Are we standing on the shifting sands of post-transplant metabolic-associated steatotic liver disease?

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the predominant global cause of chronic liver disease and represents a major indication for liver transplantation. Post-transplant MASLD manifests as recurrent disease in nearly all recipients by five years post-transplantation, while de novo MASLD shows variable incidence (18%-78%). Although histologically similar, recurrent MASLD follows a more aggressive trajectory, with accelerated fibrosis and cirrhosis. Metabolic disturbances, immunosuppression regimens, donor-related factors, and chronic inflammation synergistically contribute to disease pathogenesis. The disorder not only compromises graft function but is also associated with elevated cardiovascular and overall morbidity, and malignancy risk. Despite advancements in noninvasive diagnostics, histopathology remains essential for definitive diagnosis and prognostic stratification. Management should prioritize metabolic optimization, lifestyle intervention, and tailored immunosuppressive regimens. Glucagon-like peptide-1 receptor agonists represent a promising therapeutic avenue. However, the absence of standardized, transplant-specific guidelines is a significant limitation. Further research is necessary to define diagnostic criteria, risk stratification, and targeted therapy to improve graft survival and patient outcomes.

Key Words: Metabolic syndrome; Steatotic liver disease; Metabolic dysfunction-associated steatotic liver disease; Liver transplantation; Recurrence; Outcomes

Core Tip: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the fastest-growing indication for liver transplantation (LTx) in Western countries, and the recurrence rate approaches 100% at 5 years. Recurrent disease progresses faster than native liver MASLD and is driven by immunosuppression-mediated metabolic dysregulation. Immunosuppressive regimens may have limitations, and even though there is need for tailored strategies, evidence is lacking for their application in post-LTx MASLD. Histological assessment remains essential for risk stratification despite advances in noninvasive diagnostics. Optimized immunosuppression, metabolic control, and emerging therapies are key research priorities to improve outcomes. Standardized guidelines for post-LTx MASLD management are urgently needed.

INTRODUCTION

Metabolic syndrome comprises a cluster of interrelated conditions including insulin resistance, hypertension, dyslipidemia, and central adiposity. Collectively, these conditions elevate cardiovascular risk[1]. Steatosis is the hepatic manifestation of this syndrome, and the aforementioned cardiovascular metabolic risk factors (CMRFs) are intimately associated with its development[2-5]. As the prevalence of metabolic syndrome increases, metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the main cause of advanced chronic liver disease in the world with an estimated prevalence of 30%[2-5]. Approximately 20% of the affected individuals develop metabolic dysfunction-associated steatohepatitis (MASH), and 15%-20% of these individuals progress to advanced fibrosis and cirrhosis. This has resulted in significantly higher liver transplantation (LTx) rates for decompensated cirrhosis and hepatocellular carcinoma (HCC) secondary to MASLD[2,3,5,6].

The pathogenesis of MASLD involves complex interactions between dysglycemia, obesity or sarcopenia, hypertension, poor dietary habits, oxidative stress, genetic predisposition, intestinal dysbiosis, and increased gastrointestinal permeability[2-5]. The post-transplant period adds another layer of complexity. Steroids and immunosuppressants negatively affect systemic inflammation and insulin resistance. In addition, the presence of steatosis on the liver graft or metabolic syndrome in the donor alters the risk of post-LTx MASLD[2,7-11]. PostLTx, MASLD can present as either recurrent or de novo disease. There is no histological difference between them. Therefore, we rely on clinical criteria, such as the presence of CMRFs and pre-existing MASLD. De novo disease is distinguished by the new occurrence of steatosis and metabolic dysfunction in individuals transplanted for other etiologies[2,8,9].

Preliminary studies showed rates of 100% for recurrent MASLD and 25% for de novo MASLD. However, current data show a wider variation according to the length of follow-up. These dates range from 8%-100% for recurrent disease and 18%-78% for de novo MASLD[2,7-11]. Similarly to individuals who did not receive LTx, 29% of the patients with post-transplant MASLD develop MASH, and 14% further progress to advanced fibrosis. Recurrent disease seems to progresses to higher grades of fibrosis more aggressively than de novo MASLD[2,7,8,10,11].

