The picture of chronic liver diseases (CLDs) has changed considerably in recent years. One of them is the increase of non-alcoholic fatty liver disease. More and more CLD patients, even those with liver cirrhosis (LC), tend to be presenting with obesity these days. The annual rate of muscle loss increases with worsening liver reserve, and thus LC patients are more likely to complicate with sarcopenia. LC is also characterized by protein-energy malnutrition (PEM). Since the PEM in LC can be invariable, the patients probably present with sarcopenic obesity (Sa-O), which involves both sarcopenia and obesity. Currently, there is no mention of Sa-O in the guidelines; however, the rapidly increasing prevalence and poorer clinical consequences of Sa-O are recognized as an important public health problem, and the diagnostic value of Sa-O is expected to increase in the future. Sa-O involves a complex interplay of physiological mechanisms, including increased inflammatory cytokines, oxidative stress, insulin resistance, hormonal disorders, and decline of physical activity. The pathogenesis of Sa-O in LC is diverse, with a lot of perturbations in the muscle–liver–adipose tissue axis.
1. Sarcopenia and Sarcopenic Obesity in Liver Cirrhosis
Sarcopenia refers to the loss of skeletal muscle mass (SMM) and muscle strength or physical function [1]. Sarcopenia is rapidly evolving in the clinical research fields, especially in the last few years, after the proposal of its concept by Irwin Rosenberg in 1989 [2]. Primary sarcopenia is defined as a condition in which SMM and muscle strength or physical function decline with aging, while secondary sarcopenia is defined as a condition in which SMM and muscle strength or physical function are impaired due to underlying diseases [3][4]. In recent years, a large amount of evidence on sarcopenia has been accumulated, and the disease has been registered in ICD-10, and sarcopenia is now recognized as a disease rather than a concept.
Sarcopenia refers to the loss of skeletal muscle mass (SMM) and muscle strength or physical function [1]. Sarcopenia is rapidly evolving in the clinical research fields, especially in the last few years, after the proposal of its concept by Irwin Rosenberg in 1989 [2]. Primary sarcopenia is defined as a condition in which SMM and muscle strength or physical function decline with aging, while secondary sarcopenia is defined as a condition in which SMM and muscle strength or physical function are impaired due to underlying diseases [3,4]. In recent years, a large amount of evidence on sarcopenia has been accumulated, and the disease has been registered in ICD-10, and sarcopenia is now recognized as a disease rather than a concept.
Liver cirrhosis (LC) is the end-stage form of chronic liver disease (CLD) and presents with a variety of complications. Liver cirrhosis (LC) is a representative disease that causes secondary sarcopenia [5]. LC leads to secondary sarcopenia, due to characteristic conditions such as protein-energy malnutrition (PEM). In cirrhotic patients, fasting for only 6–10 h is equivalent to fasting for 2–3 days in healthy individuals, which is also associated with the development of sarcopenia [6]. In LC patients, there is an amino acid imbalance with the decrease of branched-chain amino acids (BCAAs) and increase of aromatic amino acids [5]. BCAAs are amino acids that are metabolized by muscles, to detoxify ammonia, and are a good source of energy for the liver [5]. BCAAs were found to improve homeostasis model assessment of insulin resistance (HOMA-IR) scores and the function of beta cells in CLD patients [7]. The complication rate of sarcopenia in LC patients is reported to be 30–70%, which is obviously high, considering that the complication rate of sarcopenia in inflammatory bowel disease (a typical disease that causes secondary sarcopenia) is about 20% [8]. This fact may be related to both the fact that cirrhosis is likely to be complicated with secondary sarcopenia and the fact that Japanese LC patients are aging. Direct-acting antivirals can almost eliminate the virus in patients with cirrhosis C, and nucleoside analogues can also control the disease in patients with cirrhosis B. As a result, the survival has significantly improved, but at the same time, Japanese LC patients have become older. In cirrhotic patients, the annual rate of SMM loss was reported to be 1.3% in Child-Pugh A, 3.5% in Child-Pugh B, and 6.1% in Child-Pugh C [9]. The annual rate of muscle loss increases with worsening liver reserve, which is clearly higher than the 1% annual rate of muscle loss in the general elderly population [9].
