Non-alcoholic fatty liver disease (NAFLD) is currently the fastest growing indication to liver transplantation (LT) both in United States and Europe [1,2]. NAFLD is the hepatic expression of a systemic metabolic dysfunction. Indeed, NAFLD is commonly associated to cardiovascular (CV) disease, obesity, glucose impairment and dyslipidemia, which make more challenging the management of NAFLD patients in the transplant setting (Fig. 1). The term metabolic-associated fatty liver disease (MAFLD) was recently proposed to better characterize the metabolic dysfunction associated fatty liver disease [3], launching the debate on potential change in diagnosis, development of new therapies and improved clinical management.

MAFLD is defined by the evidence of hepatic steatosis (based on histologic, radiologic or blood test findings), associated with at least one of the following three criteria: overweight/obesity, type 2 diabetes mellitus (DM), and evidence of metabolic dysregulation [4]. Metabolic dysregulation is in turn defined by the presence of at least two of the following criteria: waist circumference ≥102/88 cm in Caucasian men/ women and ≥90/80 cm in Asian men/women; blood pressure ≥130/85 mmHg or the use of specific treatment, triglycerides ≥150 mg/dL or the use of specific treatment, high-density lipoprotein ≤40/50 mg/dL in men/women or the use of specific treatment, pre-diabetes, reactive C protein (RCP) ≥2 mg/dL and insulin resistance index (HOMA-IR) ≥2.5 [4]. The definition of MAFLD does not imply the absence of significant alcohol consumption or other causes of liver injury [4], but these patients should be defined as having dual etiology fatty liver disease [5]. The term MAFLD may improve patients characterization and help to identify individuals at higher risk for future adverse events and mortality. Indeed, Kim et al. [6] recently found a strong association between MAFLD and all-cause and cause-specific mortality, whereas NAFLD per se is not related to all-cause and cause-specific mortality. Specifically, patients who met the definition of MAFLD but not of NAFLD, had a 1.7-fold higher risk of all-cause mortality (hazard ratio [HR] 1.66; 95% confidence interval [CI] 1.19–2.32; P=0.003) and a 24% higher CV mortality (HR 1.24; 95% CI 1.01–1.51; P=0.041). Changing the nomenclature from NAFLD to MAFLD could focus on the metabolic underpinning and adjust the management of these patients, including in a transplant setting.

Currently, approximately 25% of the global population is affected by NAFLD and up to 25% of these individuals have non-alcoholic steatohepatitis (NASH) [7], with an alarming growth of incidence in young population [8]. The estimated incidence of NAFLD and NASH in 2030 are 101 million and 27 million, respectively. A recent analysis reported an increment trend of 168% for decompensated cirrhosis, 178% for liver-related death and 137% for hepatocellular carcinoma (HCC), between 2015 and 2030 [9]. Similarly, a modelling study predicted an increased rate of HCC cases of 117% in France and 88% in UK [9]. LT is the only lifesaving approach for NASH-related end stage liver disease (ESLD) and non-resectable HCC [10]. It is therefore not surprising that NAFLD is rapidly growing as indication for LT and is currently the second leading cause for LT in USA, accounting for 21.5% of performed transplants in adults during 2018 [1]. An exponential growth has also been seen in Europe, going from 1.2% in 2002 to 8.4% in 2016 [2]. Patients transplanted for NASH have more frequently HCC than non-NASH patients, 39.1% vs. 28.9% respectively (P<0.001), are older (median: 60 vs. 55 years, P<0.001) and with higher body mass index (BMI) (mean: 32.6 vs. 25.8 kg/m2, P<0.001) [11]. The reason why HCC seems to be more prevalent as indication to LT in NASH than in non-NASH patients has not yet been thoroughly understood. Proposed mechanisms include the presence of a chronic systemic inflammatory environment, genetic polymorphisms as PNPLA3 and TM6SF2, greater iron absorption, gut dysbiosis, increased lipid storage with lipotoxicity, insulin resistance and higher insulin-like growth factor (IGF) levels [12,13]. In addition, NASH patients are often obese, thus making more difficult to perform ultrasound screening of HCC.

Notably, a significant proportion of HCC in patients with NAFLD/NASH may arise in a non-cirrhotic liver. In an Italian multicenter study on 756 patients with HCC, Piscaglia et al. [14] showed that 46.2% of NAFLD-HCC occurred in a pre-cirrhotic liver. Similar results have been reported by independent cohort in Germany and Japan (41.7% and 49%, respectively) [15,16].

