Era of metabolic dysfunction-associated steatotic liver disease and impact on the liver donor pool

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a silent epidemic having substantial clinical implications, with liver transplantation being one of the areas most impacted. The increasing prevalence of metabolic fatty liver disease has reduced the quality of available donor organs. While noninvasive methods are increasingly applied to evaluate liver steatosis in deceased donors, liver biopsy remains the gold standard. Many aspects of liver biopsies are not yet fully standardized. Macrovesicular hepatic steatosis is associated with decreased allograft quality and poorer short- and long-term transplant outcomes, especially in moderate and severe steatotic cases. Donation after cardiac arrest further exacerbates these poor outcomes. Matching marginal allografts with suitable recipients based on recipient characteristics is crucial for improving transplant outcomes. Living donor liver transplant is a feasible option for addressing organ shortages. Noninvasive evaluation is preferred for assessing liver health; however, when the results are inconclusive, a liver biopsy is recommended. Lifestyle modifications can improve graft, living donor and recipient outcomes. Analysis of the impact of MASLD on the donor pool and the implementation of new optimization strategies are essential to ensure the sustainability of transplantation as a curative treatment for advanced liver cirrhosis. The aim of this review was to summarize the effect of MASLD on the liver donor population, highlighting how to evaluate steatosis in donors, and to discuss its clinical implications as well as strategies to optimize organ allocation in the MASLD era.

Key Words: Liver donor; Metabolic dysfunction-associated steatotic liver disease; Deceased donor; Liver transplantation; Cardiac arrest; Brain dead donor; Macrovesicular steatosis; Macrosteatosis

Core Tip: Metabolic dysfunction-associated steatotic liver disease has been associated with a decline in the quality of available donor organs. Evaluation of liver graft steatosis is crucial for optimizing the donor pool. To maximize transplant success, decision-making algorithms need to be established, taking into account the degree of steatosis, donor characteristics, ischemia time, and recipient variables. New technologies and artificial intelligence represent future valuable tools.

INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as one of the leading causes of liver disease worldwide, replacing the previous terminology of nonalcoholic fatty liver disease. This change, proposed by a multi-society consensus and detailed by Rinella and Sookoian[1] and Rinella et al[2], aims to more accurately reflect the underlying pathophysiology and metabolic factors driving the disease. MASLD affects a significant proportion of the global population, as described by Younossi et al[3], positioning itself as a silent epidemic with substantial clinical implications.

The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and MASH-related hepatocellular carcinoma[2]. Hepatic steatosis is characterized by the presence of more than 5% lipid content in hepatocytes, a diagnosis established through imaging or histological examinations[3]. Classification of the degree of hepatic steatosis is based on the percentage of fat content in hepatocytes. It is categorized as mild (< 30%), moderate (30%-60%), or severe (> 60%). There are two histological types of steatosis: Macrosteatosis and microsteatosis. Macrosteatosis is characterized by the presence of one or more large lipid droplets within a hepatocyte that fills most of the cytoplasm and displaces the nucleus toward the periphery of the cell. By contrast, microsteatosis is defined by the accumulation of multiple smaller lipid vacuoles in the cytoplasm, without nuclear displacement. Historically, it has been recognized that macrosteatosis has a greater impact on graft function compared to microsteatosis[4].

One of the areas most affected by this new reality is liver transplantation (LT). The increasing prevalence of metabolic fatty liver disease has reduced the quality of available donor organs, as hepatic steatosis, particularly moderate to severe, is associated with poorer posttransplant outcomes[4,5]. To address this challenge, new strategies for the evaluation, preservation, and management of steatotic livers, including methods such as normothermic perfusion and “defatting” techniques, are gaining prominence[6-8]. In this context, understanding the impact of the MASLD era on the liver donor pool and the emerging strategies to optimize marginal organs is essential. Sato-Espinoza et al[9] documented how this evolution has transformed the dynamics of LT, highlighting the ongoing need for adaptation in organ selection and management policies.

As a consequence of the increase in MASLD, it is expected that a greater number of organ donors will have liver steatosis. Up to 30%-50% of deceased graft livers are expected to have steatosis[1]. One study that analyzed 22741 Liver grafts in the UNOS-STAR registry found that 13557 (59.6%) exhibited macrovesicular steatosis (mild: 92.8%, moderate: 6%, severe: 1.1%)[2]. Another study, using the National United Kingdom registry data on adult LT between January 2006 and December 2019, revealed that of the 10821 Liver grafts analyzed, 5416 (50.05%) exhibited some degree of steatosis (mild: 62.9%, moderate: 31.6%, severe: 5.5%)[3]. However, in many centers, liver biopsy is not routinely performed. The aim of this review was to analyze the effect of MASLD on the liver donor population. It specifically addressed how to evaluate steatosis in donors and discussed the clinical implications for graft availability and quality, highlighting the unmet challenges as well as strategies to optimize organ allocation in the MASLD era.

BASIC AND MOLECULAR MECHANISMS OF MASLD IN DONOR LIVERS: IMPLICATIONS FOR GRAFT INJURY AND FITNESS

MASLD profoundly changes the biology of the liver, disrupting lipid homeostasis, increasing inflammation and impairing resilience under the pressure of transplantation. Detailed knowledge of these pathways will help clinicians and researchers to understand not just the “what” but the “why” behind graft vulnerability and, ultimately, to formulate novel and effective strategies that will either protect or restore liver viability.

Lipid accumulation and metabolic dysregulation

In MASLD, the liver is a cauldron of metabolic disarray, filled with fat. This disordered condition stems from increased fat formation (de novo lipogenesis), diminished fat breakdown (β oxidation) and disabled fat exportation mechanisms. Ipsen et al[10] and Arguello et al[11] have eloquently outlined how these alterations are coordinated at the molecular level by factors such as sterol regulatory element-binding protein 1c, peroxisome proliferator-activated receptor α, and AMP-activated protein kinase. Loss of these regulators’ functionality favors accumulation of lipids. However, lipid build-up in hepatocytes is not the exclusive causality; uncontrolled cholesterol causes the cellular membranes to stiffen and, effectively, throws a spanner in the workings of the sensitive machinery of the endoplasmic reticulum[12]. Collectively, these pathological processes weaken the liver structurally and functionally, rendering it both more susceptible to and less capable to overcoming additional insults such as those encountered during procurement and reperfusion.