Post-transplant MASLD is a matter of great concern. Graft survival may be impaired by progressive fibrosis. The components of metabolic syndrome increase morbidity and the risk of cardiovascular events, which are an important cause of long-term mortality. Neoplasms are also more frequent and may be a consequence of the combination of metabolic factors and chronic immunosuppression[2,8,10,11]. In this review we examine the current knowledge on post-transplantation MASLD and explore potential gaps in the knowledge to foster future research that improves long-term outcomes for transplant recipients.

DEFINITION

MASLD is defined by the presence of hepatic steatosis on imaging or liver biopsy in association with at least one CMRF including: (1) Body mass index ≥ 25 kg/m² (or ≥ 23 kg/m² for Asian ethnicity) or waist circumference > 94 cm for males or > 80 cm for females; (2) Fasting serum glucose ≥ 5.6 mmol/L (≥ 100 mg/dL), or 2-hour post-load glucose levels ≥ 7.8 mmol/L (≥ 140 mg/dL), or glycated hemoglobin ≥ 5.7% (≥ 39 mmol/L), or type 2 diabetes mellitus (T2DM), or treatment for T2DM; (3) Blood pressure ≥ 130/85 mmHg or specific antihypertensive drug treatment; (4) Plasma triglycerides ≥ 1.70 mmol/L (≥ 150 mg/dL) or lipid lowering treatment; and (5) Plasma high-density lipoprotein (HDL) cholesterol ≤ 1.0 mmol/L (≤ 40 mg/dL) for males and ≤ 1.3 mmol/L (≤ 50 mg/dL) for females or lipid lowering treatment (Table 1). MASH requires histological documentation of macrovesicular steatosis in ≥ 5% of hepatocytes, lobular inflammation, and hepatocellular ballooning[3,4,5,12].

Table 1 Metabolic dysfunction-associated steatotic liver disease definition.

Components	Criteria
Evidence of hepatic steatosis	Detected by imaging or histology
Presence of ≥ 1 CMRF
Overweight or obesity	BMI ≥ 25 kg/m2 (≥ 23 kg/m2 in people of Asian ethnicity) or WC ≥ 94 cm in males and ≥ 80 cm in females
Dysglycemia or T2DM	Fasting serum glucose ≥ 5.6 mmol/L (100 mg/dL) or 2-hour post-load glucose levels ≥ 7.8 mmol/L (≥ 140 mg/dL) or HbA1c ≥ 5.7% (39 mmol/L) or T2DM or treatment for T2DM
Arterial hypertension	Blood pressure ≥ 130/85 mmHg or specific antihypertensive drug treatment
Dyslipidemia	Plasma triglycerides ≥ 1.70 mmol/L (≥ 150 mg/dL) or lipid lowering treatment or plasma HDL-cholesterol ≤ 1.0 mmol/L (≤ 40 mg/dL) for males and ≤ 1.3 mmol/L (≤ 50 mg/dL) for females or lipid lowering treatment

BMI: Body mass index; CMRF: Cardiovascular metabolic risk factor; HbA1c: Glycated hemoglobin; HDL: High-density lipoprotein; T2DM: Type 2 diabetes mellitus; WC: Waist circumference.

The entity nonalcoholic fatty liver disease (NAFLD) was recently renamed to MASLD. The change in nomenclature was to better encompass the disease so that it was not a definition based on the exclusion of other liver diseases but to one based on the recognition of CRMFs and the understanding that MASLD is the hepatic manifestation of metabolic syndrome. This nomenclature changes also facilitated the recognition and allowed for the possibility of superimposed etiologies such as metabolic-dysfunction and alcohol-associated steatotic liver disease. The nomenclature change is a patient-oriented change as well because it reduces the stigma associated with the term “fatty”[3,4]. With this in mind, we have adopted MASLD and MASH as equivalent to NAFLD and nonalcoholic steatohepatitis (NASH), respectively.