Acute on chronic liver failure (ACLF) is defined as an “Acute decompensation of cirrhosis (ascites, hepatic encefalopathy [HE], gastrointestinal [GI] bleed and/or infection) associated with organ failure (OF) and high 28-day mortality (>15%)” [17,18]. In a recent study based on National Inpatient Sample (NIS) database, Axley et al. [19] showed that NASH cirrhosis is the most rapidly growing etiology causing hospital admission for ACLF, with an increase of 63%, from 3.5% in 2006–2008 to 5.7% in 2012–2014 (P<0.001). In this series, infection was the most common precipitating event in ACLF (80%). Compared with non-NASH ACLF, these patients required a longer hospitalization though inpatient mortality was lower. A retrospective study based on the Veteran Health estimated an incidence of ACLF (based on European Association for the Study of the Liver - chronic liver failure criteria [EASL-CLIF] criteria) among NASH cirrhosis patients of 3.4/1,000 (95% CI, 2.9–4.0), confirming bacterial infections as the most common precipitant factor. Among individuals with ACLF grade 3, in NASH patients, kidney failure was the most common organ failure, although NASH and hepatitis C etiology shared the highest rates of circulatory failure [20]. Growing evidence suggests that patients with ACLF grade 3 should be evaluated for LT and may achieve an excellent outcome after transplant [21], provided that they are appropriately selected [22]. Pre-transplant evaluation is important in NAFLD/NASH patients due to their increased CV and systemic risk. Importantly, NASH was not associated to an increased risk of post-transplant mortality in patients undergoing transplantation for ACLF [21,22].

Metabolic syndrome, DM, and CV diseases that are often present in patients with NASH should be considered at time of LT evaluation, as they are important causes of death after LT and may be an absolute or relative contraindication to transplantation (Fig. 2) [23]. The CV issues in patients with NASH may act synergistically with the cardiac alterations associated with cirrhosis (e.g., cirrhotic cardiomyopathy, prolonged QTc) [24]. Adequate risk stratification of coronary artery disease (CAD) is essential to improve post-transplant survival. CAD is present in approximately 25% [25] of LT candidates, and patients with NASH or renal dysfunction are more likely to have a higher burden of CAD and critical coronary artery stenosis [26,27]. Worldwide, there is considerable variability in how LT programs assess cardiac risk, as models used to predict cardiovascular risk in the general population have not been validated in patients with liver disease. Regardless of the risk stratification approach used, a dedicated cardiology and anesthesia team must be involved in selecting candidates for LT [28]. As a first approach, it is necessary to obtain a medical history and search for the presence of CAD risk factors to determine the need for screening and the choice of the type of investigations. Traditional CV risk factors: male sex, hypertension, hyperlipidemia, smoking, age >60 years, left ventricular hypertrophy, previous CV disease or diabetes have been identified as the main risk factors associated with significant coronary artery stenosis in LT candidates [29,30]. So far, only three clinical risk scores have been proposed to stratify cardiac risk in LT candidates:

· CArdiovascular Risk in Orthotopic Liver Transplantation (CAR-OLT) [31]: a prognostic model designed to predict the overall 1-year risk of death or hospitalization for a significant CV event; however, it has not yet received external validation and does not estimate long-term CV risk.

· Cardiac arrest risk index [32]: a point-based model to predict cardiac arrest and ventricular arrhythmias within 30 days after transplantation.

· CAD-LT (coronary artery disease in liver transplantation) [33]: effectively stratifies pre-LT risk for significant CAD and thus can guide more targeted evaluation of candidates with less number of tests and faster waiting list inclusion.

Troponin-I and RCP, appear to have high sensitivity in predicting cardiac risk in liver transplant candidates, but more studies are needed before they can be used in clinical practice [34,35]. Current studies have revealed that coronary artery calcium scoring has a negative predictive value of 95–100% for significant coronary heart disease (CHD) [36,37]. Therefore, the most recent American Society of Transplantation guidelines proposed its use in the risk stratification of LT candidates [23]. Non-invasive stress testing (e.g., dobutamine stress echocardiography, myocardial perfusion imaging and CV magnetic resonance) have been validated to detect CAD in general but are suboptimal for patients with ESLD [28]. According to the current European Society of Cardiology [38] guidelines, non-invasive testing should be offered to patients with more than two risk factors for CAD and poor functional status. Invasive coronary angiography is the gold-standard test to identify significant CHD in the general population, but currently, in LT candidates, studies are inconclusive and not able to predict the impact of asymptomatic pre-LT CV abnormalities on long-term outcomes [39,40]. Coronary computed tomography angiography (CCTA) is a non-invasive test valid for assessing the risk of CHD in LT candidates, although no studies are comparing it with invasive coronary angiography (ICA) in this population [41]. CCTA alone does not provide a functional assessment of coronary stenosis, which can be obtained by integrating this examination with fractional flow reserve obtained from computed tomography in this population [42].