Inflammation and ischemia-reperfusion injury

Indeed, MASLD is not simply a passive repository of surplus fat but rather an active player in converting the liver into a proinflammatory organ. Liu et al[13] suggested that the metabolic stress from fat load in an enlarged liver accelerates the weakening of repair mechanisms for effects related to ischemia and reperfusion injuries in LT. Furthermore, their multiomics approach unveiled a flurry of reactive oxygen species, energy stores that were wasted, and a cytokine cascade that may flood the graft. Zhou et al[12] added to this knowledge by identifying the individual genes (for example, CCL2 and ADRB2) that can serve as molecular signatures of this heightened vulnerability; importantly, their data revealed an association between chemokine signaling and adrenergic challenge with injury. Wang et al[14] also showed that the sinusoidal endothelium of the liver is incompletely spared from stress and that, by becoming stressed, it too becomes damaged and contributes to microvascular stasis. Collectively, these papers demonstrate that MASLD livers are inherently inflamed, exhausted, and compromised at transplant.

Gut–liver axis and immune modulation

Less apparent perhaps but equally significant is the relationship between the gut and liver health. In MASLD, the gut microbiome falls out of balance (“dysbiosis”) which enables bacterial toxins like lipopolysaccharide to bypass the gut barrier and enter the liver through the blood. Bhardwaj and Mazumder[15] and Qian et al[16] described the mechanisms of how these microbial products trigger immune receptors (e.g., Toll-like receptor 4) and enhance hepatic inflammation. This “gut liver dialogue” sets up a vicious cycle, in which a fatty, inflamed liver impairs the gut barrier, while a damaged gut feeds more toxins back to the liver. For donor livers this means that even before procurement they may harbor a heightened inflammatory load that compromises their suitability.

Insights from animal models

Animal models have played an essential role in deciphering the intricate pathways of MASLD. Fu et al[17], Cui et al[18], and Jeong et al[19] have reported on how well-designed agonistic models of rodents could reproduce the entire sequence of MASLD, from simple steatosis to the advanced stages of fibrosis and cancer. These models have revealed, for example, how steatosis makes hepatocytes more sensitive to ischemia and how certain molecular pathways become disrupted in a stepwise fashion. Importantly, such models remind us that the human donor liver we evaluate in the operating room carries the legacy of a long biological history, shaped by diet, inflammation, and metabolic disease, which these animal studies help to illuminate.

In murine models, high-fat (45% fat) and high-fructose (15% of total energy intake) diets have demonstrated associations with multiple deleterious effects on liver health. Compared to a standard diet (10% fat), this dietary pattern leads to elevated triglyceride and cholesterol levels, increased lipid peroxidation, and histopathological evidence of hepatic steatosis and inflammatory infiltrates after 8 weeks. Furthermore, these changes are accompanied by a significant reduction in antioxidant enzyme activity, reflecting oxidative stress and liver damage commonly associated with Western-style diets[20]. A key molecular mediator implicated in diet-induced liver injury is phosphoglycerate mutase 5 (commonly referred to as PGAM5), which plays a role in the progression of hepatic fibrosis and steatosis. Its expression is modulated by the dietary composition, with both high-fat/high-fructose and choline-rich diets increasing phosphoglycerate mutase 5 Levels and choline-deficient diets suppressing expression compared to controls[21].

Mitochondrial dysfunction also appears to be a central feature in the pathogenesis of diet-induced liver disease. Diets rich in both fructose and fat exacerbate mitochondrial stress, which contributes not only to metabolic and biochemical changes (e.g., altered glucose levels and liver enzyme profiles) but also to worsened histological outcomes, including steatosis and fibrosis[22]. Even in the absence of weight gain, high-fructose intake alone induces significant metabolic shifts, particularly in carbohydrate and protein metabolism. These changes promote insulin resistance in murine models, underscoring the metabolic risk of fructose consumption independent of adiposity[23].

Still another mechanism contributing to liver damage induced by diet is gut microbiota dysbiosis. Prolonged consumption of high-fructose diets is associated with a shift in microbial composition, characterized by an increase in Bacteroides, Candida, Lactobacillus, and Desulfovibrio species and a reduction in Inhella, Opitutus, and Prevotella species. The latter microbial changes have been linked to development of MASLD[24]. Beyond the effects on microbial composition, such diets also compromise intestinal barrier function and promote systemic inflammation. These effects include a reduction in regulatory T cells and an increase in T helper type 1 cells, contributing to an inflammatory milieu that exacerbates liver damage[25].

The type of dietary fat consumed also plays a modulatory role in liver injury. In mouse models fed a high-fat, choline-deficient, and methionine-low diet, those receiving higher levels of saturated fatty acids exhibited greater hepatocellular apoptosis and more preneoplastic lesions compared to those consuming diets richer in unsaturated fats[26]. Conversely, omega-3 fatty acid supplementation in similar dietary contexts has demonstrated protective effects. These include improved histopathological and biochemical markers, elevated adiponectin levels, and reduced leptin concentrations[27].

Finally, choline deficiency itself, regardless of body weight, has been shown to induce hepatic steatosis. More severe deficiencies can progress to steatohepatitis, likely driven by choline-deficiency-induced mitochondrial dysfunction[28]. Taken together, these findings highlight the need for targeted nutritional strategies aimed at reducing dietary fructose and saturated fat intake, promoting unsaturated fat and omega-3 consumption, and ensuring adequate intake of essential micronutrients. Such approaches may represent effective interventions for preventing or mitigating the onset and progression of MASLD and related metabolic disorders.

Broader molecular context

The studies by Bessone et al[29] and Zhang et al[30] highlight MASLD as a disorder situated on a spectrum of liver disorders and that the characteristic overlapping molecular pathways of oxidative stress, fibrogenesis, and immune activation could potentially modulate the pathobiology of other liver disorders, such as alcoholic fatty liver disease. These wider contexts also serve as a reminder that MASLD is not just a clinical label but a complex, dynamic, multi-level biological phenomenon. The more we understand about these layers, the better we can make subtle decisions about graft acceptance and develop treatments that can correct unsuitability.

