Sarcopenic obesity in patients awaiting liver transplant: Unique challenges for nutritional recommendations

Abstract

Sarcopenic obesity increases the risk of mortality in patients with liver disease awaiting liver transplantation and in the post-transplant period. Nutrition recommendations for individuals with sarcopenia differ from recommendations for patients with obesity or sarcopenic obesity. While these nutrition guidelines have been established in non-cirrhotic patients, established guidelines for liver transplant candidates with sarcopenic obesity are lacking. In this paper, we review existing literature on sarcopenic obesity in patients with chronic liver disease and address opportunities to improve nutritional counseling in patients awaiting liver transplantation.

Key Words: Nutrition; Sarcopenia; Sarcopenic obesity; Liver transplant; Cirrhosis; Chronic liver disease; Body composition; Myostatin

Core Tip: Sarcopenic obesity is common among patients with chronic liver disease and is associated with increased mortality both pre- and post-liver transplantation. Although nutrition guidelines exist for non-cirrhotic patients with sarcopenic obesity, there is limited data on nutrition recommendations for those with liver disease. Here, we discuss sarcopenic obesity in liver transplant candidates and review nutrition recommendations for this specific population.

INTRODUCTION

Malnutrition and sarcopenia are common in patients with chronic liver disease (CLD) and are critical predictors of outcomes for those pursuing liver transplant (LT)[1]. The American Association for the Study of Liver Disease defines malnutrition as deficiency in caloric or nutrient intake and defines sarcopenia as the loss of muscle mass[1]. Importantly, malnutrition and sarcopenia can occur independently of weight or body mass index (BMI). In fact, 20% to 35% of patients with cirrhosis experience both substantial muscle wasting and accumulation of body fat, and up to 35% of patients with cirrhosis who are obese have low muscle mass[2-4]. Despite this burden, there is a paucity of literature on nutrition in patients with cirrhosis who have concurrent sarcopenia and obesity. This gap in the literature prevents comprehensive nutritional support for our patients with the phenotype of both sarcopenia and obesity. In this review, we discuss the definitions, pathophysiology, and clinical implications of sarcopenic obesity in LT candidates and review nutrition recommendations aimed toward weight management with concurrent preservation of muscle mass in the pre-transplant setting.

DEFINING SARCOPENIA, OBESITY, AND SARCOPENIC OBESITY

Sarcopenia is a progressive and generalized disorder of skeletal muscle that is defined by low muscle mass with or without loss of muscle strength[1]. Most studies conducted in patients with cirrhosis define sarcopenia by muscle mass metrics detected on routine imaging studies alone[1]. Professional guidelines recommend the use of Skeletal Muscle Mass Index (SMI) as assessed by computed tomography at the time of routine health assessments[1,5].

Obesity is a chronic disease clinically characterized by excess fat accumulation and elevated body weight (BW) relative to height. Historically, obesity is defined by BMI ≥ 30 kg/m²[6]. Several well-recognized limitations exist for BMI as an index for health. Limitations include the inability to characterize body composition or to account for additional factors that influence muscle vs fat mass such as ethnicity, sex, and age[7]. These limitations are particularly important in patients with liver disease who experience additional dynamic shifts in volume status in the setting of ascites and anasarca[8]. Alternative definitions for obesity are either based on the percentage of body fat or the abdominal fat distribution. Specifically, central obesity is defined as either elevated waist circumference or high visceral fat content on imaging[3].

Sarcopenic obesity is characterized the presence of concurrent low muscle mass and excess visceral fat[3]. However, a universal definition of this term is lacking, and the metrics used to define sarcopenic obesity vary across studies. Key radiographic indicators of sarcopenic obesity include visceral adipose tissue and subcutaneous adipose tissue (SAT)[8]. The prevalence of sarcopenia is higher than that of sarcopenic obesity in patients with cirrhosis[9]. This can be explained by the positive correlation between SMI and BMI[10]. Routine use of BMI in the definition of sarcopenic obesity is not recommended as BMI has been shown to correlate poorly with visceral fat indices in both the pre- and post-transplant setting[11].

PATHOPHYSIOLOGY OF SARCOPENIC OBESITY

Obesity and sarcopenia are closely connected at a biochemical level. Pre-disposition to sarcopenic obesity is largely tied to changes in body composition throughout aging, such as skeletal muscle mass loss and adipose tissue dysfunction and associated chronic, low-grade inflammation[12]. Sarcopenic obesity ultimately develops from maladaptive interactions between adipose tissue and skeletal muscle that occur in states of metabolic derangement (e.g., liver disease), as these organ systems cross-talk with one another to reach a new state of homeostasis[13,14].