Sarcopenic obesity (Sa-O) was first defined by Baumgartner as the co-existence of sarcopenia and obesity, as measured by dual-energy X-ray absorptiometry, describing an interplay between obesity and sarcopenia related to physical activity decline and reduced energy expenditure [10]. The rapidly increasing prevalence and poor clinical consequences of Sa-O are recognized as an important public health problem in the aging population. The main alterations in body composition due to aging include an increase in body fat and a decrease in SMM, which are not accompanied by much change in BMI [11]. These alterations of body composition are often difficult to notice on the outside, and detection tends to be delayed, making it easier for lifestyle-related diseases and other conditions to progress without being noticed. The picture of CLDs has changed considerably in recent years. One of them is the increase of non-alcoholic fatty liver disease (NAFLD). In Asia, NAFLD prevalence increased significantly over time (25.3% between 1999 and 2005, 28.5% between 2006 and 2011, and 33.9% between 2012 and 2017; p < 0.0001) [12]. More and more CLD patients, even those with LC, tend to be presenting with obesity these days, due to the changes of lifestyle. As PEM in LC can be invariable, the patients probably present with Sa-O. In most cases, sarcopenia and obesity are judged separately, and Sa-O is considered when both are present. However, the biggest problem in clinical studies of Sa-O is the lack of a common definition, despite the fact that Asian Working Group for Sarcopenia (AWGS) and European Working Group on Sarcopenia in Older People (EWGSOP) recommend a definition of sarcopenia [3][4]. The indexes of obesity and the definition of obesity are not consistent among studies, and thus the frequency of Sa-O varies widely.
< 0.0001) [12]. More and more CLD patients, even those with LC, tend to be presenting with obesity these days, due to the changes of lifestyle. As PEM in LC can be invariable, the patients probably present with Sa-O. In most cases, sarcopenia and obesity are judged separately, and Sa-O is considered when both are present. However, the biggest problem in clinical studies of Sa-O is the lack of a common definition, despite the fact that Asian Working Group for Sarcopenia (AWGS) and European Working Group on Sarcopenia in Older People (EWGSOP) recommend a definition of sarcopenia [3,4]. The indexes of obesity and the definition of obesity are not consistent among studies, and thus the frequency of Sa-O varies widely.
2. Obesity Paradox and Liver Cirrhosis
Obesity can be a major risk factor for morbidity and mortality in metabolic and cardiovascular diseases and is an important health threat. WHO proposes the definition of obesity according to body mass index (BMI): ≥30 kg/m
2
in Caucasians, and ≥25 kg/m
2 in Asians, with further classifications into class I, II, and III obesity [13][14]. The prevalence of obesity in adults has doubled since 1980 and globally continues to elevate [11]. Obesity can accelerate the progression of LC status, but the data are not consistent on the extent to which it affects mortality. This discrepancy is partly due to the lack of correction for body weight for excess body water and partly due to the obesity paradox [15][16][17]. Obesity paradox is a phenomenon in which obese people are found to have a reduced risk of death compared to people with standard weight, and it has attracted attention in considering the pathological significance of obesity. Karagozian et al. reported, in their large cohort study (32,605 LC subjects), that crude mortality was lower for obese LC subjects than for non-obese LC subjects (2.7% vs. 3.5%,
in Asians, with further classifications into class I, II, and III obesity [13,14]. The prevalence of obesity in adults has doubled since 1980 and globally continues to elevate [11]. Obesity can accelerate the progression of LC status, but the data are not consistent on the extent to which it affects mortality. This discrepancy is partly due to the lack of correction for body weight for excess body water and partly due to the obesity paradox [15,16,17]. Obesity paradox is a phenomenon in which obese people are found to have a reduced risk of death compared to people with standard weight, and it has attracted attention in considering the pathological significance of obesity. Karagozian et al. reported, in their large cohort study (32,605 LC subjects), that crude mortality was lower for obese LC subjects than for non-obese LC subjects (2.7% vs. 3.5%, p
= 0.02), and in their multivariate analysis, obesity significantly lowered a risk of inpatient mortality (hazard ratio (HR) = 0.73,
p
= 0.02) [16]. Most studies on obesity paradox use BMI as an index of obesity, but obesity is essentially a condition associated with increased adipose tissue mass, and it is difficult to accurately assess adipose tissue mass with BMI, which includes muscle mass and bone mass in addition to fat. There are cases of excess visceral fat even when BMI is within the normal range, and attention should also be paid to the amount of visceral fat in cases with sarcopenia.