Even though the new nomenclature represents an advancement, we are aware that the current body of evidence on the old definitions of NAFLD and NASH is far more robust than for MASLD and MASH. We also recognize that the direct extrapolation of data may be inadequate. One example is the adoption of MASLD as it relates to the new definition, and of the new concepts for LTx recipients[10,11,13]. Hepatic steatosis occurs frequently after LTx. It is unknown whether the current definition of MASLD, based on imaging findings plus at least one of the CMRFs is directly applicable to LTx recipients because of the unique metabolic and immunological specificities related to LTx. It is likely that the current definition of MASLD may need to be adapted to this specific medical condition[10,11,14].

EPIDEMIOLOGY

The prevalence of MASLD has risen sharply over the past two decades, mirroring increases in obesity, T2DM, and other metabolic syndrome components. From 1990-2006, its estimated prevalence was 25.3%, climbing to 38.2% between 2016-2019-a 50.4% increase over three decades[3-5,12]. Projections indicate this trend will persist, driven by rising obesity and T2DM rates[3,15]. Geographically, prevalence varies widely, from 25.1% in Western Europe to 44.4% in Latin America[3-5].

The changing epidemiology of advanced liver disease and its complications reflects the introduction of highly effective therapies for hepatitis C virus infection[16] and continuous improvement in the vaccination rates for hepatitis B virus. The availability of effective treatments results in a lower prevalence of decompensated disease[17]. Alcoholic liver disease and MASLD are the most common causes of advanced liver disease worldwide[18], leading to a significant growth in the indications for LTx[19,20]. In the United States, MASLD advanced liver disease is the second most common indication for LTx, corresponding to 27% of adult recipients without HCC and 31% of those with HCC in 2022[6]. In Europe, the indications for LTx have risen from 1.2% in 2002 to 8.4% in 2016[19].

MASLD-RELATED HCC

The prevalence of HCC has been impacted by this epidemiological change. HCC is the most common primary liver tumor and one of the leading causes of cancer-related mortality[21]. It is expected that its incidence and impact will increase in the coming years[22,23]. Historically, the etiology of HCC was mostly associated with viral hepatitis. However, as the prevalence of MASLD continues to increase, MASLD-related HCC (MASLD-HCC) increases as well. Currently, MASLD is the fastest growing etiology of HCC in regions including the United States[24], China[25], and the United Kingdom[26]. Since 2010, 15%-20% of HCC cases in Western countries are MASLD-related[26]. Indirect evidence of this is the growth of LTx indications for MASLD-HCC, which rose from 2.1% in 2000 to 16.2% in 2016[27].

While it is common knowledge that HCC develops more frequently in patients with advanced fibrosis[28], there is a growing body of evidence demonstrating that 25% to 50% of the MASLD-HCC affect individuals without significant fibrosis[28-30]. The mechanisms related to the hepatocarcinogenesis in MASLD seem to be independent from those related to the progression of fibrosis[22]. Some of these mechanisms include: (1) Generation of reactive oxygen species through lipotoxicity, which promotes chronic low-grade inflammation, and induces alterations in DNA[31]; (2) Obesity- and insulin resistance-related oncogenesis[32]; and (3) Increased intestinal permeability, leading to changes in the intestinal microbiota, and in the metabolism of biliary acids[33,34]. Furthermore, the presence of variants for the PNPLA3 gene has been associated with the occurrence of MASLD-HCC regardless of the presence of advanced fibrosis[22,35,36]. Other risk factors for HCC in this population include male sex, age > 65 years, smoking habit, T2DM, and elevated levels of alanine aminotransferase[36].

PATHOPHYSIOLOGY

The pathophysiology of MASLD is complex, multilayered, and dependent upon the interplay between metabolic, genetic, inflammatory, and environmental factors.

Insulin resistance is a major metabolic contributing factor for MASLD. It leads to lipid metabolism dysfunction that is characterized by increased lipolysis of adipose tissue and de novo hepatic lipogenesis. The former results in increased serum levels of free fatty acids, while the latter promotes the conversion of carbohydrates into free fatty acids within the liver, leading to the accumulation of triglycerides within hepatocytes (a hallmark histological sign of MASLD)[3,15,37]. Lipid accumulation induces dysfunction in organelles such as the endoplasmic reticulum and mitochondria, culminating in hepatocellular apoptosis, an impairment of the oxidation of fatty acids, and excessive production of reactive oxygen species. A cascade of proinflammatory cytokines and cell death ensues. The transition from MASLD to MASH and the development of fibrosis depends on sustained inflammation and the activation of macrophages and stellate cells, provoking the deposition of extracellular matrix and fibrosis[37,38].