Patients with obesity often have excessive adipose tissue, characterized by adipocyte hyperplasia and hypertrophy. Excessive adipose tissue leads to diminished capacity to store lipids and result in ectopic accumulation of free fatty acids (FFAs) within skeletal muscle[15]. Oversupply of FFAs drives an adaptive increase in mitochondrial β-oxidation and production of active lipid metabolite. In the absence of increased energy demand, this leads to excess production of reactive oxygen species and oxidative stress, and results in adipocyte dysfunction[16]. This cascade impairs the endocrine function of adipose tissue, which produces hormones crucial to maintaining skeletal muscle health.

Leptin and adiponectin have been recognized as the chief adipokines mediating the reciprocal control of fat and skeletal muscle[17]. While leptin has long been implicated in the pathogenesis of insulin resistance in obesity, new studies have indicated that minimal threshold levels of adipose-derived leptin are necessary to achieve normal skeletal muscle mass and contraction[18]. It has been suggested that leptin resistance and the consequent downregulation of leptin receptors contribute to muscle atrophy and persistent visceral fat[19,20]. Conversely, adiponectin promotes muscle regeneration and suppression of proteolysis[21]; with obese patients demonstrating both lower adiponectin levels and a significant decrease in muscle strength[22]. Additionally, irisin has been identified as an exercise-induced myokine that contributes to the browning of white fat and acts as a regulator of adipocyte differentiation. Decreased irisin level contributes to skeletal muscle adiposity, while upregulation may lead to decreased myostatin gene expression and delay muscle catabolism[23,24]. Myostatin, a member of the transforming growth factor-β superfamily, is also considered a key regulator for maintaining muscle mass. An overexpression of this protein leads to muscle atrophy, whereas knockout studies have reported muscle overgrowth[23]. At the same time, although myostatin is predominantly secreted by skeletal muscle, animal models have shown that this myokine is also implicated in the regulation of brown fat. Specifically, deletion of myostatin has shown to activate both brown and beige adipocytes, while also protecting from adipocyte hypertrophy and hepatic steatosis[25,26]. Furthermore, myostatin overexpression has been associated with states of sarcopenic obesity both in middle-aged and older adults[27]. These hormonal pathways demonstrate the complex interactions between adipose tissue and skeletal muscle, and how alterations in this inter-organ crosstalk can contribute to development and progression of sarcopenic obesity.

PATHOPHYSIOLOGY OF SARCOPENIC OBESITY IN CHRONIC LIVER DISEASE

The liver, which acts as a hub to metabolically connect various tissues, is implicated in the critical physiological pathways that drive the skeletal muscle loss and adipocyte dysfunction of sarcopenic obesity (Figure 1). The liver is responsible for the synthesis of insulin-like growth factor-1 (IGF-1) which plays a key role in the regulation of both anabolic and catabolic pathways in skeletal muscle, adipose, and hepatic tissues[28]. In the context of sarcopenic obesity, IGF-1 acts as the gate-keeper of myostatin by controlling its expression and secretion, and therefore promotes conditions that favor adipocyte hyperplasia[29]. As part of this biochemical pathway, leptin plays a major role in stimulating hepatic production of pro- inflammatory cytokines like tumor necrosis factor alpha and interleukin-6. This state favors the recruitment of Kupfer cells and CD8+ lymphocytes that exert a critical role in both the pathogenesis and progression of metabolic dysfunction–associated steatotic liver disease (MASLD)[30]. Importantly, MASLD, which is becoming the most common indication for LT in the United States[31]. Interestingly, research has shown that not only sarcopenic obesity is associated with a significantly increased prevalence of metabolic associated fatty liver disease (MAFLD) and liver fibrosis, but that the major biomarkers of sarcopenic obesity, such as adiponectin, leptin, and IGF-1, can also be utilized for diagnosis and stratification of MAFLD[32-34]. Furthermore, the implications of sarcopenic obesity can have vast ramifications in the realm of decompensated liver disease[35,36]. In fact, as the catabolic state of sarcopenia worsens, muscle break down and the consequent increase in ammonia production may critically affect the progression of liver disease and facilitate the onset of hepatic encephalopathy[37].

