Sarcopenia is associated with the presence of nonalcoholic fatty liver disease in Zhejiang Province, China: a cross-sectional observational study

Non-alcoholic fatty liver disease (NAFLD) is currently the leading cause of chronic liver disease worldwide, ranging from simple steatosis, non-alcoholic steatohepatitis (NASH), and advanced fibrosis to end-stage liver diseases, such as cirrhosis and hepatocellular carcinoma [1]. The total NAFLD population in 2015 was estimated at 83.1 million cases with a prevalence rate of 30.0% among the population aged ≥15 years and will increase to 33.5% by 2030 [2]. NAFLD has been proven to be closely associated with systemic diseases and has attracted extensive attention in public health [3]. The biological mechanisms, such as peripheral resistance to insulin, dyslipidaemia, and the activation of inflammatory pathways associated with NAFLD, are relevant to these systemic diseases [4].

Sarcopenia is a multifactorial geriatric syndrome with the overall concept of skeletal muscle failure or insufficiency. Skeletal muscle, as an active endocrine organ responsible for insulin-mediated glucose disposal, plays a significant role in glucose homeostasis, insulin resistance and inflammation [5]. Meanwhile, sarcopenia is associated with a sedentary lifestyle, which increases the risk of obesity, metabolic syndrome and NAFLD [6]. It has been reported that up to 60% of patients with end-stage liver disease have sarcopenia. The presence of NASH in those patients was associated with a 6-fold increased risk of sarcopenic obesity [7, 8]. Thus, sarcopenia shares the common risk factors that contribute to NAFLD and have a plausible association with NAFLD.

Until now, all consensuses have agreed on two crucial components of the sarcopenia definition: sarcopenia involves both structural damage (low muscle mass [LMM]) and impaired function (low muscle strength [LMS]) [9]. Several studies have shown that sarcopenia, including its two crucial components (LMM and LMS), is associated with the prevalence of NAFLD. Kim et al. found that skeletal muscle mass was positively correlated with the occurrence of NAFLD and negatively correlated with the resolution of existing NAFLD [10]. Another study showed that men and women with NAFLD had 7.3 and 7.9% lower handgrip strength (HGS) than controls in older adults [11]. Since the trajectories of muscle mass and muscle strength decline during ageing do not overlap and muscle strength declines much more rapidly than muscle mass, it is essential to illustrate the association between NAFLD and sarcopenia with its two components at the same time [12, 13]. Furthermore, almost all clinical studies were conducted in Korean populations, and few were diagnosed according to the Asian Working Group for Sarcopenia (AWGS) consensus guidelines. Therefore, this study aimed to investigate the independent association of the two components of sarcopenia with NAFLD, stratified by sex, in the aged Chinese population according to the AWGS. In addition, we tried to assess which component could better predict NAFLD prevalence in different sex groups.

NAFLD is a spectrum of liver disease that has now become the most common cause of chronic liver disease in adults of all ethnicities. The risk of NAFLD increases with age [17]. Sarcopenia is described as involuntary loss of muscle mass, muscle strength and muscle performance that occurs with ageing, which can cause adverse health outcomes such as falls, disability, poor quality of life, and even mortality according to the AWGS. The AWGS also recommends cut-off values for muscle mass measurements (7.0 kg/m² for men and 5.4 kg/m² for women by using DXA), HGS (< 26 kg for men and < 18 kg for women), and usual gait speed (< 0.8 m/s). Sarcopenia is considered a new geriatric syndrome that is closely associated with metabolic disorders, which denotes its importance in health care for older people [18]. In this cross-sectional sample of a Chinese study, we aimed to examine the sex-specific association between NAFLD and sarcopenia with its two crucial components using hepatic imaging and DXA scans, according to the AWGS criteria. Our data indicated that men and women with NAFLD both had markedly lower muscle mass and were more likely to have lower muscle strength than controls. The status of sarcopenia and sarcopenic obesity leads to an increased prevalence of NAFLD. Moreover, LMM appeared to be a better predictor for NAFLD prevalence than LMS. Further multivariable analysis identified that participants with LMM had statistically higher odds of suffering from NAFLD than participants with LMS in both men and women.

Recent clinical studies have already demonstrated a positive relationship between sarcopenia and the prevalence of NAFLD [6, 11, 19, 20]. Hong et al. first found that the OR for NAFLD risk was 5.16 (95% CI 1.63–16.33) in the lowest quartile of SMI compared to the highest quartile [6]. Kim et al. showed that men and women with NAFLD had markedly lower HGS and were more likely to have LMS than controls [11]. However, most of these studies focused on a single component of sarcopenia, which was not sufficient to fully understand the relationship between muscle status and NAFLD. It is unclear whether LMM or LMS is independently associated with NAFLD in the same model. In the present study, we found that men and women with NAFLD had markedly lower SMIs and were more likely to have LMM than controls. LMM was associated with an increased risk of NAFLD, with ORs of 2.88 (95% CI 1.52–5.46) in men and 2.08 (95% CI 1.63–2.67) in women. However, participants with LMS showed a slightly higher odds of NAFLD, with an OR of 1.15 (95% CI 1.02–1.28) in men only.