Intestinal dysbiosis also fosters metabolic dysfunction and inflammation. The increased permeability of the intestinal barrier facilitates bacterial translocation and activation of inflammatory pathways[39]. Microbiota, however, also depends on a specific diet to promote liver injury[40]. Diets rich in refined sugars, saturated fats, and ultraprocessed foods induce hepatic lipogenesis[41], while diets high in fructose stimulate de novo lipogenesis and foster insulin resistance. These dietary patterns are typically accompanied by low physical activity, which contributes to the perpetuation of metabolic syndrome and MASLD[42].

The variability in disease presentation and progression among the general population of individuals with MASLD suggests that genetic factors in addition to environmental and metabolic factors play an important role in the development and progression of the disease. Recent genome-wide association studies identified several key genetic loci that modulate the risk and severity of MASLD, providing insights into disease pathogenesis and potential therapeutic targets. The rs738409 C>G (I148M) variant in the PNPLA3 gene impairs lipid droplet degradation and affects lipid remodeling, contributing to hepatic fat accumulation. It also increases the risk of MASLD, fibrosis, and HCC[43]. The rs58542926 C>T (E167K) variant of the TM6SF2 gene decreases lipid secretion and enhances intracellular lipid accumulation, increasing the risk of MASLD and fibrosis while paradoxically offering protection against cardiovascular disease[44]. The rs641738 C>T variant of the MBOAT7 gene reduces its expression, leading to an altered phospholipid composition and increasing susceptibility to MASLD, inflammation, fibrosis, and HCC[45]. Other genes that may also contribute to the pathogenesis and progression of MASLD include GCKR[46], HSD17B13[47], IFNL4[48], and MERTK[49].

In the post-transplant setting, the inherently complex pathophysiology of MASLD is further exacerbated by multiple factors, including chronic immunosuppression, weight gain, sarcopenia, and the interplay between the genetic profiles of the recipient and the liver graft donor[2,10,11,38].

While essential to ensure graft function, and patient survival, immunosuppressants have adverse reactions that contribute to the development and progression of MASLD[2,9-11,38,50]. Corticosteroids are strongly associated with obesity, insulin resistance, hyperglycemia, dyslipidemia, and arterial hypertension[50]. They are associated with hypercholesterolemia because they stimulate fatty acid synthesis, induce insulin resistance, increase the synthesis of very low-density lipoprotein, reduce the activity of lipoprotein lipase (LPL), and enhance the activity of hydroxy-methylglutaryl coenzyme A reductase[51,52].

Calcineurin inhibitors are the backbone of immunosuppression drugs in LTx. Both cyclosporine and tacrolimus are associated with the development of metabolic dysfunction. Their diabetogenic effect is promoted through multiple axes including the induction of insulin resistance, inhibition of transcription factors for pancreatic β cell growth, downregulation of adiponectin transcription, and hypomagnesemia, which leads to impaired insulin signaling[53]. Calcineurin inhibitors also promote dyslipidemia via multiple mechanisms including: (1) Inhibition of sterol 27-hydroxylase, which elevates 3-hydroxy-2-methylglutaryl coenzyme A activity and thereby increases cholesterol levels; (2) Impaired bile acid synthesis from cholesterol, further raising cholesterol concentrations; and (3) Reduced triglyceride degradation due to LPL inhibition[54].

Mammalian target of rapamycin inhibitors (mTORi) are associated with hyperglycemia and dyslipidemia, increasing HDL, LDL, cholesterol, and triglycerides in 40%-75% of patients[55]. These effects are dose-dependent and result from impaired lipid transport and increased lipolysis. While low-dose mTORi regimens with statins help mitigate dyslipidemia, hyperglycemia remains a concern due to PI3K/AKT pathway inhibition and impaired insulin-related gene transcription particularly in patients with baseline glucose dysregulation[56].

