Here we demonstrate the prevalence of sarcopenia in patients with liver disease overall, particularly in those with MASLD. In patients with MASLD, there are alterations of the metabolic pathways related to insulin resistance, lipogenesis, chronic inflammation, physical inactivity, and vitamin D deficiency that contribute to the development of sarcopenia [19]. In a cohort study of over 50,000 patients, MASLD (NAFLD) was associated with an increased risk of sarcopenia as measured by faster loss of skeletal muscle mass [20]. While numerous studies have demonstrated an association between sarcopenia, MASLD, and worse outcomes, the optimal diagnostic criteria for sarcopenia in patients with MASLD remains controversial. A study of 156 patients with biopsy-proven MASLD (NAFLD) found significant heterogeneity in the prevalence of sarcopenia when comparing the Foundation for the National Institutes of Health (FNIH) definition of sarcopenia to other definitions including the skeletal muscle index and the ratio of skeletal muscle mass to body fat mass, concordance 0.058 [21]. In our study, sarcopenia was defined by ALM adjusted for BMI based on the recommendation of the FNIH consortium [7]; therefore as patients have increasing BMI, which is a risk factor for MASLD, they are more likely to be sarcopenic by definition. We demonstrated this concept by assessing the prevalence of sarcopenia by ALM alone unadjusted for BMI in which case sarcopenia was least prevalent in MASLD compared to when sarcopenia was defined by ALM adjusted for BMI, where sarcopenia was most prevalent in MASLD. This discordance highlights the challenges to accurately identifying sarcopenia in patients with MASLD, and future research needs to be done to optimize the definition in this patient population.
Our study demonstrates several sociodemographic disparities in the development of sarcopenia in patients with liver disease. Specifically, we identified racial and ethnic disparities in the development of sarcopenia, particularly in all minorities other than non-Hispanic White and Black races. Black race was significantly associated with decreased prevalence of sarcopenia. In an NHANES study comparing ALM/BMI to grip strength and gait speed, Bigman and Ryan found that Black patients were less likely to have sarcopenia based on muscle mass index, however more likely to have sarcopenia by gait speed and no difference in risk was found by grip strength [22]. Therefore, the diagnosis of sarcopenia in various races must be interpreted with caution, and further research needs to be done looking at race specific definitions of sarcopenia, particularly in patients with liver disease. Similar to previous literature, we also found that lower levels of income and education were associated with a higher prevalence of sarcopenia [23, 24]. These disparities highlight additional challenges some patients may face related to their propensity to develop sarcopenia and means to intervene and treat the disease thereafter.
Physical activity level has previously been shown to be an independent predictor of sarcopenia in chronic liver disease [25]. While physical activity is beneficial in patients with cirrhosis, there are multiple reasons why patients with cirrhosis may get less exercise. In addition, patients with cirrhosis have diminished cardiac response to exercise [26] [27]. They require frequent healthcare appointments and are at risk of falls for reasons related and unrelated to sarcopenia, including hepatic encephalopathy. Furthermore, the severity of liver disease, sarcopenia, and exercise capacity are related [27], meaning patients at greatest need of physical activity may be those least likely to be able to do so. Importantly, exercise can attenuate or even reverse sarcopenia [27, 28]. While it may not be feasible or safe for all patients with cirrhosis to achieve our study’s definition of ideal physical activity, the odds ratio for developing sarcopenia in inactive patients was 1.73 as compared to 1.39 in those achieving moderate activity, indicating some activity is likely better than no activity.
In this study, the interaction between telomere length and sarcopenia was significantly associated with mortality in patients with liver disease. In an NHANES study encompassing the years 1999–2002, in patients with sarcopenia (not limited by those with liver disease), there was not a significant association between telomere length and mortality [10]. Shortened telomere length has been associated with a higher risk of all-cause mortality in patients with liver disease [12]. Our results demonstrate that sarcopenia is associated with higher mortality at younger ages, and that shorter telomeres attenuate this effect. Telomerase, the enzyme responsible for telomere length regulation, is necessary for cell immortalization and oncogenesis [29]. The shortening of telomeres has two oppositional effects on cancer development, one being a tumor-suppressive effect through arrest of cellular proliferation and the other being telomere crisis where there is significant genome instability that can result in cancer development [30]. There is significant heterogeneity within the literature as to the impact of telomere length on cancer development, however longer telomeres have been shown to increase the risk for several cancers and reduce the risk for some other diseases, including cardiovascular disease [31]. While our cross-sectional study assessed all-cause mortality, it is possible that the negative impact of longer telomeres on survival in young patients with sarcopenia seen here is actually reflective of associations between telomere length and cause of death.
Strengths of our study include the large database of patients evaluated and that the NHANES survey is designed to be representative of the US population at large. Limitations of this study include the cross-sectional survey design of NHANES which is limited by the data that is publicly available and much of the survey data is self-reported by participants. DEXA scan is widely available and validated in the literature for the assessment of sarcopenia but does have limitations in its lack of functional assessment of muscle strength, limiting its accuracy in capturing the entirety of frailty syndrome. DEXA can be used to measure three body components: fat, bone minerals, and lean tissue [6]. Appendicular lean mass (ALM) is the sum of lean mass from both arms and legs and when adjusted for BMI has been recommended by The FNIH Biomarkers Consortium Sarcopenia Project for the diagnosis of sarcopenia [7]. Advantages of the use of DEXA for defining sarcopenia include its availability, efficiency, and reproducibility [5]. Disadvantages include that the equipment is not portable, and it is an indirect measurement of lean and fat mass meaning results can be affected by hydration status, body fluid changes, and ascites [5] [8].
This study highlights the importance of assessing patients with liver disease for social determinants of health in order to identify risk factors that are associated with sarcopenia so appropriate resources can be provided. In addressing these health disparities, we may be able to prevent sarcopenia in some of our patients or at a minimum intervene more effectively. The implications of telomere length on mortality in patients with liver disease varies by age and sarcopenia status. Shorter telomeres appear to be more highly associated with increased mortality in older patients without sarcopenia. Future research on the complex interplay between sarcopenia, telomere length, and age is needed to fully elucidate their impact on outcomes including mortality in patients with liver disease.