3. Prevalence and Definition of Sarcopenic Obesity
Sarcopenia and obesity are closely related. Sa-O involves a complex interplay of physiological mechanisms, including increased inflammatory cytokines, oxidative stress, insulin resistance, hormonal disorders, and decline of physical activity [10][11][18][19]. However, as mentioned above, there is no mention of Sa-O in either the AWGS guidelines or the EWGSOP guidelines. Existing LC-related reports are limited, but they have shown that a Sa-O prevalence in cirrhotic patients is 2% to 42% [20][21][22][23][24][25][26][27][28][29]. The definition and prevalence of Sa-O in LC patients are summarized in
Sarcopenia and obesity are closely related. Sa-O involves a complex interplay of physiological mechanisms, including increased inflammatory cytokines, oxidative stress, insulin resistance, hormonal disorders, and decline of physical activity [10,11,18,19]. However, as mentioned above, there is no mention of Sa-O in either the AWGS guidelines or the EWGSOP guidelines. Existing LC-related reports are limited, but they have shown that a Sa-O prevalence in cirrhotic patients is 2% to 42% [20,21,22,23,24,25,26,27,28,29]. The definition and prevalence of Sa-O in LC patients are summarized in . The most commonly used definition of Sa-O is the combined assessment of skeletal muscle index (SMI, SMM measured by computed tomography (CT, L3 level) corrected for height squared) and BMI (>25 or 30 kg/m
2
), and in most LC-related studies regarding Sa-O, grip strength and walking speed are not incorporated in the definition. However, there are no internationally standardized diagnostic criteria for Sa-O. This may be, in part, due to differences in BMI and SMM among races.
Table 1.
Definition and prevalence of sarcopenic obesity (Sa-O) among studies.
4. Molecular Mechanism and Liver Diseases
Various molecular biological findings and clinical analyses have been reported on the mechanisms of metabolic abnormalities associated with LC. The BMI of LC patients in Japan is almost the same as that of general population of the same age, and one in four LC patients is obese with a BMI ≥ 25 kg/m
2
, and only a few LC patients have a BMI < 18.5 kg/m
2
[30]. In our 226 Japanese LC patients, 70 patients (31%) had a BMI ≥ 25 kg/m 2
, and 14 patients (6%) a BMI < 18.5 kg/m
2
.
Clinical features of glucose metabolism in LC patients are as follows: (1) not-so-higher fasting blood glucose in the early morning, (2) higher blood insulin concentration, (3) higher HOMA-IR level in more than half of LC patients, and (4) postprandial hyperglycemia. In addition, hepatitis C virus infection, which is the most common cause of cirrhosis in Japan, can be a cause of increased hepatic steatosis and insulin resistance through the action of hepatitis C virus core protein [31][32]. There are many reports that insulin resistance and obesity are important risk factors for carcinogenesis in cirrhotic patients [33]. The pathogenesis of Sa-O in LC is diverse, with a lot of perturbations in the muscle-liver–adipose tissue axis.
Clinical features of glucose metabolism in LC patients are as follows: (1) not-so-higher fasting blood glucose in the early morning, (2) higher blood insulin concentration, (3) higher HOMA-IR level in more than half of LC patients, and (4) postprandial hyperglycemia. In addition, hepatitis C virus infection, which is the most common cause of cirrhosis in Japan, can be a cause of increased hepatic steatosis and insulin resistance through the action of hepatitis C virus core protein [31,32]. There are many reports that insulin resistance and obesity are important risk factors for carcinogenesis in cirrhotic patients [33]. The pathogenesis of Sa-O in LC is diverse, with a lot of perturbations in the muscle-liver–adipose tissue axis.