The most recent guidelines, published in October 2022 by the American Transplant Society [28], recommend the following algorithm:

· Cardiac physical examination, electrocardiogram (ECG), and resting trans-thoracic echocardiography (TTE) (with measurement of myocardial strain and bubble study to assess pulmonary hypertension and intracardiac and extracardiac leads) for all LT candidates without CHD.

· In LT candidates at low risk of significant CHD (age <40 years, able to achieve ≥4 metabolic equivalents (METs), no NASH or diabetes, no CHD risk factors), if initial ECG and resting TTE are normal, additional cardiac stress testing may not be necessary.

· In intermediate-risk liver transplant candidates, non-invasive exercise testing may be considered (stress echocardiography [SE] is preferred; dobutamine SE if patient cannot exercise. Positron emission tomography as an alternative if available).

In LT candidates at high risk of significant CHD (diabetes, NASH, or ≥2 other CHD risk factors), coronary anatomic imaging (CCTA or ICA) is mandatory.

· ICA should be the last procedure performed in the evaluation before listing for liver transplantation after the patient has already been considered an acceptable transplant candidate.

Lifestyle modifications are recommended to improve clinical outcomes after transplantation. Obese patients should lose weight through a low-calorie diet and adequate physical activity [23]. Weight loss in this patient population must be carefully controlled and managed by experts to avoid loss of muscle mass and subsequent sarcopenia, which is a known risk factor that increases post-transplant mortality and worsens patient prognosis (Table 1) [43,44].

A recent analysis on patients from OPTN (Organ Procurement and Transplantation Network)/UNOS (United Network for Organ Sharing) registry showed that, in comparison to patients with alcoholic liver disease (ALD), the risk of 90-day and 1-year waitlist mortality was significantly higher in NASH patients (P=0.042 and P=0.008) [45]. Model for End-Stage Liver Disease-Na (MELD-Na) score, Chronic Kidney Disease (CKD) stage >3 and hyponatremia were significantly associated to mortality. Nagai and colleagues also demonstrated that 90- day Delta MELD-Na was lower in Alcoholic Liver Disease (ALD) patients than in NASH patients, suggesting that NASH patients may have a faster disease progression. When considering patients with HCC as indication to LT, NASH patients showed a higher risk of 1-year waitlist mortality compared to HCC-ALD; however, an explanation could be that NASH patient were older [45]. Another study based on UNOS registry data from 2002 to 2016 found a higher unadjusted cumulative incidence of exclusion from wait list (WL) for mortality and deterioration in NAFLD patients compared to patients with other indications to LT, but when adjusted for confounder factors, waitlist mortality was similar between NASH and non-NASH patients [46]. In fact, by analyzing data from the Scientific Registry of Transplant Recipients (SRTR) from 2002 to 2016, Younossi et al. [47] found no significative difference in terms of outcome during the waiting-list (transplant vs. drop out) between different etiologies. Young et al. [48] demonstrated that patients with NASH-HCC are less likely to have exception to MELD on WL and, as a result, they are less likely to receive LT than patients waitlisted for other etiologies. Another factor that may contribute to disparities in HCC exception is the better hepatic function in NASH-HCC patients at diagnosis and the slower progression of cirrhosis compared with Hepatitis C Virus (HCV)-HCC patients [48], which results in lower MELD score. As a consequence, NASH-HCC patients have significantly higher rates of primary surgical resection and lower rates of LT when compared with HCV-HCC patients [49], leading to lower likelihoods to receive LT and longer WL times. Furthermore, NASH patients—including those with a low MELD score, were more frequently delisted or died due to CV complications. It thus seems that the MELD score does not fully represent the clinical condition of NASH patients. New prognostic scores to better stratify the risk of short-term deterioration and mortality of patients with NASH are expected.