Weight gain is nearly a universal phenomenon after LTx. Weight gain is due to several factors. During end-stage liver disease a low protein and sodium diet are frequent. However, these dietary restrictions are lifted after LTx. Therefore, when combined with the use of corticosteroids, the lack of physical activity, and the improvement in overall health, weight gain occurs. A significant proportion of patients develop clinically significant obesity. This diagnosis has an impact on long-term survival regardless of transplant characteristics and the presence of other CMRFs[57].

Sarcopenia is a gradual and extensive loss in the mass and function of skeletal muscles. MASLD and sarcopenia share common underlying mechanisms including insulin resistance, hormonal imbalance, systemic inflammation, myostatin and adiponectin dysregulation, nutritional deficiencies, and physical inactivity. Therefore, patients with sarcopenia are at an increased risk of developing MASLD[58]. It is a common finding among patients with advanced chronic liver disease, and it may persist or become worse after LTx. In a cohort of 53 patients with long-term follow-up, 46 (86.8%) had sarcopenia after LTx. Of the 33 patients who had pre-LTx sarcopenia, only 2 (6.1%) patients experienced reversal of sarcopenia while the remaining patients (n = 31; 93.9%) had persistent sarcopenia after LTx. Of the 20 patients who did not have sarcopenia before LTx, 15 (75.0%) developed sarcopenia after LTx[59].

In the post-LTx setting, the genotypic presentation of the recipient as well as the donor must be considered. Recipient PNPLA3 rs738409 correlates with graft steatosis during long-term follow-up[60]. The presence of the TM6SF2 c.499A allele, and the PNPLA3 c.444G allele in the donor has an additive effect and independently predicts increased liver graft steatosis[61]. The adiponectin polymorphisms in recipients were associated with early post-LTx graft steatosis, but such associations do not seem to be true for adiponectin polymorphisms in donors[62]. Current data are considered preliminary, and we are unable to conclude the relevance of the recipient or donor genotype. However, it is reasonable to hypothesize that an additive effect may be present when both the recipient and donor possess relevant mutations.

DIAGNOSIS

As stated before, MASLD is defined by the presence of hepatic steatosis on imaging or liver biopsy in association with at least one CMRF, while the diagnosis of MASH requires a liver biopsy. It is also clinically important to estimate the risk and severity of fibrosis during diagnosis of MASLD and MASH. Liver biopsy is considered the gold-standard method for identifying hepatic steatosis and allows for the detection and estimation of fibrosis severity, as well as the classification of histological inflammatory activity with the NAFLD Activity Score[3,10,15,63].

However, liver biopsies are rarely performed in daily clinical practice. Steatosis is primarily detected through noninvasive imaging. Abdominal ultrasound is cost-effective and widely available but may be less reliable in patients with obesity. Abdominal computerized tomography (CT) offers moderate accuracy with the disadvantage of radiation exposure. Magnetic resonance imaging (MRI), particularly when combined with advanced techniques like proton density fat fraction or proton magnetic resonance spectroscopy (1H-MRS), is the most sensitive and specific method for hepatic fat quantification but is limited by high cost and technical challenges[3,10,15,63].

The estimation of the risk of advanced fibrosis is obtained through noninvasive serological or radiological tests. The most frequently used tests include the fibrosis-4 index, the NAFLD fibrosis score, and the enhanced liver fibrosis score. Transient elastography with FibroScan^®, shear wave elastography, and the magnetic resonance elastography are common radiological tests[3,15,64].

Among LTx recipients, the definitions, methods of diagnosis, and staging are extrapolated from the non-transplanted population. Notwithstanding, liver biopsy occurs more frequently due to challenges in determining the precise differential diagnosis for the several causes of graft damage. With this in mind, the current criteria for the diagnosis of MASLD require adaptations for the post-LTx period. Liver imaging with CT or MRI are necessary for the detection of steatosis as well as the exclusion of technical complications of LTx (e.g., biliary and vascular complications), which might justify the biochemical abnormalities.