Figure 1 A Pathophysiology of sarcopenic obesity. Obesity and sarcopenia share biological alterations such as insulin resistance, increased pro-inflammatory cytokines, oxidative stress and age-associated hormonal changes. Adipocyte hypertrophy induces a state of systemic inflammation characterized by decreased adiponectin and elevated levels of leptin, tumor necrosis factor, and interleukin 6 (red arrow). Also, obesity and aging contribute to changes in skeletal muscle homeostasis, leading to increased expression of myostatin and reduced irisin, which ultimately favors muscle wasting (red arrow). Concomitantly, excess delivery of fatty acids to the liver leads to fat deposition into the hepatocytes which results in hepatic insulin resistance as well as decreased insulin-like growth factor production. These processes contribute to a vicious cycle leading to adipose tissue expansion, muscle loss and hepatic dysfunction (gray and blue arrows). TNF-α: Tumor necrosis factor; IL-6: Interleukin 6; IGF-1: Insulin-like growth factor; GH: Growth hormone; SFA: Saturated fatty acid; ROS: Reactive oxygen species; MASH: Metabolic dysfunction-associated steatohepatitis. Adapted from “Cycle Diagram”, by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates with permission for re-publication.

IMPLICATIONS OF SARCOPENIC OBESITY SURROUNDING LIVER TRANSPLANT

The assessment of nutrition and strength are routinely performed in the evaluation for liver transplantation[38]. Poor nutritional status and reduced functional capacity are increasingly common reasons that patients are declined for LT candidacy or are removed from the LT waitlist. These decisions occur in light of robust showing that frailty and sarcopenia are associated with hepatic decompensation, increased healthcare use, worse quality of life, adverse post-transplant outcomes (e.g., small for size syndrome) and increased mortality in patients with cirrhosis[1,39,40]. Additionally, obesity has been associated with increased LT waitlist mortality and increased incidence of post-transplant surgical complications such as wound infections, wound dehiscence, and biliary complications[41].

Importantly, there is emerging data to suggest that sarcopenic obesity is associated with worse outcomes than sarcopenia or obesity alone. A 2016 study of 161 patients with cirrhosis found an increased risk of death in patients with elevated visceral fat area (VFA) and low muscle mass, compared to low muscle mass or high VFA alone[42]. This has been supported in larger cohorts as well, including a study of 277 patients where sarcopenia and myosteatosis were associated with a 1.5 times greater mortality risk compared to patients without muscular abnormalities[9]. In pre-liver transplant patients specifically, a study prospectively assessed sarcopenic obesity in deceased-donor LT candidates and found that sarcopenic obesity was associated with significantly increased waitlist mortality[8]. The impact of sarcopenic obesity has also been seen in post-transplant outcomes, where rates of post-transplant mortality are higher in patients with sarcopenic visceral obesity compared to patients with sarcopenia or visceral obesity alone[2]. In addition to deceased donor LT, post-transplant survival rates were lower for patients with sarcopenic obesity who underwent living donor liver transplantation (LDLT) compared to non-sarcopenic and non-obese patients[43].

GENERAL NUTRITION RECOMMENDATIONS FOR PATIENTS WITH LIVER DISEASE

For patients listed for liver transplantation, it is essential that timely nutritional assessments occur with frequent reassessments until transplant. Nutritional assessments should occur routinely using a validated tool such as the Subjective Global Assessment or Royal Free Hospital-nutritional prioritizing tool (RFH-NPT)[44]. The RFH-NPT was developed to assess nutritional status in patients with CLD and includes BMI, unplanned weight loss, dietary intake, and severity of disease in its assessment[45]. All nutritional assessments should include a physical exam that focuses on evaluating subcutaneous fat loss, muscle wasting, and fluid retention[44,46,47]. It is important to note that nutrition alone is insufficient to improve functional status in patients with CLD, malnutrition, and frailty[1]. Recent studies on prehabilitation in patients preparing for liver transplantation have shown that interventions such as increased daily step count, and introduction of strength exercises is safe, feasible, and can improve aerobic and functional capacity[48,49].

Specific nutritional recommendations for patients with CLD include shortening fasting periods by adopting a high protein breakfast and late evening snack[1]. Historically, concerns have existed that high protein intake could contribute to the development of hepatic encephalopathy. This has since been disproven, and optimal protein intake in patients with CLD should not be lower than the recommended 1.2-1.5 g/kg (BW)/d[44]. Research has shown that among patients with CLD, total energy expenditure varies between 28-38 kcal/kg (BW)/d. As a result, current studies have recommended an energy intake between 25-40 kcals/kg (BW)/d for patients depending on clinical and nutritional status[1,44,46].

For patients with sarcopenia, it is critical to optimize nutritional intake in the pre-transplant period to mitigate the loss of muscle tissue. The nutrition plan should optimize protein intake, with most studies supporting a goal of 25-30 g of high-quality protein from a diverse range of sources per meal to maximally stimulate muscle protein synthesis[1,44,46]. In some selected studies, additional supplements such as testosterone, growth hormone, and L-carnitine has shown to be helpful in improving muscle mass and suppressing muscle loss[1,5,46]. Exercise can also serve as an additional tool to improve muscle mass and function in patients with sarcopenia. Current guidelines recommend 20 to 30 min of a combination of aerobic and resistance training three times a week[1,46].