IS treatment constitutes one of the most critical factors impacting outcomes after liver transplantation. The introduction of CNIs—cyclosporine (CsA) and tacrolimus (TAC)—reported a reduction in acute rejection rates and improvements in short-term patient and graft survival [95]. Long-term survival, in contrast, is most impacted by renal, CV, and metabolic toxicity secondary to medication use, especially CNIs and glucocorticoids [96-98], in particular in predisposed patients such as those undergoing LT for NASH. The goal of the world’s LT experts is to reduce the toxicity of immunosuppression by tailoring therapy basing on individual patient characteristics. Steroids are obesogenic drugs that induce glucose intolerance, hypertension and hyperlipidemia. Their clinical use is short-lived in clinical practice, which limits their potential collectivizing effects. CNIs are associated with developing all components of the metabolic syndrome as a consequence of the inhibition of insulin secretion and increased insulin resistance. They, therefore, present a pro-diabetogenic action, more associated with TAC than with CsA, which, on the other hand, presents a more significant pro-lipidemic effect. The nephrotoxic effect of CNIs is also known to occur due to renal and systemic vasoconstriction mediated by this family of drugs, which is responsible for the onset of arterial hypertension. In patients transplanted for NASH, the strategy should be to early reduce or withdraw the steroids [24], introducing alternative immunosuppressive drugs with a lower impact on the metabolic profile. From OPTN/SRTR 2019 Annual Data Report, it was found that 75% of patients were treated with the dual regimen consisting of CsA and mycophenolate mofetil (MMF), and the MMF was reported to be used in 45% as maintenance therapy at 1- and 2-years after LT [95]. Patients treated with MMF combined with reduceddoses of CNIs had lower CV risk and reduced renal function impairment than those treated with a regimen containing only standard-dose of tacrolimus plus corticosteroids [99]. However, there still needs to be a consensus on the ideal minimization regimen. Newer mammalian target of rapamycin (mTOR) inhibitors [100] are associated with an increased risk of post-LT dyslipidemia, whereas they are neutral concerning diabetes mellitus and hypertension. Moreover they are associated with a reduction in body weight, a lower frequency of cardiac events and, compared with CNIs, are associated with a more favorable renal profile [24]. mTOR inhibitors, combined with CNIs, are associated to a prolonged long-term survival in patients transplanted for HCC [101]. In NASH patients, the use of drugs with less impact on the metabolic-cardiovascular profile, being the only modifiable factor, is the best strategy to reduce post-LT complications and improve outcomes.

Up to 20% of NASH patients are estimated to be affected by sarcopenia [102]. A synergic overlap between pathophysiology of these two conditions resulted in an increased risk of NAFLD development when sarcopenia is present and vice versa [103,104]. Pre-LT sarcopenia has been associated with increased risk of adverse outcomes after liver transplantation, such as higher risk of bacterial infection and mortality [105]. Specific data regarding sarcopenia and NASH are still needed, however patients affected by sarcopenia and NASH are found to have an increased risk of insulin resistance, atherosclerosis and CV disease [103,106]. Metabolic alterations associated with cirrhosis may reverse after liver transplantation; however, few data on the assessment of body composition after LT are available. In 2013, Tsien et al. [107] investigated the potential role of post-transplant sarcopenia evaluating changes in body mass composition in prospective cohort of transplanted patients. Among 53 Patients (7.5% affected by NASH disease), 41 (77%) experienced a decreased in abdominal wall muscles and 43% an increase in fat area in a medium follow-up of 19.3±9 months. However only patients who experienced post-transplant sarcopenia had 3.1-fold increased risk of developing DM (P=0.05, 95% CI 1.01–9.38), with no evidence in decreased overall survival [107]. A review published in 2013 showed that, despite conflicting and few data with different methods of muscle mass assessment, further reduction of skeletal muscle mass has been observed up to one year after liver transplantation [108]. Possible explanations have been proposed including persistence of hypermetabolism soon after LT, IS drugs, mostly mammalian target of rapamycin (mTOR) inhibitors and corticosteroids, length of hospitalization and occurrence of post-transplant infections that tend to be more frequent in patients with pre-LT sarcopenia resulting in an increased risk of muscle mass depletion [105,109,110]. Subsequently, Jeon et al. [111] in retrospective cohort of 145 patients who underwent LT reported that all patients with pretransplant sarcopenia remain sarcopenic soon after LT and 15% of patients with normal muscle mass pre-transplant developed sarcopenia de novo post-LT. Although there was an increased trend of mortality soon after LT in newly developed sarcopenia, these finding were not confirmed at 6 months from LT, when sarcopenia resulted not to be a predictor of death [111]. Similar findings have been reported by Bhanji et al. [112] who assessed the skeletal muscle mass in two hundred and ninety-three patients 7 month after LT (interquartile range 4.8–12 months). Ninety-eight patients (61%) resulted to be affected by post-LT sarcopenia, both with newly developed sarcopenia (25/98) and persistent sarcopenia (73/98). There was no difference in survival between post-LT sarcopenic patients (both de novo and persistent) and non-sarcopenic patients. It has been postulated that patients with post-LT sarcopenia resulted to be less affected by metabolic liver disease before LT (2.7% vs. 12.2% P=0.002). However, in contrast with these findings, Carias et al. [113], which retrospectively evaluated changing on body composition after LT in a cohort of 207 adult patients (21.7% with NASH), found that, at multivariate logistic regression analysis, NASH etiology is an independent predictor of sarcopenic obesity development (P=0.014; 95% CI: 1.44–25.26, OR 6.03). Sarcopenic obesity (SO) is defined as the contemporary presence of sarcopenia in the contest of obesity [114]. The prevalence of SO in the context of cirrhosis ranges between 20% and 35% [115]. At present, studies on SO are limited and mostly focused on pre-transplant period, but a meta-analysis on the role of SO in liver transplantation reported an increased risk of death at least two times higher in SO vs. not SO patients both at short-and long-term follow-up [116]. Indeed the original aim of the meta-analysis was to assess the role of SO in patients with NASH after LT, but Hegyi et al. [116] were not able to perform the analysis due to lack of data. Data about the impact of post-LT sarcopenia continues to be scarce as recently highlighted by a review of Ooi et al. [105] who showed that upon 35 studies on sarcopenia in the setting of liver transplantation only 6 focused on the potential role of sarcopenia and SO after LT. Further data are needed on body composition’s changes in post-transplant period to ensure better management of these patients in order to guarantee better outcomes.

