Nonalcoholic fatty liver disease (NAFLD) affects an estimated 20% to 25% of the global population and is one of the most common chronic liver diseases worldwide.1,2  High disease rates and growing prevalence underscore the importance of identifying and managing risk factors for NAFLD. Research findings increasingly point to a bidirectional relationship between sarcopenia and NAFLD, with 2 recent studies confirming the connection in both adult and pediatric populations.1,3

In a longitudinal cohort study published by Lee et al in 2021, individuals with NAFLD demonstrated an increased risk for low skeletal muscle mass compared against those without NAFLD (hazard ratio [HR], 1.21; 95% CI, 1.05-1.40); participants with lower muscle mass showed an increased risk for NAFLD compared against those with higher muscle mass (HR, 1.56; 95% CI, 1.38-1.78).1

In a retrospective study published by Yodoshi et al in 2020, researchers examined muscle mass as indicated by the total psoas muscle surface area (tPMSA) on magnetic resonance imaging (MRI) corrected for height (tPMSA index) in 100 pediatric patients with histologically confirmed NAFLD and 236 patients with MRI evidence of hepatic steatosis. Results of multivariable regression analyses revealed that higher steatosis scores were associated with lower a tPMSA index (odds ratio [OR], 0.73; 95% CI, 0.56-0.96) and younger age (OR, 0.84; 95% CI, 0.73-0.97).3


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In addition, MRI-measured proton density fat fraction (PDFF) was significantly associated with the tPMSA index (P =.029) as well as sex (P =.019) and Community Deprivation Index (CDI; P =.005); no association was found between liver stiffness (measured by magnetic resonance elastography) and tPMSA.3

The results of these studies generally align with those of earlier research, demonstrating an association between lower muscle mass and increased liver disease severity in adults with NAFLD.

In a 2017 study performed by Koo et al, of 309 participants, sarcopenia was observed in 8.7% of those without NAFLD vs 17.9% of those with NAFL and 35.0% of those with nonalcoholic steatohepatitis (NASH; P <.001). Individuals with sarcopenia also demonstrated a higher prevalence of significant fibrosis (≥F2) compared against those without sarcopenia (45.7% vs 24.7%, respectively; P <.001).4

Notably, while obesity has been identified as a major risk factor for NAFLD, lean/non-obese NAFLD accounts for roughly 20% of cases. Some findings have linked sarcopenia with complications of NAFLD, independent of obesity status.2

Emerging studies have found that exercise training improves NAFLD parameters, regardless of weight loss.5,7 Babu et al performed a meta-analysis of 10 studies that included a total of 316 individuals with NAFLD who engaged in exercise interventions. Following these interventions, there were significant reductions in intrahepatic lipid content (standardized mean difference [SMD], -0.76; 95% CI, -1.04 to -0.48), alanine aminotransaminase concentrations (SMD, -0.52; 95% CI, -0.90 to -0.14), aspartate aminotransferase (AST) levels (SMD, -0.68; 95% CI, -1.21 to -0.15), low-density lipoprotein cholesterol (SMD, -0.34; 95% CI, -0.66 to -0.02), and triglycerides (SMD, -0.59; 95% CI, -1.16 to -0.02), without significant weight loss.6

Similarly, research published by Oh et al reported that participants in a 3-month program consisting of moderate to vigorous physical activity (MVPA) showed reductions in liver steatosis (9.5%), liver stiffness (6.8%), and FibroScan-AST scores (16.4%), despite a weight reduction of only 1.2%.7 These improvements were associated with a reduction in adipose tissue, preservation of muscle mass, increased muscle strength (+11.6%), and reductions in inflammation and oxidative stress (ferritin, -22.3%; thiobarbituric acid, -12.3%), as well as alterations in organokine concentrations (selenoprotein-P, -11.2%; follistatin, +17.1%; adiponectin, +8.9%; myostatin, -21.6%).7

“Moreover, the expression of target genes of the transcription factor Nrf2, an oxidative stress sensor, was higher in monocytes, suggesting that Nrf2 is activated,” Oh et al stated. The improvements appeared to result from modification of inter-organ crosstalk, and greater improvements were observed with increasing amounts of exercise.7 “Therefore, exercise, and especially MVPA, should be used to help prevent and treat NAFLD to improve prognosis,” they concluded.7

The following experts were consulted to glean additional insights regarding the connection between muscle mass and NAFLD: Arun J. Sanyal, MD, professor in the division of gastroenterology, hepatology, and nutrition at Virginia Commonwealth University School of Medicine in Richmond, and Manal F. Abdelmalek, MD, MPH, FAASLD, professor of medicine in the division of gastroenterology at Duke University School of Medicine in Durham, North Carolina.