It is reasonable to assume the diagnosis of MASLD in patients with at least one of the CMRFs, normal liver enzymes, and steatosis on imaging studies. Whenever a LTx recipient presents with elevated liver enzymes, an imaging study for the detection of vascular and/or biliary complications must be undertaken. If this imaging study is negative, the liver biopsy is essential regardless of the observation of steatosis on imaging studies. The histological patterns are paramount for differentiating between MASH and the other causes of graft dysfunction (i.e. rejection, disease recurrence, drug-induced liver injury, and many others)[10,11,13,38,65]. Furthermore, MASH is a non-exclusive entity and may coexist with other forms of graft damage.

Noninvasive tests for the estimation of fibrosis are most useful when liver biopsy is not necessary or desirable. It is important to note that there is a lack of proper validation of these noninvasive tests in the post-LTx period as well as a lack in the granularity and details potentially offered by histology[65]. Future research should focus on validating these noninvasive methods for assessing fibrosis and steatosis in LTx recipients. Efforts should establish a reliable set of biomarkers and imaging techniques tailored to the unique challenges of post-LTx care, particularly in distinguishing MASLD or MASH from other forms of graft damage. Multicenter trials with large sample sizes are needed to evaluate the accuracy of these tests across diverse post-LTx populations.

NATURAL HISTORY AND THE IMPACT OF STEATOTIC LIVER DISEASE ON GRAFT AND PATIENT OUTCOMES

The natural history and progression of MASLD among LTx recipients are not completely understood. Transition rates of MASLD to MASH range from 27% to 29%[11,14]. Recurrent MASH affects 38%-57% of patients and seems to be more frequent, and to occur earlier than de novo MASH (observed in 13%-17% of LTx recipients)[7,11,14,66,67].

The development of liver fibrosis affects 14% of patients and may appear as early as the first postoperative year. Its prevalence increases in a time-dependent manner. Advanced fibrosis, defined as stage 3 or greater, varies from 2% to 5% after 5 years, from 5% to 10% after 10 years, and up to 24% after 15 years[7,11,14,68]. Fibrosis progression seems to be more severe among patients with recurrent disease when compared with those with de novo disease. This observation is likely due to a combination of immunological factors and persistent metabolic dysregulation[11,14]. Fibrosis advancement is also much faster among LTx recipients, with one degree of fibrosis every 2.5 years vs 7 years among the non-transplanted population[68,69].

Fortunately, this aggressive behavior rarely results in decompensated advanced liver disease or graft loss. However, this may result in patients with additional non-metabolic risk factors for graft fibrosis[69]. The 15-year overall survival for patients with MASH who received LTx is similar to the survival rates for individuals who received LTx for other indications[11,38,70,71]. Nevertheless, LTx recipients with steatotic liver disease present with higher rates of cardiovascular events and a wide array of solid non-hepatic tumors[7,11,38,70,71].

MANAGEMENT

MASLD management typically involves aggressive control of CMRFs and significant dietary and lifestyle modifications. Specific drugs for the treatment of MASLD/MASH may be required. After LTx a layer of complexity is added, and variables, such as immunosuppression and the need to prevent neoplasms, should be considered[2,7,8,11,72]. The management of post-LTx MASLD is summarized in Table 2. It is beyond the scope of this review to examine the treatment of MASLD in the general population. We instead focused on the significant changes from these recommendations for the population of LTx recipients.

Table 2 Management of post-liver transplantation metabolic dysfunction-associated steatotic liver disease.

Topics	Management
Lifestyle modifications	Dietary modifications; regular physical activity
Aggressive control of CMRFs
Weight control	Highly recommended due to the undisputable overall benefits; orlistat (adequate safety profile but limited benefits); bariatric surgery/gastric sleeve (promising approach but ideal timing and patient selection remain uncertain)
Glycemic control	General management similar to general population; early postoperative period preference for insulin therapy; transition to oral antidiabetics when steroid dosage is reduced or stopped, and insulin needs decrease; choice of oral therapy follows current guidelines
Arterial hypertension	General management follows guidelines for general population; preferred first-line therapy is calcium channel blockers
Dyslipidemia	General management follows guidelines for general population; LTx recipients considered high or very high risk for therapeutic cholesterol targets; preferred drugs are hydrophilic statins (e.g., pravastatin, rosuvastatin)
Immunosuppression	No specific guidance for immunosuppressant choice in post-LTx MASLD or MASH; immunosuppressive regimen must be tailored individually
Specific therapies for MASLD and MASH	Resmetirom, pioglitazone, and GLP-1 RAs show promise in the general population, but there is insufficient evidence to support their use in LTx recipients at this time

CMRF: Cardiovascular metabolic risk factor; GLP-1 RAs: Glucagon-like peptide-1 receptor agonists; LTx: Liver transplantation; MASH: Metabolic dysfunction-associated steatohepatitis; MASLD: Metabolic dysfunction-associated steatotic liver disease.