EVALUATION OF LIVER STEATOSIS IN DECEASED LIVER ORGAN DONORS: WHAT IS PERFORMED TODAY

Imaging studies

Ultrasound B-mode is widely available and a useful tool for qualitative detection of moderate to severe steatosis. Acoustic structure quantification is used primarily for detection of hepatic steatosis and has shown good diagnostic performance; however, its ability to classify the severity of steatosis is limited[31]. According to Ricci et al[32], portable ultrasound underestimates the presence of hepatic steatosis. Ultrasound evaluation relies on the operator's experience and is less accurate for quantitative assessment of liver steatosis, especially in mild cases or obese patients[6].

The most common, useful, and accessible radiologic modality for study of deceased donors is computed tomography (CT), which is valuable for evaluation of the liver size, lesions, vascular anatomy, and presence of steatosis. CT scans are noninvasive, objective, and faster than magnetic resonance imaging (MRI), making them convenient for patients who are hemodynamically unstable. Liver density, measured in Hounsfield units (HU), can identify and quantify hepatic fat, and CT scans can provide important information for organ procurement decisions[32,33]. Also, the liver-to-spleen attenuation ratio on CT scans can be used to detect hepatic steatosis of > 30% with a sensitivity of 79% and a specificity of 97%[34]. However, in developing and third world countries, deceased organ donors often lack abdominal imaging prior to organ procurement. MRI is highly accurate for detecting liver steatosis, even mild liver steatosis (< 30% fat accumulation), with a sensitivity of 90% and specificity of 91%[6]. However, its limited availability, logistical challenges, and higher cost prevent its routine use in the deceased donor scenario.

Transient elastography is portable, easy to perform, accurate, and reproducible. There is no established cutoff value for discarding donor livers based solely on steatosis; although, a controlled attenuation parameter (CAP) value of 230 dB/m or higher can help identify moderate and severe steatosis, with a negative predictive value of 100%. Additionally, liver stiffness measurement correlates with fibrosis staging in discarded grafts[35]. More studies are needed to spread its use in the procurement setting.

Macroscopic assessment at retrieval

All donor organs are assessed by the transplant surgeon at retrieval. Liver steatosis can be identified by observing liver color (yellowness) before and after flushing, rounded edges, absence or presence of scratch marks, and firmness. Visual assessment and palpation of the liver provide a general estimate of steatosis and are widely used during procurement in all centers. However, this is a subjective evaluation, dependent on the surgeon’s expertise, and does not differentiate between microsteatosis and macrosteatosis. While the surgeon’s evaluation correlates better with macrosteatosis, it is not a reliable method for assessing the overall fat content. Yersiz et al[36] reported that visual and texture assessment can predict macrosteatosis > 30% with good accuracy (86.2%). A recent study by Ho et al[37] showed that visually assessed moderate and severe steatosis were significant independent risk factors for primary non-function, led to poorer graft survival, and were associated with 90-day graft loss.

Liver biopsy

Frozen section biopsy with hematoxylin and eosin staining remains the gold standard for assessing liver graft steatosis. While oil red O can be used, it is not usually available and takes longer to be processed[38]. It is important to distinguish between the two forms of steatosis, macrosteatosis, and microsteatosis, according to histological findings due to the implications on posttransplant outcomes. Macrosteatosis is traditionally defined by the presence of one or more large intracytoplasmic lipid vacuoles within a hepatocyte that displaces the nucleus toward the periphery of the cells. Microsteatosis is characterized by multiple small lipid vacuoles in the cytoplasm without nuclear displacement. There is a lack of standardization of these definitions and thus there is discrepancy among pathologists when estimating microsteatosis and macrosteatosis as well as overall steatosis. The Banff Working Group on Liver Allograft Pathology documented these inconsistencies and standardized the assessment of steatosis in donor liver biopsies, focusing on large droplet fat and proposing a three-step approach for calculating its percentage[39]. There is also lack of a standardized approach to liver graft biopsies, including of the quantity, technique, timing, and location. Biopsy is usually taken from both the right and left lobules. Some centers obtain biopsies on the back table (prior to reperfusion) or after reperfusion as a routine practice, while others only biopsy if there is doubt about the organ’s viability or other specific indications.

Limitations on deceased liver graft assessment in developing and third world countries

In this setting, deceased organ donors often lack abdominal imaging prior to organ procurement. For most deceased organ donors, postmortem diagnoses are made in general hospitals with limited access to CT and biopsy or even by physicians who have very limited experience with such analyses. Point-of-care ultrasound could be a fast and readily available alternative tool in this setting; unfortunately, there are yet no studies on its usage in assessment of liver steatosis. The most common and many times the only available form of evaluation of a liver graft is macroscopic assessment at retrieval, and the decision to discard or retain a graft is made according to the experience of the transplant center and with reliance on the recipient’s characteristics.

It is important to note that deceased donation rates are lower in most of these countries, compared to those in developed countries. Such organ shortages combined with the increasing incidence of chronic hepatic disease add weight to the encouragement of more extended criteria being applied in high volume centers. While some countries have successfully increased living donor (LD) rates for liver, especially in the East, the lack of national liver transplant registries, such as in some countries in Asia and Latin America, continues to hinder organ allocation, undermine donor-recipient matching, and interfere with implementation of effective models adapted to each country and region[40,41].

SURVIVAL AND RISK OF DYSFUNCTION ACCORDING TO THE DEGREE OF MACROVESICULAR STEATOSIS IN LIVER GRAFTS

Macrovesicular hepatic steatosis is a common histopathological finding in liver grafts, particularly in the era of orthotopic LT, which is characterized by the increasing use of steatotic liver grafts. This consequence of lipid accumulation, where large lipid droplets in hepatocytes cause significant displacement of the nucleus, is an imbalance in host metabolism following transplantation that directly impacts graft survival and recipient outcomes. The extent of steatosis has significant implications for graft viability because it is associated with liver susceptibility to ischemia-reperfusion injury, posttransplant function, and recipient survival. Therefore, it is crucial to define the relationship between the degree of steatosis and graft survival to optimize LT criteria.

