data in LT recipients remain limited, early reports in five patients demonstrate that ESG is both feasible and metabolically beneficial in this highrisk group[64]. Table 2 for further management considerations for post-LT MetS.

Table 2 Management considerations for post-liver transplant metabolic syndrome.

Aspect	Management considerations	Notes/challenges
Lifestyle modification	Diet (low saturated fat, sugar), physical activity, weight control	Tailor to immunosuppression side effects
Immunosuppression adjustment	Minimize steroids, consider calcineurin inhibitor-sparing regimens	Balance graft rejection risk vs metabolic risk
Hypertension control	ACE inhibitors or ARBs preferred	Monitor renal function closely
Dyslipidemia treatment	Statins (with liver function monitoring), fibrates if needed	Watch for drug interactions with immunosuppressants
Diabetes management	Lifestyle, oral agents (metformin, SGLT2 inhibitors), insulin if needed	Adjust for renal function and liver metabolism
Regular monitoring	Routine screening for glucose, lipids, blood pressure, and waist circumference	Early detection allows timely intervention
Patient education	Emphasize adherence, lifestyle, and recognition of symptoms	Support via multidisciplinary team
Referral to specialists	Endocrinology, nephrology, nutrition as indicated	Manage complex metabolic and renal issues

ACE: Angiotensin-converting enzyme; SGLT2: Sodium-glucose cotransporter 2.

MULTIDISCIPLINARY AND LONG-TERM CARE MODELS

A multidisciplinary approach is essential for effective management of post-LT MetS[40]. This involves the collaborative efforts of transplant hepatologists, endocrinologists, cardiologists, and nutritionists to provide comprehensive care[40]. Transplant hepatologists play a crucial role in the initial assessment and long-term monitoring of liver function and immunosuppression management. Endocrinologists are essential for managing glucose metabolism and addressing diabetes, which is a common component of MetS[6]. Cardiologists are vital for assessing cardiovascular risk, managing hypertension and dyslipidemia, and preventing cardiovascular events, which is the leading cause of mortality after LT[9]. Nutritionists can provide specialized dietary guidance to address obesity, dyslipidemia, and insulin resistance, promoting healthy eating habits and weight management[64-66]. Integrated post-transplant care teams should be established to facilitate seamless communication and coordination among specialists, ensuring that patients receive holistic and patient-centered care[67].

Patient education and empowerment are integral to the successful management of MetS post-LT[9]. Providing patients with comprehensive information about their condition, risk factors, and treatment options empowers them to actively participate in their care[68]. Structured education programs should be implemented to educate patients about the importance of lifestyle modifications, including dietary changes, regular physical activity, and smoking cessation[6]. Patients should be well-informed of the early markers of MetS, such as elevated blood pressure, blood glucose levels, and lipid profiles, enabling them to seek timely medical attention for this specific condition. Motivational interviewing techniques can be used to encourage patients to adopt and maintain healthy behaviors, fostering long-term adherence to treatment plans.

KNOWLEDGE GAPS AND FUTURE RESEARCH DIRECTIONS

Despite advancements in LT, significant knowledge gaps remain regarding the long-term impact of MetS on cardiovascular outcomes in this population[65]. Longitudinal studies are needed to investigate the natural history of MetS post-transplant, identify predictors of cardiovascular disease, and evaluate the effectiveness of different treatment strategies[68]. Further research is needed to determine the optimal immunosuppressive regimens for minimizing the risk of metabolic complications while preserving graft function. Studies examining the effects of various interventions, such as lifestyle modifications, pharmacological therapies, and bariatric surgery, on MetS and cardiovascular outcomes are crucial for informing clinical practice.

Future research should focus on addressing the underutilization of weight loss interventions in transplant populations and investigating novel therapeutics such as glucagon-like peptide-1 analogues in post-LT patients. Weight loss interventions, including lifestyle modifications and bariatric surgery, are often underutilized in transplant populations, despite their potential benefits in improving metabolic health and reducing cardiovascular risk[64]. Given that the transplant population is aging and becoming more often overweight or obese, further studies are needed. Personalized medicine and precision transplant care approaches, incorporating genetic and biomarker data, may help identify individuals at high risk of developing MetS and tailor interventions accordingly[68]. Additional research is needed to refine risk stratification strategies, develop personalized treatment plans, and optimize long-term outcomes for LT recipients with MetS.

LIMITATIONS

This review has several limitations. First, as a narrative review, it is inherently subject to selection bias despite the use of a structured search strategy. To compensate the selection bias, we included several meta-analyses results and updated guidelines. Second, the studies discussed vary in methodology, patient populations, follow-up durations, and diagnostic criteria for MetS, limiting direct comparisons and generalizability. Third, many of the new therapies addressed, such as GLP-1 RAs, PCSK9 inhibitors, and endoscopic bariatric interventions are supported primarily by preliminary data or small case series, and their safety and efficacy in liver transplant recipients remain to be validated in larger trials. Lastly, we did not perform meta-analysis or assessment of study quality or risk of bias in our review.

CONCLUSION

MetS poses a significant and increasingly prevalent challenge among LT recipients, impacting both their short-term and long-term health outcomes. Its development is influenced by a complex interplay of pre-existing conditions, immunosuppressive medications, lifestyle factors, and potentially genetic predispositions. Given the heightened risk of cardiovascular events and the potential for rapid onset post-transplant, a proactive and comprehensive management strategy is essential.

Despite recent advances in LT care, significant knowledge gaps remain regarding the long-term impact of MetS and optimal surveillance and treatment strategies. Further research is needed to determine the long-term benefits of weight loss interventions, including optimal pharmacologic, endoscopic, and surgical approaches to MetS after LT. Ultimately, a comprehensive and integrated approach is essential to mitigate the impact of MetS and improve the overall health and well-being of LT recipients, especially considering that cardiovascular disease is a common cause of mortality after LT.