What does the literature suggest about the relationship between muscle mass and NAFLD, and what are the proposed underlying mechanisms?   

Dr Sanyal: There are data to suggest that sarcopenic obesity is commonly present in NASH. However, most patients do not have frailty until cirrhosis develops. This is due to metabolic changes in obesity where the muscle has impaired glucose and fat oxidation for energy and uses proteins. Also, with progression, branched chain amino acids are used in the muscle, leading to a decrease. Finally, cytokines such as myostatin and conditions such as functional hypogonadism may play a role in sarcopenia in NAFLD.

Dr Abdelmalek: There is a relationship between sarcopenia and NAFLD, particularly as liver disease progresses to more advanced hepatic fibrosis and cirrhosis. The relationships between these associations have not been well-defined but may include mechanisms that may pertain to accelerated cellular injury and aging in patients with increased metabolic stress and increased fibrogenesis.

What are the clinical considerations for addressing low muscle mass in NAFLD?  

Dr Sanyal: This is particularly crucial for those with advanced fibrosis. Recent studies from UK Biobank suggest that assessment of muscle fat infiltration along with loss of mass may be very important in prognosis and prevention.8 This is an emerging field, and we need more data to elucidate the impact of muscle mass on clinical outcomes and to identify ways to maintain muscle mass.

Dr Abdelmalek: While there are no systematic approaches to specifically addressing low muscle mass in NAFLD, the general recommendations for increased physical activity, either resistance or aerobic exercise, and diets enriched with high-protein content may maintain muscle mass. Further investigation in this area is necessary.

What are a few other important remaining needs pertaining to this topic?

Dr Sanyal: We need more research on the topic, along with education of the healthcare community and patients – particularly those with diabetes and those with advanced disease. Maintaining muscle mass is a major goal in the cirrhotic patient.

Dr Abdelmalek: Multidisciplinary research evaluating the muscle-liver cross talk and the associated signaling changes across the spectrum of liver injury is warranted. Further research to assess whether increasing muscle mass improves clinical outcomes in patients with NAFLD, and specifically those with NAFLD-related advanced hepatic fibrosis, is necessary.

References

  1. Lee JH, Lee HS, Lee BK, Kwon YJ, Lee JW. Relationship between muscle mass and non-alcoholic fatty liver disease. Biol. (Basel). 2021;10(2):122. doi:10.3390/biology10020122
  2. Kuchay MS, Martínez-Montoro JI, Choudhary NS, Fernández-García JC, Ramos-Molina B. Non-alcoholic fatty liver disease in lean and non-obese individuals: current and future challenges. Biomed. 2021;9(10):1346. doi:10.3390/biomedicines9101346
  3. Yodoshi T, Orkin S, Arce Clachar AC, et al. Muscle mass is linked to liver disease severity in pediatric nonalcoholic fatty liver disease. J Pediatr. 2020;223:93-99.e2. doi:10.1016/j.jpeds.2020.04.046
  4. Koo BK, Kim D, Joo SK, et al. Sarcopenia is an independent risk factor for non-alcoholic steatohepatitis and significant fibrosis. J Hepatol. 2017;66(1):123-131. doi:10.1016/j.jhep.2016.08.019
  5. Schneider CV, Zandvakili I, Thaiss CA, Schneider KM. Physical activity is associated with reduced risk of liver disease in the prospective UK Biobank cohort. JHEP Rep. 2021;3(3):100263. doi:10.1016/j.jhepr.2021.100263
  6. Babu AF, Csader S, Lok J, et al. Positive effects of exercise intervention without weight loss and dietary changes in NAFLD-related clinical parameters: a systematic review and meta-analysis. Nutrients. 2021;13(9):3135. doi:10.3390/nu13093135
  7. Oh S, Tsujimoto T, Kim B, et al. Weight-loss-independent benefits of exercise on liver steatosis and stiffness in Japanese men with NAFLD. JHEP Rep. 2021;3(3):100253. doi:10.1016/j.jhepr.2021.100253
  8. Linge J, Ekstedt M, Dahlqvist Leinhard O. Adverse muscle composition is linked to poor functional performance and metabolic comorbidities in NAFLD. JHEP Rep. 2020;3(1):100197. doi:10.1016/j.jhepr.2020.100197