Insulin has metabolic effects that promote anabolism and inhibit catabolism of nutrients. As skeletal muscle is the target organ of insulin, loss of SMM is a cause of insulin resistance [34]. Insulin resistance in skeletal muscle is involved in the pathogenesis of sarcopenia and may contribute to obesity [34]. Sarcopenia can increase the risk of liver fibrosis progression in patients with obesity, insulin resistance, metabolic syndrome, and liver steatosis, which can easily fall into Sa-O [35][36][37]. LC patients are likely to be involved in insulin resistance and chronic inflammation [38]. Oxidative stress is thought to be a mechanism linking insulin resistance and inflammation to sarcopenia. Oxidative stress can damage mitochondria and nuclear DNA, stimulate apoptosis, and lead to muscle fiber atrophy and myocyte loss [39]. Dysbiosis indicates a state where the diversity of gut microbiota and the number of bacteria in the gut are reduced [5]. LC associated dysbiosis also induces oxidative stress [5]. Testosterone, which is important for skeletal muscle formation, is decreased in LC patients [40]. A previous randomized trial emphasized the significance of testosterone supplementation therapy on the improvement of SMM in male LC patients [40].
Insulin has metabolic effects that promote anabolism and inhibit catabolism of nutrients. As skeletal muscle is the target organ of insulin, loss of SMM is a cause of insulin resistance [34]. Insulin resistance in skeletal muscle is involved in the pathogenesis of sarcopenia and may contribute to obesity [34]. Sarcopenia can increase the risk of liver fibrosis progression in patients with obesity, insulin resistance, metabolic syndrome, and liver steatosis, which can easily fall into Sa-O [35,36,37]. LC patients are likely to be involved in insulin resistance and chronic inflammation [38]. Oxidative stress is thought to be a mechanism linking insulin resistance and inflammation to sarcopenia. Oxidative stress can damage mitochondria and nuclear DNA, stimulate apoptosis, and lead to muscle fiber atrophy and myocyte loss [39]. Dysbiosis indicates a state where the diversity of gut microbiota and the number of bacteria in the gut are reduced [5]. LC associated dysbiosis also induces oxidative stress [5]. Testosterone, which is important for skeletal muscle formation, is decreased in LC patients [40]. A previous randomized trial emphasized the significance of testosterone supplementation therapy on the improvement of SMM in male LC patients [40].
Adipose tissue produces inflammatory proteins and cytokines, such as CRP, TNF-α, IL-6, and IL1β, forming a chronic inflammatory environment that leads to muscle atrophy and sarcopenia [41]. Adipose tissue produces a number of hormones and bioactive substances, including leptin and adiponectin. Adiponectin is present in large amounts in the blood, declines with fat accumulation, and increases with weight loss. Adiponectin has the ability to improve insulin sensitivity throughout the body. Adiponectin stimulates the AMPK pathway and suppresses the NF-κB pathway. It also suppresses the production of TNF-α and IFN-γ secreted by monocytes, macrophages, and dendritic cells, and it increases anti-inflammatory cytokines. TNF- α and IFN-s-dependent muscle decline is linked to NF-κB pathway [42]. The AMPK stimulation of adiponectin is attenuated in obesity [41]. The obesity-induced suppression of adiponectin leads to persistent chronic inflammation in muscle tissue [41]. Especially in patients with NAFLD, the protective effects of adiponectin for hepatocytes have been widely examined [43][44]. Adiponectin exerts an anti-fibrotic and anti-inflammatory effect in LC [45]. A previous prospective study reported that adiponectin was associated with the degree of liver decompensation and worse prognosis in LC patients [46]. Adiponectin levels are reported to be independently associated with sarcopenia in LC patients [47]. Leptin, on the other hand, reflects whole-body fat mass. Leptin is an adipokine that regulates energy balance and glucose homeostasis. Obesity causes leptin resistance, which is thought to be indirectly related to sarcopenia through insulin resistance and other mechanisms [41]. In obesity-associated fatty liver, leptin induces CD14 expression via activation of STAT3 signaling in Kupffer cells, leading to marked inflammation and fibrosis by increasing the responsiveness of the liver to low dose of endotoxin [48].