The frequency and degree of macrovesicular steatosis may differ substantially between deceased donor and LDs, as they are affected by the unique pathogenic mechanisms of each donor type. In donation after brain death (DBD), the transition to brain death frequently involves aggressive hemodynamic and endocrine manipulation, such as vasopressors, corticosteroids, and thyroid hormone replacement, which can minimize hepatic damage and lipid deposition in the liver. Consequently, liver grafts from DBD donors generally exhibit less steatosis and have less cellular damage than grafts from donation after circulatory death (DCD) donors. By contrast, DCD donors experience a period of functional warm ischemia between the discontinuation of life support and organ retrieval. This ischemic period, which is often relatively longer and less predictable than in DBD, causes metabolic and oxidative stress to the liver. The related hypoxia, acidosis, and deprivation of cellular energy promote lipogenesis and hinder the clearance of hepatic fat, contributing to the development of macrovesicular steatosis[42].

Effect of steatosis on posttransplant outcomes

It is well documented that the level of macrovesicular steatosis is one of the major determinants of allograft quality and is highly associated with both short- and long-term transplant results. Specifically, the presence of steatosis is a risk factor for delayed graft dysfunction, primary nonfunction, and early allograft dysfunction, with the severity of these complications increasing with the level of steatosis. Several large cohort studies and meta-analyses have established a link between the severity of steatosis and survival, categorizing it into three grades: Low risk (grade 1: < 30%); moderate risk (grade 2: 30%-60%); and severe risk (grade 3: > 60%).

Grade 1 steatosis (< 30%): Liver grafts with ≤ 20% steatosis have low steatosis content, and function well with favorable transplant outcomes. In these grafts, 1-year graft survival rates are greater than 90%, with some studies reporting 95% survival. This category is commonly considered safe for use across a broad range of recipients, even in advanced liver disease or urgent transplant cases. The safety and good outcomes from liver grafts with < 20% steatosis have led to the practice of always accepting such livers for transplantation, particularly if the donor is in good general condition and ischemia times are as low as possible[43].

Grade 2 steatosis (30%-60%): When the extent of steatosis increases to a moderate level (20%-39%), the risk of complications, including primary nonfunction and delayed graft dysfunction, becomes concerning. The 1-year graft survival rates in this group fall to about 89%-90%, representing a modest increase in risk. Moderate steatosis has a profound impact on the hepatic metabolic profile, making the liver more susceptible to ischemia-reperfusion injury and oxidative stress during LT. However, grafts with grade 2 steatosis may still produce acceptable results if donor-recipient matching is favorable and perioperative management is optimized by strategies such as reducing ischemic times and administering vasoprotective agents. Recent prospective studies have demonstrated the clinical feasibility of transplanting these allografts to carefully selected recipients, indicating that advanced preservation techniques, such as normothermic machine perfusion (NMP), may optimize outcomes in this cohort[5,44].

Grade 3 steatosis (> 60%): The most severe grade of hepatic steatosis, grade 3, is a significant risk factor for both graft failure and patient death following a liver transplant. Graft survival at 1 year in this group is generally less than 80%, and sometimes as low as 75%-78%. Such grafts with severe steatosis exhibit severe mitochondrial damage, low ATP production, and increased oxidative stress. These abnormalities contribute to the high rates of ischemia-reperfusion injury, graft loss, and post-LT complications. These grafts are generally not accepted as transplants in most centers. Still, recent developments in organ perfusion, particularly NMP, have provided a way to improve the viability of high-risk donor livers. Carefully selected recipients with a favorable clinical presentation may still be acceptable for LT using grade 3 steatotic grafts, particularly when warm ischemia times are minimized and machine perfusion technology is used. Nevertheless, it is crucial to offer these grafts to good surgical candidates with low comorbidity given that the risk of posttransplant complications remains high, even under these ideal circumstances[5,37,44] (Table 1).

Table 1 Outcomes in liver graft according to the degree of steatosis.

Steatosis grade	Steatosis range (%)	1-year survival (%)	Associated risks	Risk of PNF	Additional notes	Ref.
Grade 1 (low risk)	< 30	> 90	Low risk of DGF and PNF	Very low (almost nonexistent)	Grafts with low risk, acceptable for a wide variety of recipients. Very low rates of PNF and DGF	[21]
Grade 2 (moderate risk)	30-60	89-90	Moderate risk of DGF and PNF	Moderate	Requires careful recipient evaluation and optimized perioperative management. Use of NMP improves outcomes	[5,22]
Grade 3 (high risk)	> 60	< 80	High risk of PNF, early allograft dysfunction, and increased mortality	High	High rate of ischemia-reperfusion injury and graft dysfunction. Use of NMP may improve outcomes when the right recipient is selected	[5,17,22]

PNF: Primary nonfunction; DGF: Delayed graft dysfunction; NMP: Normothermic machine perfusion.

Pathogenic factors for differential survival according to steatosis grade

The pathophysiology of the reduced survival of steatotic livers is very complex. Hepatic steatosis can damage mitochondrial function, leading to a decrease in oxidative phosphorylation, which is essential for energy production during ischemia-reperfusion injury. In addition, steatotic livers are more susceptible to lipid peroxidation, which contributes to injury that occurs during and after LT. The detrimental metabolic state of the hepatocytes in fatty grafts may hinder adequate liver regeneration and function following LT.

Other factors influencing graft choice and utilization

Other donor characteristics: Selection of an expanded criteria graft for transplant requires careful consideration of donor age and comorbidities before transplantation. In particular, older donors are more likely to have steatosis, and the concomitant use of older and highly steatotic grafts greatly increases the probability of poor results. Recent studies have emphasized the need for careful donor selection based not only on the extent of steatosis but also on other donor factors including body mass index (BMI), presence of diabetes, and vasopressor usage. For instance, liver transplants from obese donors or donors with poorly controlled diabetes mellitus are associated with higher levels of steatosis, which limit their transplant ability[45] (Table 2).