Weight control

Excess weight and obesity are the most significant risk factors for the development and progression of post-LTx MASLD due to their effect on insulin resistance. Despite the lack of longitudinal data evaluating the benefits of weight loss after LTx, this is a reasonable and highly recommended lifestyle modification due to the indisputable overall benefits[2,7,11,72,73]. Orlistat is the only drug tested in this population. It shows an adequate safety profile but limited benefits[74].

Post-transplant bariatric surgery, particularly sleeve gastrectomy (SG), is a very promising treatment for LTx recipients with excess weight. Its benefits include sustained weight loss, improved metabolic profiles, and reduced insulin requirements without increasing the risk of graft rejection[75,76]. SG is technically feasible in this population and has been associated with a median excess weight loss of 76% at 2 years, along with resolution or improvement of comorbidities such as diabetes and obstructive sleep apnea[77]. However, criteria defining the best candidates and the most advantageous time (i.e. before or after LTx) has not been established[75,76]. LT recipients undergoing post-LTx SG face increased risks including higher postoperative morbidity (up to 28%) and mortality (up to 11%), as well as significantly elevated hospitalization costs compared to non-LT patients (e.g., €8250 vs €5583 per surgery)[78]. Thus, while SG can be effective, it requires careful selection and multidisciplinary management to optimize outcomes and reduce complications.

Glycemic control

T2DM is the primary risk factor for negative outcomes in patients with post-LTx MASLD. Its management is very similar to the recommendations for the general population with a few adaptations[2,7,11,72,73].

During the early postoperative period, insulin therapy should be adopted because it is easier to adjust in adverse contexts (e.g., renal failure). Glycemic control can also be obtained faster, and insulin therapy does not interact with immunosuppressants. The ideal moment to transition from insulin therapy to oral antidiabetics is not properly defined. However, it is usually feasible after steroids are reduced or suspended, and the necessity for higher dosages of insulin is reduced[7,70,72,73,79,80].

The choice of oral therapy follows current guidelines and considers patient preferences and estimation of cardiovascular risk. Certain specificities related to the context of organ transplantation, such as previous hepatic disease, renal function, and type and dose of immunosuppressants, should be considered[7,72,73,80].

Arterial hypertension

The management of arterial hypertension follows the guidelines for non-transplanted patients. In general, all classes of anti-hypertensive drugs are safe. Clinicians should consider variables such as the patient profile, comorbid conditions, and cardiovascular risk. We tend to adopt calcium channel blockers (e.g., amlodipine) as first-line therapy for its vasodilator effect on the efferent arteriole of the glomeruli, which suffer direct vasoconstriction due to the calcineurin inhibitors[2,7,11,72,73].

Dyslipidemia

Post-transplant dyslipidemia requires pharmacological therapy more frequently than the non-transplanted population[2,73]. While its management follows current recommendations, LTx recipients can have a high or very high cardiovascular risk for the therapeutic targets of cholesterol fraction levels[7,11,81]. Hydrophilic statins, such as pravastatin and rosuvastatin, are preferable because they are not metabolized by CYP450. Therefore, the risk of drug-induced liver disease or pharmacological interactions with immunosuppressants is lowered[2,7,11,72].

Immunosuppression

Despite their impact on metabolic homeostasis, there are no commonly prescribed immunosuppressants for LTx recipients that are directly linked to hepatic steatosis. As a result, there are no specific recommendations regarding the choice of immunosuppressants for patients with post-LTx MASLD or MASH. The immunosuppressive regimen must be tailored individually according to the metabolic profile of the patient but considering other factors such as their etiology, the severity of the previous liver disease, and the immunological, oncological, and infectious risk of the patient. Still, it is reasonable to consider strategies to mitigate metabolic repercussions, such as smaller dosages, less toxic regimens, and even early suspension should be considered in the case of corticosteroids[2,7,11,72,73].