and IFN-s-dependent muscle decline is linked to NF-κB pathway [42]. The AMPK stimulation of adiponectin is attenuated in obesity [41]. The obesity-induced suppression of adiponectin leads to persistent chronic inflammation in muscle tissue [41]. Especially in patients with NAFLD, the protective effects of adiponectin for hepatocytes have been widely examined [43,44]. Adiponectin exerts an anti-fibrotic and anti-inflammatory effect in LC [45]. A previous prospective study reported that adiponectin was associated with the degree of liver decompensation and worse prognosis in LC patients [46]. Adiponectin levels are reported to be independently associated with sarcopenia in LC patients [47]. Leptin, on the other hand, reflects whole-body fat mass. Leptin is an adipokine that regulates energy balance and glucose homeostasis. Obesity causes leptin resistance, which is thought to be indirectly related to sarcopenia through insulin resistance and other mechanisms [41]. In obesity-associated fatty liver, leptin induces CD14 expression via activation of STAT3 signaling in Kupffer cells, leading to marked inflammation and fibrosis by increasing the responsiveness of the liver to low dose of endotoxin [48].
Ectopic fat accumulation and SMM decline may exist in a vicious cycle due to their mutual influence [18]. Sarcopenia reduces physical activity, leading to energy expenditure loss and the elevated risk of obesity [19]. In contrast, increase of a visceral fat induces inflammation, contributing to the sarcopenia incidence [49]. Kim et al. reported, in a longitudinal study, that visceral obesity was associated with future SMM decline in Korean individuals [50]. In male cirrhotic patients with hepatocellular carcinoma (HCC) undergoing liver transplantation, a visceral adipose tissue ≥ 65 cm 2
/m
2
raised the risk of HCC recurrence more than five times [51]. Accumulation of subcutaneous adipose tissue can be an adverse predictor in patients with alcoholic LC [52]. High subcutaneous adipose tissue density and high visceral adipose tissue density on CT significantly correlated negatively with survival in HCC patients [53].
It has been widely accepted that the inhibition of myostatin contributes to reduced adipose tissue, indicating myostatin acts either directly or indirectly on adipose tissue [54]. Myostatin also has the effect of inhibition of protein synthesis in skeletal muscle [55]. Increased myostatin levels have been associated with both obesity and insulin resistance [56][57][58]. Serum myostatin levels can be lowered by aerobic exercise [58]. Resistance training can reduce myostatin levels, leading to the improvement of insulin resistance [59]. Hittel et al. reported that extremely obese individuals have been reported to have a 35% increase in plasma mature myostatin level and a 23% increase in skeletal muscle precursor myostatin level, as compared to lean controls, and BMI strongly correlated with myostatin level in skeletal muscle [56]. Visceral fat area, HbA1c, myostatin, and leptin are reported to be contributing factors associated with increased liver fat accumulation in patients with non-obese NAFLD [60]. Ammonia is a cytotoxic substance produced via several physiological processes, such as amino acid catabolism and gut microbiota metabolism [61]. The hepatocyte is the only cell that is able to metabolize ammonia to urea, which is a nontoxic metabolite being excreted by the kidneys. The enzymes that catalyze the urea cycle are zinc-containing enzymes, and when zinc deficiency occurs, ammonia processing is reduced. Most LC patients have zinc deficiency [62]. In LC patients, due to liver dysfunction and portosystemic shunts, serum ammonia concentrations tend to increase [56]. In our previous data in LC patients, serum myostatin level significantly increased with the worsening of liver function and the increase of serum ammonia level, and was associated with clinical outcomes [55]. Higher serum ammonia level can cause higher myostatin level in skeletal muscle, resulting in the progression of sarcopenia through the suppression of muscle protein synthesis [55].