Table 2 Risk factors associated with liver steatosis in grafts from living and deceased brain-dead donors.

Factor	Living donor	Deceased donor	Ref.
Age (years)	> 40	> 50	[96-98]
BMI (kg/m²)	> 25	> 30	[96,98]
Sex	Male	Male	[96,98]
Metabolic syndrome	Diabetes, hypertension, dyslipidemia	Common, often underdiagnosed	[45,97]
MASLD	Personal or family history	High prevalence, especially in obese individuals	[45]
Alcohol consumption (g/day)	> 20	> 40 chronically (> 5 years) or recent acute use	[45]
Preoperative assessment	Imaging (MRI, US, CAP) + selective biopsy	Limited, visual or back table biopsy if available	[34,36,99,100]
Perimortem conditions	N/A	Hypoxia, sepsis, prolonged support (> 72 hours MV, > 48 hours vasopressors, > 5 days in the ICU)	[101]
Cold ischemia	30-60 minutes	> 10 hours	[97]
Expected outcome	Minimal damage, good recovery	Higher risk of dysfunction due to ischemia and steatosis	[102]
Graft preservation	Excellent (scheduled)	Variable (depending on logistics and center)	[102]

BMI: Body mass index; MASLD: Metabolic dysfunction-associated steatotic liver disease; MRI: Magnetic resonance imaging; US: Ultrasound; CAP: Controlled attenuation parameter; N/A: Not applicable; MV: Mechanical ventilation; ICU: Intensive care unit.

Nutritional treatment for DBDs: The nutritional modulation of liver donors is principally achieved through the reduction of fasting and subsequent improvement in oxidative stress. While the efficacy of alternative strategies, such as the administration of vitamin E and epigalocatechin-gallate, has been demonstrated, further research is required to determine the most effective measures to implement[46]. In a preclinical study, it was shown that in DBD with steatosis, presurgical lipid administration benefited ATP production and reduced ischemia-reperfusion injury compared to glucose infusion due to changes in nutrient utilization after transplantation[47]. The majority of clinical studies on the impact of nutrition on ischemia-reperfusion injury have been conducted in nonsteatotic livers, with some studies suggesting that reducing the duration of fasting for a period of 48 hours prior to surgery can enhance graft functionality[48]. This is consistent with the current consensus for managing organ donors in the intensive care unit, where it is stipulated that nutritional support should be continued unless there is a contraindication[49].

Cold ischemia time: Steatotic livers are more susceptible to cold preservation injury than lean livers. This combination of steatosis and prolonged cold ischemia time significantly increases the risk of graft loss (up to 54%), especially when the cold ischemia exceeds 10-11 hours[50-52].

DCD grafts: The impact of liver graft steatosis is more significant in DCD grafts than DBD grafts. Most centers avoid using livers for transplantation from DCD donors, especially those with severe steatosis. Croome et al[38] reported a higher rate of postreperfusion syndrome, postreperfusion cardiac arrest, primary nonfunction, early allograft dysfunction, and acute kidney injury in DCD recipients with moderate steatosis and compared to DCD recipients with no steatosis[53]. According to Fu et al[17], DCD recipients with moderate or severe steatosis may experience a greater reduction in graft survival at 1 year and 3 years compared to DBD recipients with similar levels of steatosis[54].

Recipient characteristics: Preoperative evaluation of an LT recipient (including liver function, comorbidities, and nutritional status) should be considered in conjunction with donor organ quality to optimize the recipient-donor match and minimize the risk of graft dysfunction and failure. Some groups prioritize moderate to severely sick liver transplant candidates when a suitable donor becomes available. However, others advocate for a less ill patient, usually with a Model for End-Stage Liver Disease (MELD) score < 30 and exclude patients with acute liver failure. It is also important to anticipate a difficult hepatectomy in a recipient, for example, in cases with multiple abdominal surgeries, secondary biliary cirrhosis, portal vein thrombosis, retransplantation, multiple episodes of spontaneous bacterial peritonitis, and BMI > 40 kg/m². In such scenarios, a prolonged warm ischemia time, more cold ischemia time, prolonged surgery time, and higher need for transfusion can be anticipated and another recipient should be considered[46,47]. In Figure 1, we propose an algorithm based on the revised literature as a guidance to consider in liver steatotic grafts and recipient selection.

Figure 1 Liver graft selection algorithm for deceased donors. DCD: Donation after circulatory death; MELD: Model for End-Stage Liver Disease; ICU: Intensive care unit.

Progress in maintenance and machine perfusion

Although hypothermic oxygenated and sub-NMP has shown an increase in quality of extended criteria liver grafts, they have failed in reducing hepatic steatosis[55]. The improvement is attributed to mechanisms other than reduction in fat content, such as reducing inflammation, decreasing production of reactive oxygen species, and increasing mitochondrial function[56-58]. Indeed, many studies in rats using hypothermic and sub-NMP for fatty liver grafts have not found a reduction of fat content or any significant alterations in histology and intracellular triglycerides of hepatocytes, despite using a defatting cocktail[59-61].

To optimize steatotic grafts in general, and those with moderate to severe steatosis in particular, a range of more sophisticated preservation protocols have been developed, of which NMP is one of the most exciting. NMP perfuses the liver at body temperature for the ex vivo preservation of grafts, which provides opportunities for improved functional testing and cellular repair. NMP significantly improves hepatocellular function and decreases early graft dysfunction and ischemia-reperfusion injury in steatotic livers, particularly those with grade 2 and 3 steatosis. The use of NMP has increased the range of acceptable liver steatosis, expanding the pool of available organs for transplantation. Nevertheless, despite the promising results reported for NMP in another study[37], organ allocation remains challenging and should be conducted cautiously, taking into account the potential risks and specific needs of the recipients[62].