Liver transplantation represents the only life-saving therapy in patients with ESLD. In an analysis by Haldar et al. [11] on data from the European Liver Transplant Registry (ELTR) of patients transplanted between January 2002 and December 2016, NASH was not an independent predictor of patient or graft survival. However, older recipient age (61–65 years: HR 2.07; 95% CI 1.39–3.08; >65 years: HR 1.72; 95% CI 1.10–2.71; relative to ≤45 years), MELD score >23 (HR 1.48; 95% CI 1.04– 2.30; relative to ≤11) and BMI either ≤18.5 kg/m² (HR 4.29; 95% CI 1.01–18.21; 18.5–25 kg/m² : HR 2.24; 95% CI 1.27–3.96) or >40 kg/m² (HR 1.96; 95% CI 1.16–3.32; relative to 25–30 kg/m²) were independent predictors of post-LT mortality. A systematic review with meta-analysis [117] evaluated the variables associated with patient and graft survival in individuals with NASH-related liver disease, showing that recipient age >65 years, pre-transplant DM, MELD >23, functional status, HCC, dialysis prior to LT, hepatic encephalopathy and time/year of LT were predictors of mortality after transplantation. As previously described in patients transplanted for other etiologies of ESLD, increased patient mortality was associated with older age of the recipient (HR=2.07, 95% CI: 1.71–2.50, I²=0, τ₂=0, P=0.40) and pre-transplant DM (HR=1.18, CI 95%: 1.08–1.28, I²=0, τ₂=0, P=0.76). No difference in term of patient and graft survival rates were found between NAFLD/NASH and non-NAFLD/NASH patients transplanted for HCC [11]. Likewise, post-transplant HCC recurrence rates have been shown to be similar between NASH and non-NASH aetiologies, 13.3% vs. 14%, respectively (P=0.879). Median time to HCC recurrence did not change between the two groups, 22.6 vs. 13.3 months (P=0.274) [118]. NASH and obesity may be associated with a reduced quality of life [119], however no specific studies investigating quality of life (QoL) in NASH transplanted patients are yet available.

NAFLD/NASH has now become one of the most common indication for liver transplantation worldwide. Multidisciplinary management of NASH and NASH-associated comorbidities may mitigate morbidity and mortality in patients with NASH both before and after liver transplantation. Patients selection is crucial to achieve post-transplant survival comparable to other etiologies of liver disease. In transplant recipients, diet, physical activity, and adjustment of IS therapy are key for prevention of NASH recurrence. In the future, an improved risk stratification in NASH candidates for transplantation and new drugs for the treatment of NASH recurrence are expected.