It has been widely accepted that the inhibition of myostatin contributes to reduced adipose tissue, indicating myostatin acts either directly or indirectly on adipose tissue [54]. Myostatin also has the effect of inhibition of protein synthesis in skeletal muscle [55]. Increased myostatin levels have been associated with both obesity and insulin resistance [56,57,58]. Serum myostatin levels can be lowered by aerobic exercise [58]. Resistance training can reduce myostatin levels, leading to the improvement of insulin resistance [59]. Hittel et al. reported that extremely obese individuals have been reported to have a 35% increase in plasma mature myostatin level and a 23% increase in skeletal muscle precursor myostatin level, as compared to lean controls, and BMI strongly correlated with myostatin level in skeletal muscle [56]. Visceral fat area, HbA1c, myostatin, and leptin are reported to be contributing factors associated with increased liver fat accumulation in patients with non-obese NAFLD [60]. Ammonia is a cytotoxic substance produced via several physiological processes, such as amino acid catabolism and gut microbiota metabolism [61]. The hepatocyte is the only cell that is able to metabolize ammonia to urea, which is a nontoxic metabolite being excreted by the kidneys. The enzymes that catalyze the urea cycle are zinc-containing enzymes, and when zinc deficiency occurs, ammonia processing is reduced. Most LC patients have zinc deficiency [62]. In LC patients, due to liver dysfunction and portosystemic shunts, serum ammonia concentrations tend to increase [56]. In our previous data in LC patients, serum myostatin level significantly increased with the worsening of liver function and the increase of serum ammonia level, and was associated with clinical outcomes [55]. Higher serum ammonia level can cause higher myostatin level in skeletal muscle, resulting in the progression of sarcopenia through the suppression of muscle protein synthesis [55].
Growth hormone (GH), as well as insulin-like growth factor (IGF)-1, regulates the growth of tissues, including skeletal muscle. Fatty acids inhibit the production of GH and decrease IGF-1 levels. The anabolic hormone IGF-1 is also involved in the regulation of GH, and IGF-1 acts in response to GH. IGF-1 decreases with increasing fat mass. In obese individuals, these anabolic hormones are decreased, and these decreases may be related to skeletal muscle disorders. LC is a condition of acquired resistance to GH. Impaired GH-IGF-1 system in LC can lead to LC-related complications [63]. In LC patients, IGF-1 level was correlated with the degree of liver dysfunction [63].
5. Myosteatosis and Liver Diseases
Myosteatosis refers to the pathological fat accumulation in skeletal muscle within the muscular fibers or within the fascia of the skeletal muscle [64]. Myosteatosis is associated with insulin resistance and type 2 diabetes mellitus [65]. Myosteatosis meditates inflammatory responses and can be linked to decreased muscle function and SMM decline caused by muscle atrophy and physical disabilities [66][67].
Myosteatosis refers to the pathological fat accumulation in skeletal muscle within the muscular fibers or within the fascia of the skeletal muscle [64]. Myosteatosis is associated with insulin resistance and type 2 diabetes mellitus [65]. Myosteatosis meditates inflammatory responses and can be linked to decreased muscle function and SMM decline caused by muscle atrophy and physical disabilities [66,67].
Myosteatosis in LC patients increased the risk of death by 1.5-to 2-fold, mainly due to the higher incidence of sepsis-related death [20]. Kaibori et al., reported, in their 141 HCC patients undergoing hepatectomy, that the five-year overall survival (OS) rates in patients with and without higher intramuscular adipose tissue content (IMAC) were 46% and 75%, and the five-year disease-free survival rates in patients with and without higher IMAC were 18 and 38%, and that higher IMAC was an independent predictor for OS in their multivariate analysis [21]. They also reported the significant correlation between higher IMAC and liver dysfunction, a higher amount of intraoperative blood loss, and complications of diabetes mellitus [21]. Another Japanese study reported the close correlation between higher IMAC and bacteremia after liver transplantation [68]. A significant correlation between preoperative higher IMAC and pulmonary dysfunction after hepatectomy was also reported [69]. Meanwhile, Bhanji et al. reported, in their LC subjects ( n
= 675), that myosteatosis was identified in 348 patients (52%), sarcopenia in 242 (36%), and hepatic encephalopathy in 128 (19%), and in their multivariable analysis, both myosteatosis and sarcopenia were independent factors for hepatic encephalopathy (HR = 2.25 and 2.42;
p
-values both < 0.01) [70].
Encyclopedia