Defatting agents, such as L-carnitine, rapamycin, scoparone, visfatine, peroxisome proliferator-activated receptor, forskolin, Epigallocatechin-3-gallate, applied alone or in various combinations, along with NMP have yielded inconsistent results in preclinical trials[8,55,63]. NMP combined with a defatting cocktail has been reported to reduce liver steatosis. Banan et al[64], in 2016, performed one of the first studies of a combination of L-carnitine and exendin-4 in discarded human liver grafts and found a mild reduction of macroglobular steatosis (10%), an 8.8-fold release of triglycerides, and a 2.6-fold release of low-density lipoprotein. Then, Boteon et al[65], in 2019, published their study of 10 steatotic discarded liver grafts treated with NMP and a defatting cocktail composed of forskolin, hypericin, scoparone, visfatin, GW501516 and L-carnitine; the results reported included a reduction of tissue triglycerides by 38% and macrovesicular steatosis by 40% over 6 hours.

In 2017, He et al[66] reported a successful liver transplant from a liver graft with 85-95% macrovesicular steatosis. The liver graft had undergone continuous NMP in order to significantly reduce the ischemia time; although, they did not report if there was a related improvement in the macrovesicular steatosis. To date, clinical trials focusing on macrosteatotic liver grafts or with subgroup analysis of this specific graft characteristic are still needed. The use of NMP with defatting cocktail remains, nonetheless, an interesting and promising development in the MASLD era.

Artificial intelligence

Artificial intelligence is an intriguing and promising tool for improving and facilitating decision-making in clinical settings to achieve better donor-recipient match. In routine clinical practice, many variables are taken into account by the transplant group in order to select the most suitable recipient or discard an organ, especially when extended criteria are used (e.g., donor grafts with steatosis). Artificial intelligence could process more than 100 variables and useful classifiers, and through artificial neural networks or random forest could provide and predict a better donor-recipient match[67].

LDLT IN MASLD

LDLT represents a key strategy to address organ shortages and the complications associated with the use of steatotic grafts from deceased donors. Livers from deceased donors with moderate to severe steatosis carry a higher risk of primary graft dysfunction, early rejection, and reduced graft and patient survival[5]. By contrast, the use of grafts from LDs allows for more rigorous donor selection, ensuring organs with minimal or no steatosis, which translates into better postoperative outcomes[68]. Furthermore, LDLT offers the opportunity to optimize the timing of the procedure, reduce cold ischemia time, and minimize preservation-related injuries, which are critical factors in the management of steatotic grafts. For these reasons, in settings where the prevalence of steatotic livers among deceased donors is high, LDLT has emerged as an effective alternative to improve clinical outcomes and expand access to LT under safer conditions. A study by Kwong et al[69] suggested that macrovesicular steatosis is a risk factor for postoperative complication after LT and thus may be a reason to restrict the use of such grafts in LT. Previously, steatotic grafts from deceased donors were generally avoided due to a higher risk of graft dysfunction. However, with the advent of LDLT, where donors can be selected and their fat burden reduced, there is renewed hope for expanding the pool of steatotic grafts in translational medicine.

LDLT and donor safety of those with steatosis

One of the important benefits of LDLT is the ability to preselect and optimize the graft before donation and transplantation, which is advantageous for both the donor and the recipient. Trakroo et al[70] showed that right lobe grafts from LDs with a maximum of 20% macrovesicular steatosis can be utilized safely and effectively, without compromising donor safety or recipient outcome. This finding is of interest, as it indicates that donors with moderate steatosis may be acceptable candidates if adequate interventions to manage hepatic fat content are implemented. Preoperative optimization (e.g., preoperative dietary interventions) is a key strategy to reduce liver fat in liver LDs. These techniques not only enable the use of livers that would otherwise be discarded but also promote the general well-being of donors by decreasing the potential development of chronic liver disease later in life. Several studies support the idea that optimizing the donor might increase the pool of available transplantable organs without adversely affecting graft quality or donor safety[70].

Evaluation of liver steatosis in living organ donors: What is performed today

Due to the growing prevalence of metabolic syndrome and obesity worldwide, including in LT recipients, fatty liver (steatosis), mainly MASLD, is becoming increasingly important in LDs. Donor livers with macrovesicular steatosis exceeding 30% can lead to diminished liver function and postoperative complications in recipients[71,72]. Therefore, accurately assessing hepatic fat preoperatively during the donor work-up is crucial.

Histological examination

Liver biopsy remains the gold standard for assessing steatosis, because it allows for the quantification of lipid content and distinguishes between microvesicular and macrovesicular steatosis[73]. Noninvasive methods are increasingly preferred over liver biopsy due to risks associated with the procedure such as bleeding, sampling variability, and patient reluctance or refusal[74].

Imaging techniques

CT scans are often used to assess liver fat content, because they are readily available and can measure liver fat by comparing the ratio of hepatic to splenic attenuation (measured in HU). Liver attenuation < 1.0 HU or < 30 HU indicates significant steatosis[50]. There is a fair correlation between the CT attenuation index and histological fat content, but CT’s sensitivity decreases for detecting mild steatosis (< 10%)[51,52]. MRI, especially using the proton density fat fraction (PDFF), offers greater accuracy and reproducibility for measuring hepatic fat without the use of ionizing radiation. Compared with liver biopsy and other biochemical markers, there is also a strong correlation between MRI-PDFF and steatosis[53,75]. Magnetic resonance spectroscopy, while a precise tool for quantifying liver fat, is less practical for routine clinical use due to its technical complexity[53].

Ultrasound is the most widely available and cost-effective imaging method, although it is not as accurate as MRI-PDFF or magnetic resonance spectroscopy for detecting mild steatosis. Its accuracy is highly dependent on the operator. Using these quantifiable methods, vibrational elastography has become a more practical tool. CAP is used to quantify liver fat content and assess steatosis. It has been validated against histological analysis in numerous studies and is favored for bedside evaluation of donor candidates as it is less invasive and less expensive[76]. The ability to assess liver fat noninvasively before donation will allow transplant teams to better tailor donor selection and improve long-term outcomes for donors and recipients[54,77].

Novel approaches and biomarkers

New ultrasound methods, such as attenuation imaging, have been suggested as being potentially more accurate for diagnostic performance than conventional ultrasound or CAP. However, to confirm this hypothesis, it is necessary to conduct extensive validation studies[78]. Scoring systems and serologic markers (e.g., fatty liver index, nonalcoholic fatty liver disease liver fat score) have been examined but do not yet have sufficient diagnostic accuracy to be used as a means of selecting donors at present[79].