Moreover, since sarcopenia has been described as an age-associated decline in muscle mass as well as muscle function (defined by muscle strength or physical performance), it is also important to focus on the relationship between physical performance and NAFLD. We found that subjects with NAFLD had significantly lower GS than NAFLD-free subjects in both men and women. Further Pearson correlation coefficients showed that GS had a positive association with muscle strength (men: r = 0.315, P = 0.002, women: r = 0.538, P<0.001). A wide range of tests for physical performance are recommended when diagnosing sarcopenia, including the Short Physical Performance Battery (SPPB), usual gait speed walk test, stair climb power test, and timed-up-and-go test (TUG) [15]. A Taiwanese study examined the association of NASH with physical fitness, which demonstrated that men with NASH had fewer 2-min sit-up numbers and longer times to complete a 3000-m run than unaffected men [21]. Exercise, such as aerobic exercise, resistance training, and their combination, can increase muscle protein synthesis and promote anabolism, which can effectively improve the progression of sarcopenia and NAFLD [22, 23]. Therefore, since both NAFLD and sarcopenia may result in reduced physical capability and poor quality of life, the status of comorbidity in older adults should be given extensive attention.

Previous studies also attempted to elucidate the mechanism of sarcopenia development in patients with NAFLD. Currently, growing attention has been given to sex-specific differences in the development of sarcopenia and NAFLD. In this study, men with LMM had an increased risk of suffering from NAFLD, with higher odds after adjustment compared to female participants. Regarding muscle strength, low HGS was associated with an increased NAFLD prevalence in men only. Yang et al. found that some metabolic syndromes may make men more prone to sarcopenia, likely due to the low levels of physical activity associated with such conditions [24]. A small cross-sectional study from Japan revealed that the SMI had a negative association with hepatic steatosis only in men with type 2 diabetes [25]. Then, a more extensive population-based study involving 4210 men and women also suggested that sarcopenia was independently associated with NAFLD in men with type 2 diabetes, while no significant difference was found in women [26]. In our study, we found that male subjects with NAFLD were younger than those without NAFLD; in contrast, female subjects with NAFLD were older than those without NAFLD. In addition to the reasons of genetic predisposition and different lifestyles, changes in basal hormone levels with age may also lead to this opposite outcome between older men and women. Some studies have confirmed that dysregulated sex hormone disorders are involved in the pathogenesis of NAFLD and sarcopenia. Testosterone, a potent anabolic hormone, can promote muscle protein synthesis [27]. Sarcopenia, which is related to the reduction in physical activity, the lack of anabolic hormones, and the decrease in proinflammatory cytokines, has been associated with NAFLD independent of metabolic syndrome features [5, 28]. Extrapolating from these findings, the regulation of sex hormones may be involved in the mechanism of sex-specific differences in the development of sarcopenia and NAFLD.

Several epidemiological and experimental studies have shown that insulin resistance may have an essential role in sarcopenia. Skeletal muscle is recognized as a tissue that is primarily responsible for peripheral insulin-mediated glucose disposal. Insulin resistance may reduce the stimulation of the protein synthesis pathway and increase the activation of the protein degradation pathway, which might eventually lead to muscle loss [18, 29]. Indeed, the prevalence of sarcopenic obesity was higher among the participants with NAFLD in our study. Meanwhile, Pearson correlation coefficient analyses confirmed that the level of FPG was inversely associated with muscle mass in men and HGS in women. The serum level of TG was also negatively correlated with HGS in women. In this context, our current research also implied that both LMM and LMS might participate in the progression of NAFLD through dyslipidaemia and insulin resistance.

It is also worth mentioning that compared to LMS, LMM had higher odds of increasing the risk of NAFLD in our study. In women, sarcopenia was only found to have a statistically significant relationship with NAFLD when defined in terms of muscle mass alone, which was consistent with early research focused on the relationship between sarcopenia and metabolic syndrome. This might suggest that muscle mass, to some extent, was more significant than muscle strength in the context of NAFLD.

However, several limitations should also be considered when interpreting the results. First, the diagnosis of NAFLD was based on hepatic ultrasonography, and histologic confirmation of NAFLD by liver biopsy was not available. Second, the study was limited to verifying causality due to the cross-sectional design. Third, the information regarding past medical history was self-reported, which might have led to recall bias. Additionally, the number of subjects with sarcopenic obesity was low, which needs further enlargement of the sample size to allow for an adequate statistical comparison. Finally, our study population was exclusively Chinese, so the results might not be generalizable to other populations.

This work is among the few studies to examine the independent association of the two crucial components of sarcopenia (LMM and LMS) with NAFLD, stratified by sex according to the AWGS. LMM was consistently associated with NAFLD in both men and women, while LMS was associated with NAFLD only in men after adjustment for potential confounders. Moreover, compared to muscle strength, muscle mass was a better predictor for the presence of NAFLD in both sexes. Given that the understanding of the close relationship between NAFLD and sarcopenia is of great interest in this era of the ageing population, further well-designed studies should focus on common therapeutic strategies to prevent muscle wasting as well as NAFLD.