Specific therapies for MASLD and MASH

Several drugs have been tested specifically for MASLD and MASH but not in LTx recipients. Resmetirom, a thyroid hormone receptor β agonist, demonstrated fibrosis improvement in 26% of MAESTRO-NASH trial participants vs 14% in the placebo group (P < 0.001)[82]. Pioglitazone is an oral antidiabetic drug that activates the gamma isoform of peroxisome proliferator-activated receptor (PPAR-gamma), and improves insulin sensitivity by acting on muscle, adipose, and liver tissues. This increases peripheral tissue glucose utilization and decreases glucose production in the liver. It has a positive effect on liver enzymes but a variable efficacy in fibrosis[2,7,8].

After the results of the ESSENCE trial, the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are considered safe and effective for the treatment of liver disease and the control of CMRFs[83,84]. The SYNERGY-NASH trial, a phase 2 trial involving participants with MASH and moderate or severe fibrosis, were treated with tirzepatide for 52 weeks. They showed that this drug was more effective than placebo with respect to resolution of MASH[85,86].

Despite these promising data, LTx recipients were not included among the populations of the studies testing therapies for MASLD and MASH. The line of evidence for this use is scarce, and based on individual experience and extrapolation of information derived from the general population. Therefore, it is not possible to make specific recommendations for the use of these options for LTx recipients currently. Future studies specifically designed to evaluate the safety and efficacy of these therapies in LTx recipients are needed to guide clinical decision-making in this population[2,7,11,72,73].

CONCLUSION

MASLD is an increasing healthcare issue and we probably are on the early years of its repercussions for the LTx community. Hepatic steatosis and metabolic syndrome frequently occur during the long-term care of the LTx recipient. However, current diagnostic criteria are merely educated guesses derived from patients who did not undergo transplantation. The frequent use of liver biopsies is an example of how the needs of this population must be addressed differently. Furthermore, the tools available for noninvasive diagnosis and staging of fibrosis require calibration and validation in patients who have undergone transplantation.

Both the natural history and the risk factors for progression of post-transplant MASLD are tabula rasae, and current lines of evidence are usually borne of studies retrospective in nature, having the known limitations of this design. Its impacts on significant graft-related and patient-centric metrics are lacking, and there is a great demand for adequately designed longitudinal studies due to the many specificities of this population.

Researchers must focus on refining the diagnosis of MASLD in LTx recipients. The performance of noninvasive diagnostic tools must also be validated. Currently, the frequent reliance on liver biopsy may increase healthcare costs and expose patients to procedural risks. Therefore, the development and validation of novel diagnostic methods and noninvasive biomarkers tailored to this population are urgently needed to reduce dependence on biopsy as the diagnostic gold standard.

Additionally, studies focusing on the natural history of post-LTx MASLD and on identifying specific predictors of disease progression are essential to determine the optimal timing for clinical investigation and intervention, thereby helping to prevent fibrosis progression and graft dysfunction. Furthermore, lifestyle and pharmacological interventions currently under evaluation for MASLD and MASH in the general population must be specifically studied in transplant recipients because their efficacy and safety profiles may differ significantly in this group.

Once we have made advancements in diagnosis, noninvasive staging, and understanding the natural history of post-LTx steatotic liver disease, we will be able to evaluate different immunosuppressive strategies as well as specific therapies for the treatment of MASLD. Are we standing on unstable and uneven shifting sands? We believe not. Even though substantial research opportunities remain, we have the hopeful belief that we stand on the shoulders of giants looking at a promising path ahead of us.

ACKNOWLEDGEMENTS

The authors would like to thank the colleagues from the LTx Unit at Hospital Israelita Albert Einstein and the Discipline of Gastroenterology at Escola Paulista de Medicina/UNIFESP for their valuable discussions and critical insights that contributed to the development of this manuscript.