Integrative assessment and recommendations

When selecting donors, protocols are commonly used that consider risk factors identified through imaging, laboratory, and clinical findings. However, when imaging findings are equivocal or a donor has risk factors (e.g., BMI > 30 kg/m², significant size, diabetes), a biopsy may still be necessary to assess the organ’s suitability[72,80]. Although acceptable thresholds for steatosis vary between institutions, most centers do not use livers with more than 30% macrovesicular steatosis[50,73].

As the frequency of MASLD increases, it is crucial to assess hepatic steatosis in living LDs. Noninvasive imaging modalities, such as MRI-PDFF and CAP, are becoming increasingly important tools for predonation screening and may eventually replace invasive biopsies. However, in borderline or higher risk cases, biopsy is still irreplaceable. Further development and harmonization are essential to ensure maximum safety for the donor and survival of the graft after liver venous deprivation[80].

Lifestyle strategies to optimize LDs

Reducing the degree of hepatic steatosis in LDLT is important for graft quality, donor/recipient safety, and minimizing postoperative complications. Strategies like controlled nutrition, physical activity, and pharmacological treatment, including glucose control agents and insulin sensibilizers, can effectively reduce steatosis and improve the donor’s metabolic background. In their meta-analyses, Trakroo et al[70] reported that weight loss interventions reduced hepatic fat content in LDLT recipients with steatosis, making them more suitable for transplantation.

There is no single approach to managing MASLD, but lifestyle changes are recommended like weight loss. Patients with normal weight can benefit from losing 3%-5% of their body weight, while those who are overweight or obese should aim for greater weight loss (> 5%) to improve steatosis, and even more weight loss to reduce MASH (> 7%-10%) or fibrosis (> 10%)[81]. However, only 18% of patients with MASLD achieve a weight loss of 7%, while 10% of the population experiences a weight loss of greater than 10%. In donors with MASLD, this weight gain may be as high as 55%[82].

The preferred dietary pattern for the nutritional treatment of MASLD is the Mediterranean diet; however, these recommendations should be individualized, since the use of hypocaloric diets, hyperproteic diets, or intermittent fasting could also be effective. Another fundamental aspect is the quality of the diet, with an abundance of whole grains, fruits, vegetables, legumes, poultry, low-fat dairy products, fish, and vegetable oils. At the same time, red meat, processed meats, trans fats, saturated fats, refined grains, and added sugars should be limited. Adherence to these guidelines has been associated with a decrease in steatosis, less progression to fibrosis, and even hepatocellular carcinoma[83]. Exercise helps to achieve weight loss goals, but it also has other benefits such as the various histologic changes of steatosis, hepatocyte ballooning, steatohepatitis and fibrosis regression. According to the American College of Sports Medicine, there is no single approach for managing patients with MASLD, so the current recommendation is 150 minutes per week of moderate physical activity or 75 minutes per week of vigorous activity[84].

This personalized method of focusing on the donor’s hepatic health prior to surgery not only maximizes transplant success but also safeguards the long-term liver health of the donor. Moreover, frequent follow-up and serial assessment of liver fat during the optimization period maintain donors within safe donation limits[70]. Early and personalized interventions have played key roles in increasing the potential donor pool and facilitating the significant alleviation of the global organ shortage problem.

Recipient outcomes of LDLT according to steatosis

The presence of hepatic steatosis in an LD can impact the long-term outcomes for recipients of LDLT. Although modifiable, steatosis can significantly impact transplant outcomes. Notably, improvements in graft optimization techniques before transplantation, including reduction of hepatic fat content, have led to better outcomes. Multiple concerted strategies to reduce donor weight and meticulous evaluation of graft steatosis have successfully reduced the risks of steatotic grafts. These approaches have resulted in markedly improved graft function and decreased postoperative complications[72]. So, even if steatosis remains a heavy burden for a donor graft, there is an urgent need for very early intervention to improve both graft and recipient outcomes.

Psychological effects in living liver donors and recipients of MASLD

MASLD poses significant emotional and psychological hurdles for both the liver donor and recipient. Recognizing these effects is crucial for offering comprehensive, patient-centered care to patients through the entire process of transplantation. The LD undergoes a rigorous evaluation to ensure that he or she is not only physically fit but also psychologically ready for donation. The exclusion of a prospective donor upon diagnosis of MASLD-related steatosis can be a deeply wrenching experience. In the multicenter A2ALL 2 study, Butt et al[85] found major mental illnesses to be relatively rare among the donors post-transplant but an appreciable amount (between 4.7% and 9.6%) to experience impaired mental well-being up to 2 years after their donation. These psychological challenges may unleash powerful stress on those who have donated to a recipient who subsequently succumbs because they perceive themselves as guilty, perhaps even responsible for the failure.

Furthermore, Weng et al[86] found that candidates who were excluded from donation because of MASLD-related steatosis, often due to factors in their own health profile that contributed to the onset of such, tended to display certain characteristics that were psychological in nature. They noted that these individuals commonly experienced emotional distress as well as indifference and had strained family relationships, especially when they felt that their exclusion might endanger the recipient’s survival. Candidates described how they felt deficient, with their feelings of frustration and disappointment being particularly strong when they believed they had let a loved one down. There were also reports of blame by family members against them making them feel even worse. Ultimately, these findings underscore the importance of not only providing psychological support and counseling to donors but also to people who are excluded from donation.

MASLD also contributes to differing psychological burdens for donation recipients. First of all, living with chronic liver disease carries an emotional burden as it is often seen as “self-inflicted”, thereby leading to shame and self-recrimination. However, this may be associated more with the stigma surrounding obesity and metabolic syndrome than any intrinsic aspects of living with chronic liver disease. Labenz et al[87] reported that patients with MASLD had a significantly higher risk for anxiety and depression than controls, during 10 years of follow-up, showing the long-time consequences on mental health related to this disease and its treatment. Brodosi et al[88] further reported that social and demographic factors closely influenced the severity of anxiety and depression in patients with MASLD, namely socioeconomic status, education level, family support, and stage of liver disease. They also discovered that while patients with MASLD often showed moderate or severe symptoms of depression and anxiety, these were not entirely determined by their liver disease but also related to the social context in which they lived. This latter finding implies that meeting the psychological needs of transplant recipients demands a comprehensive effort to address individual circumstances and vulnerabilities. Furthermore, those recipients who accept steatotic grafts (often unavoidable given the current scarcity of organs) may feel ambivalent about their choice. Steggerda et al[89] reported that while well-selected low-MELD recipients can safely accept transplant of a graft with up to 50% steatosis, making this decision can trigger worries about complications and failure in future transplants. Recipients may also undergo a positive surge of relief that a liver has finally become available while in the same moment fearing for their own safety due to the quality of that graft.