Despite current recommendations to avoid using BMI as the sole measure of obesity, some guidelines still recommend that all patients awaiting LT with a BMI greater than 35 implement lifestyle changes to achieve a BMI target below 30[41]. However, while it is generally agreed upon that although weight loss may be beneficial, very low-calorie diets should be avoided in this population[1,5,44,46,50]. Currently, limited data exists on energy use among patients with cirrhosis across a spectrum of BMIs. When making calorie intake recommendations, resting energy expenditure should be assessed using indirect calorimetry, or can be estimated using the Harris Benedict or Mifflin St Jeor equation[44]. There are also tools available to provide personalized daily caloric targets using BMI stratification based on ideal body weight corrected for fluid retention[5].

To facilitate achievement of nutritional goals, care should also be taken to improve diet palatability in patients following a sodium restriction, as unfavorable flavors can cause a reduction in calorie intake[1]. For patients who cannot tolerate an oral diet or oral supplementation, enteral nutrition is recommended, and nasogastric tubes can be placed in patients with non-bleeding esophageal varices. Parenteral nutrition should be considered if enteral nutrition is not feasible. Due to the risk of platelet dysfunction and ascites, percutaneous endoscopic gastrostomy insertion is contraindicated in patients with CLD[44].

NUTRITION RECOMMENDATIONS FOR SARCOPENIC OBESITY

Few studies exist that have investigated the effects of nutritional interventions on sarcopenic obesity in both the general population and in patients with CLD. It is understood that a nutrition strategy for sarcopenic obesity must target optimal nutrient intake to preserve muscle, while simultaneously preventing excess fat mass[44] (Figure 2). There are conflicting opinions on whether calorie deficit is effective for achieving fat reduction while preserving muscle mass. One study done in older adults supports an energy deficit of 200-700 kcal/d[51]. However, a very low-calorie diet increases the risk of skeletal muscle loss and worsening micronutrient status[4,44]. Although there are limited long-term studies evaluating the optimal protein intake for patients with sarcopenic obesity, it is generally accepted that these patients may have higher protein needs. One study recommends a minimal protein intake of at least 1-1.2 g/kg[4]. Additionally, many studies have shown that resistance exercise is an effective strategy, in addition to nutrition, to preserve muscle mass in patients with sarcopenic obesity[4,52].

Figure 2 A summary of nutrition and lifestyle recommendations for concurrent chronic liver disease and sarcopenic obesity. Lifestyle recommendations for patients with chronic liver disease and sarcopenic obesity include thorough nutritional assessments and re-assessments, weight management, and exercise. Nutritional recommendations include maintaining an appropriate caloric, shortening fasting periods, and obtaining and adequate amount of protein through diet. Adapted from “Cycle Diagram”, by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates with permission for re-publication.

Patients with CLD and concurrent sarcopenic obesity frequently have multiple providers involved in their care and may subsequently receive conflicting advice regarding specific nutritional needs. While some studies argue against weight loss in patients with decompensated cirrhosis and sarcopenic obesity given the role of adequate protein[1], others guidelines propose that nutritional management specific to cirrhotic patients with sarcopenic obesity be no different than general nutritional management of cirrhosis[53]. However, it is agreed upon that excessive energy restriction in very low-calorie diets should be avoided in this patient population due to the poor tolerance of fasting and risk of worsening sarcopenia. As a result, it is recommended to achieve specific caloric goals using BMI-stratified target caloric intake guidelines[3]. If caloric restriction must occur, such as for cases in metabolic dysfunction-associated steatohepatitis, protein intake should not drop below 1.2-1.5 g/kg/d[1]. Although recommendations for structured exercise exists for patients with CLD, limited data exists on recommendations for this specific population with concurrent sarcopenic obesity[48]. Current literature supports 150 min per week of moderate intensity resistance exercise for improving body composition and physical function, but this an area where future study is needed[3,54].

CONCLUSION

It is widely known that nutrition status substantially contributes to outcomes in patients with CLD. Sarcopenic obesity among patients with CLD is common, and this phenotype is associated with increased mortality in patients pursuing LT. Although extensive literature focuses on nutritional recommendations for patients with CLD and concurrent sarcopenia or obesity, we identified a lack of data specifically supporting nutritional recommendations for patients with sarcopenic obesity and concurrent CLD. More primary literature is needed on optimal nutrition recommendations for patients with liver disease and coexisting sarcopenic obesity.