In transplantation, the psychological effects of MASLD are multifaceted and profound. For both LDs and their recipients, guilt, anxiety, depression or insecurity can surface at different stages of the process, beginning with evaluation and spanning through post-transplant recovery while on dialysis. For LDs, an MASLD exclusion can bring feelings of inadequacy and shame. As for the recipients, they must bear not only the stigma attached to their chronic disease but also this fear: Will my marginal graft last long enough for me to reach old age? Transplant programs should creatively tackle the problem of training their professionals to run a psychosocial screening for all patients, with no discrimination in the endeavors. Culturally sensitive counseling will help both the donors and recipients by providing a perspective of the individual’s health and cultural beliefs in their own terms, avoiding the feeling of being pushed into a one-size-fits-all view that can be interpreted as disrespectful and frightening. Supportive communities can help bridge this gap, not only ideationally but also geographically.

Ethics of accepting a higher-risk steatotic liver for a low-MELD recipient

While the shortage of appropriate donor livers continues, transplant centers are continuing to evaluate high-risk steatotic grafts with the aim of increasing the number of potential donors. However, this strategy becomes ethically problematic when you want to give a graft to people with low MELD score and good potential for increased overall utility of organs.

Avoiding harm to the recipient: The principle of nonmaleficence requires physicians to not consign recipients to needless suffering. Steatotic livers are more prone to ischemia reperfusion injury, primary non-function, and early graft dysfunction, especially when macrosteatosis is ≥ 30%-50%. The balance of risk (BAR) score constructed by Dutkowski et al[90] facilitates evaluation of the degree of risk that a fat-replete graft presents to a recipient; acceptably good outcomes equate to BAR score ≤ 18, even when moderate steatosis is present. Similarly, Schlegel et al[91] presented a nomogram to assess futility in DCD transplantation, emphasizing that, by exceeding a certain number of risk factors (including steatosis), the use of the graft may be ethically and medically unjustifiable. For low-MELD recipients (at lower risk of imminent death), a high-risk graft can be justified if careful risk stratification demonstrates the expected harm is outweighed by the expected benefit.

Fair and efficient allocation: A resource allocation is called fair if, for any player, resources received are proportional to the contribution made. From the principles of fairness of use of scarce resources and utility, accommodating marginal grafts for recipients having lower MELD score may be considered ethical if it allows giving higher quality grafts to sicker patients and not rejecting good grafts. Steggerda et al[89] showed that in appropriately selected low-MELD patients, grafts with approximately ≤ 50% steatosis resulted in acceptable short-term outcomes, implying that such allocation can increase overall efficiency as well as diminish organ wastage. This is in line with the position of advocating total life-years gained rather than prioritizing urgent need alone[92,93]. It also represents a move to the growing perception that allocation systems should take into account both urgency (MELD-based) and likely benefit (survival benefit), particularly for marginal organs.

Autonomy and informed consent: Information is key and the patient must have it. It is well known that there is heterogeneity among recipient wishes and risk tolerance, which highlights the importance of open patient-level discussion[94]. Informed consent should be perceived as establishing the understanding that, although accepting a higher-risk graft could potentially result in shorter waitlist times and avoid decompensation, it is also associated with a potential for early post-transplant graft dysfunction and retransplantation.

Stewardship is responsible, equitable management of resources: While the proportion of steatotic livers discarded is still large, many steatotic grafts appear safe for use when they are matched adequately[89,90]. Policies should incorporate validated risk prediction tools (e.g., BAR, futility nomograms) and artificial intelligence-based models to assist with ethical allocation and minimization of discard. The decision to transplant a higher-risk steatotic organ into a low-MELD recipient represents a tension in competing ethical values. At the present time, such grafts are likely to be deemed acceptable upon careful risk assessment, informed patient consent, and transparent allocation plans. The use of tools such as the BAR score and futility nomograms, in combination with patient-centered deliberations, supports efforts towards practice becoming congruent with ethical and best clinical standards.

FUTURE PERSPECTIVES

In the era of MASLD, the future of LT will depend heavily on the field’s ability to adapt to a changing donor profile and demand both technological innovation and systemic reform to maintain the effectiveness and equity of LT in a progressively steatotic world. Nevertheless, establishment of public health strategies focusing on prevention and reduction of risk factors are key to reducing this pandemic. The development and improvement of NMP and other similar technologies will represent an important advance in the optimization of extended-criteria liver grafts[63]. With the use of artificial intelligence and machine learning, new tools and algorithms are being developed to improve the selection and match donor livers and recipients. Their use combined with images of liver grafts represent an interesting approach for a more objective liver evaluation[95].

CONCLUSION

The emergence of MASLD as the leading cause of liver disease worldwide represents a paradigm shift with profound implications for the field of LT. The high prevalence of this disease in the general population directly impacts the quality of the donor pool, as it significantly increases the proportion of liver grafts with some degree of steatosis and in advanced cases is associated with worse outcomes, which has prompted the development of more sophisticated strategies for the evaluation and treatment of these organs. Early recognition and accurate staging of steatosis in donors are critical steps to improve organ allocation and maximize transplant outcomes in the MASLD era. However, important challenges remain, such as the lack of standardization in the assessment of steatosis and the need to adapt organ selection and preservation policies to this new epidemiological reality at each transplant center. Analysis of the impact of MASLD on the donor pool and the implementation of new optimization strategies are essential to ensure the sustainability of transplantation as a curative treatment for advanced liver cirrhosis.